[House Hearing, 108 Congress]
[From the U.S. Government Publishing Office]




 FDA'S ROLE IN PROTECTING THE PUBLIC HEALTH: EXAMINING FDA'S REVIEW OF 
    SAFETY AND EFFICACY CONCERNS IN ANTI-DEPRESSANT USE BY CHILDREN

=======================================================================

                                HEARING

                               before the

                            SUBCOMMITTEE ON
                      OVERSIGHT AND INVESTIGATIONS

                                 of the

                    COMMITTEE ON ENERGY AND COMMERCE
                        HOUSE OF REPRESENTATIVES

                      ONE HUNDRED EIGHTH CONGRESS

                             SECOND SESSION

                               __________

                           SEPTEMBER 23, 2004

                               __________

                           Serial No. 108-125

                               __________

       Printed for the use of the Committee on Energy and Commerce


 Available via the World Wide Web: http://www.access.gpo.gov/congress/
                                 house

                               __________


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                    COMMITTEE ON ENERGY AND COMMERCE

                      JOE BARTON, Texas, Chairman

W.J. ``BILLY'' TAUZIN, Louisiana     JOHN D. DINGELL, Michigan
RALPH M. HALL, Texas                   Ranking Member
MICHAEL BILIRAKIS, Florida           HENRY A. WAXMAN, California
FRED UPTON, Michigan                 EDWARD J. MARKEY, Massachusetts
CLIFF STEARNS, Florida               RICK BOUCHER, Virginia
PAUL E. GILLMOR, Ohio                EDOLPHUS TOWNS, New York
JAMES C. GREENWOOD, Pennsylvania     FRANK PALLONE, Jr., New Jersey
CHRISTOPHER COX, California          SHERROD BROWN, Ohio
NATHAN DEAL, Georgia                 BART GORDON, Tennessee
RICHARD BURR, North Carolina         PETER DEUTSCH, Florida
ED WHITFIELD, Kentucky               BOBBY L. RUSH, Illinois
CHARLIE NORWOOD, Georgia             ANNA G. ESHOO, California
BARBARA CUBIN, Wyoming               BART STUPAK, Michigan
JOHN SHIMKUS, Illinois               ELIOT L. ENGEL, New York
HEATHER WILSON, New Mexico           ALBERT R. WYNN, Maryland
JOHN B. SHADEGG, Arizona             GENE GREEN, Texas
CHARLES W. ``CHIP'' PICKERING,       KAREN McCARTHY, Missouri
Mississippi, Vice Chairman           TED STRICKLAND, Ohio
VITO FOSSELLA, New York              DIANA DeGETTE, Colorado
STEVE BUYER, Indiana                 LOIS CAPPS, California
GEORGE RADANOVICH, California        MICHAEL F. DOYLE, Pennsylvania
CHARLES F. BASS, New Hampshire       CHRISTOPHER JOHN, Louisiana
JOSEPH R. PITTS, Pennsylvania        TOM ALLEN, Maine
MARY BONO, California                JIM DAVIS, Florida
GREG WALDEN, Oregon                  JANICE D. SCHAKOWSKY, Illinois
LEE TERRY, Nebraska                  HILDA L. SOLIS, California
MIKE FERGUSON, New Jersey            CHARLES A. GONZALEZ, Texas
MIKE ROGERS, Michigan
DARRELL E. ISSA, California
C.L. ``BUTCH'' OTTER, Idaho
JOHN SULLIVAN, Oklahoma

                      Bud Albright, Staff Director

                   James D. Barnette, General Counsel

      Reid P.F. Stuntz, Minority Staff Director and Chief Counsel

                                 ______

              Subcommittee on Oversight and Investigations

               JAMES C. GREENWOOD, Pennsylvania, Chairman

MICHAEL BILIRAKIS, Florida           PETER DEUTSCH, Florida
CLIFF STEARNS, Florida                 Ranking Member
RICHARD BURR, North Carolina         DIANA DeGETTE, Colorado
CHARLES F. BASS, New Hampshire       TOM ALLEN, Maine
GREG WALDEN, Oregon                  JANICE D. SCHAKOWSKY, Illinois
  Vice Chairman                      HENRY A. WAXMAN, California
MIKE FERGUSON, New Jersey            EDWARD J. MARKEY, Massachusetts
MIKE ROGERS, Michigan                JOHN D. DINGELL, Michigan,
JOE BARTON, Texas,                     (Ex Officio)
  (Ex Officio)

                                  (ii)




                            C O N T E N T S

                               __________
                                                                   Page

Testimony of:
    Knudsen, James, Food and Drug Administration; accompanied by 
      Robert Temple, Food and Drug Administration; Paul Seligman, 
      Food and Drug Administration; Thomas Laughren, Food and 
      Drug Administration; and Tarek Hammad, Food and Drug 
      Administration.............................................    64
    Mosholder, Andrew D., Food and Drug Administration...........    21

                                 (iii)

  

 
 FDA'S ROLE IN PROTECTING THE PUBLIC HEALTH: EXAMINING FDA'S REVIEW OF 
    SAFETY AND EFFICACY CONCERNS IN ANTI-DEPRESSANT USE BY CHILDREN

                              ----------                              


                      THURSDAY, SEPTEMBER 23, 2004

                  House of Representatives,
      Subcommittee on Oversight and Investigations,
                          Committee on Energy and Commerce,
                                                    Washington, DC.
    The subcommittee met, pursuant to notice, at 11:05 a.m., in 
room 2123, Rayburn House Office Building, Hon. Joe Barton 
(chairman) presiding.
    Members present: Representatives Bilirakis, Stearns, Bass, 
Walden, Ferguson, Rogers, Barton (ex officio), Deutsch, 
DeGette, Allen, Schakowsky, and Waxman
    Also present: Representative Stupak.
    Staff present: Mark Paoletta, majority counsel; Alan 
Slobodin, majority counsel; Kelli Andrews, majority counsel; 
Joby Fortson, majority counsel; Billy Harvard, majority staff 
assistant; David Nelson, minority investigator; and Jessica 
McNiece, minority research assistant.
    Chairman Barton. Today we are continuing a series of 
hearings on FDA's role in protecting the public health, 
examining the FDA's review of safety and efficacy concerns in 
anti-depressant use in children.
    As part of this committee's jurisdiction over public 
health, the subcommittee today will examine the FDA's process 
in determining the safety and public health concerns of anti-
depressants in children.
    The controversy over the use of anti-depressants in 
children is of great public interest. Over 10 million children 
a year are prescribed anti-depressants in the United States. 
The committee's interest in this issue began in January of this 
year in response to media reports about the concerns over the 
safety and efficacy of anti-depressants used by children.
    One month earlier, in December 2003, British regulators 
contra-indicted all anti-depressants for children except Prozac 
due to the risk-benefit analysis of safety concerns related to 
suicidal behavior coupled with a weak showing of efficacy. 
Despite the action taken by British regulators in December 
2003, at that time in the United States there appeared to still 
be substantial support in the medical community for the use of 
anti-depressants in children and for the belief that these 
drugs saved children's lives.
    The U.S. psychiatric establishment had repeatedly assured 
the public that the drugs are very safe. At around the same 
time that the British regulators announced their decision, an 
internal FDA analysis of the pediatric clinical trials of these 
drugs did show an increased risk of suicide related events, and 
seemed to be at odds with these assurances of safety.
    This analysis was prepared by a medical review officer 
specializing in pediatric anti-depressants named Dr. Andrew 
Mosholder. Dr. Mosholder was first requested in June 2003 by 
the Neuropharm Division of FDA to perform this consult after 
GlaxoSmithKline provided the FDA and other regulatory agencies 
with an internal analysis showing an increase in suicidality 
during their pediatric clinical trials of the anti-depressant 
Paxil.
    The Neuropharm Division requested that Dr. Mosholder review 
the Paxil data as well as the data from other pediatric 
clinical trials to determine whether the signal was limited to 
Paxil or whether other anti-depressants showed a similar 
association.
    In September of this year--excuse me, in September 2003 Dr. 
Mosholder informed the agency at an internal briefing of his 
preliminary conclusions. He concluded that the pediatric 
clinical data showed an association between children taking the 
drug and suicide related behavior.
    Dr. Mosholder completed a second consult in December 2003 
which confirmed his preliminary findings reported in September. 
Although initially scheduled to present his findings at a 
February 2004 Advisory Committee meeting, the purpose of which 
was to publicly discuss how the agency should handle the safety 
issues raised in pediatric anti-depressant trials, Dr. 
Mosholder was informed in early January of this year he would 
not be presenting at the Advisory Committee.
    It is my understanding that the individuals within the 
Neuropharm Division, who incidentally were in charge of this 
February meeting, told Dr. Mosholder that they had, ``reached a 
different conclusion'' about the data. As a result of this 
disagreement, he was prevented from presenting his analysis 
before the FDA Advisory Committee.
    The first question that this raises is quite simple: Why? 
Isn't an Advisory Committee a panel of experts? Aren't those 
people capable of hearing different points of view and making 
decisions? What was the harm in allowing Dr. Mosholder an 
opportunity to present his data, his analysis, and his opinion 
to a group of experts?
    I am looking forward to hearing from Dr. Mosholder and some 
of the other FDA witnesses about these issues to get to the 
very heart of this matter.
    On September 13, 2004, which was just several weeks ago, 
the FDA convened another meeting of the Advisory Committee to 
consider the question again, whether there was an increased 
risk of suicide related behavior in children taking anti-
depressants. This time at this meeting, Dr. Mosholder did 
present his data.
    As I understand it, the FDA also presented another analysis 
recently completed by Dr. Hammad. Both Dr. Hammad's analysis 
and Dr. Mosholder's December 2003 analysis essentially reached 
the same conclusions. There is an increase in suicide related 
behavior with children taking anti-depressants.
    Let me repeat that. Their two analyses essentially reached 
the same conclusions. There is an increase in suicide related 
behavior with children taking anti-depressants. The agency now 
acknowledges this association.
    Where do we go from here? The FDA has now looked at the 
issue in depth and has indicated that they are just about ready 
to announce a final course of action. What that course of 
action is and when it will be implemented are two questions 
this committee is very interested in knowing.
    Will we have a black box on these drugs? Will we have a new 
and stronger warning label? Will we have a pamphlet, known as a 
Med Guide, attached to the drug? Will we contra-indict the drug 
like they did in Britain when they banned it from pediatric 
populations? Will we have an informed consent form signed by 
the patient, parent and physician? These are all questions that 
need to be addressed at today's hearing.
    We look forward to getting answers to these questions and a 
better sense of direction about where the FDA is going.
    One final issue that I want an answer today from the FDA: 
When the FDA first become aware of the potential link between 
anti-depressants and suicidality in children, and what did they 
do to get to the bottom of it?
    Throughout our investigation, we have learned that as far 
back as 1996, 8 years ago, a medical review at FDA, Dr. James 
Knudsen, raised the question of an increase in suicidality in 
pediatric clinical trials of a drug called Zoloft. There was 
also an analysis in 1997 of Luvox, another anti-depressant, 
where the review, the same Dr. Mosholder, noted that there was 
an increase in hostility in children versus adults. The issue 
is noted in the Luvox labeling as a result.
    The fact that children taking anti-depressants were 
experiencing psychiatric adverse events at greater rates than 
adults was known at the agency as far back as 1996 and 1997. 
This committee wants to know what did the agency do to respond 
to these concerns? Did they require that pediatric clinical 
trials conducted pursuant to the Best Pharmaceuticals for 
Children Act be designed to capture these types of safety 
issues? If not, why not? Did the agency alert their medical 
reviewers to this potential issue, tell them to look closely at 
that type of data that the companies were submitting in their 
pediatric trials? If not, why not?
    I hope that today we will be able to view the whole picture 
concerning anti-depressants and their effect on children as 
well as the FDA approval process as a whole. The FDA's task is 
quite commendable. It is not easy. They are entrusted with 
being the guardians of our safety. That is a very difficult 
trust to maintain.
    As Members of Congress, it is our duty to ensure through 
the oversight process that the FDA undertake this task in an 
earnest and diligent and, I might also say, an open and 
transparent fashion. We must ensure that the FDA fulfills its 
public health role and its public trust.
    The FDA serves the American people. We are the client. The 
mission of the FDA is not to protect the FDA's internal 
workings, but to promote and protect the public health by 
helping safe and effective products reach the market by 
monitoring for safety, by disclosing the accurate, science 
based information, and for providing this in a clear and 
concise and timely fashion to the American people.
    Is the FDA accomplishing its mission with anti-depressants 
used by children? I would have to say the record is open on 
that, and I would say that, unless we get some very straight 
answers at today's hearing, it is probably going to be answered 
that the FDA is not fulfilling its mission in this particular 
issue.
    At the September 9 hearing concerning the publication of 
anti-depressant clinical trial data, I was upset with the FDA's 
lack of full cooperation with the documentation production 
process pursuant to this committee's request. Since that 
hearing, I have met with the Acting FDA Commissioner, Dr. 
Lester Crawford, about the issue of FDA's cooperation in this 
matter.
    I would like to take note that, since that meeting, there 
has been improvement in the FDA's cooperation in document 
production, and for that I want to thank Dr. Crawford publicly. 
I also want to thank Dr. Crawford for his assistance with 
securing the appearances of some of the witnesses that will be 
speaking today.
    Finally, I would like to thank the FDA in their diligence 
to responding to several member questions that were raised at 
the September 9 hearing.
    Having said that, I must say that we continue to be 
somewhat surprised when we questioning them about their policy 
of document retention at the FDA. The answer we got back was, 
in writing, that they had none--that they have no policy for 
document retention, which is something that we still need to 
address with them.
    I must say, though, that since the last hearing the FDA is 
cooperating much more cooperatively with this committee, and 
again for that I want to thank all of our FDA representatives.
    [The prepared statement of Hon. Joe Barton follows:]
 Prepared Statement of Hon. Joe Barton, Chairman, Committee on Energy 
                              and Commerce
    As part of the Committee's jurisdiction over public health, the 
Subcommittee today will examine the Food and Drug Administration's 
(FDA's) process in determining the safety and public health concerns of 
anti-depressants in children.
    The controversy over the use of anti-depressants in children is of 
great public interest. Over 10 million children a year are prescribed 
anti-depressants in the United States. The Committee's interest in this 
issue began in January of this year in response to media reports about 
the concerns over the safety and efficacy of anti-depressants used by 
children. One month earlier, in December 2003, British regulators 
contraindicated all anti-depressants for children, except Prozac, due 
to the risk-benefit analysis of safety concerns related to suicidal 
behavior coupled with a weak showing of efficacy.
    Despite the action taken by British regulators in December of 2003, 
at that time, in the United States there appeared to still be 
substantial support in the medical community for the use of 
antidepressants in children, and for the belief that these drugs save 
children's lives. The U.S. psychiatric establishment had repeatedly 
assured the public that the drugs are very safe. At around the same 
time that the British regulators announced their decision, an internal 
FDA analysis of the pediatric clinical trials of these drugs showed an 
increased risk of suicide-related events and seemed to be at odds with 
these assurances of safety. This analysis was prepared by a medical 
review officer specializing in pediatric anti-depressants named Dr. 
Andrew Mosholder. Dr. Mosholder was first requested in June 2003, by 
the Neuropharm division of FDA to perform this consult, after 
GlaxoSmithKline provided the FDA and other regulatory agencies, with an 
internal analysis showing an increase in suicidality during their 
pediatric clinical trials of the anti-depressant Paxil. The Neuropharm 
division requested that Dr. Mosholder review the Paxil data, as well as 
the data from the other pediatric clinical trials, to determine whether 
the signal was limited to Paxil or whether other anti-depressants 
showed a similar association. In September 2003, Dr. Mosholder informed 
the agency at an internal briefing of his preliminary conclusions: the 
pediatric clinical data showed an association between children taking 
the drug and suicide-related behavior. Dr. Mosholder completed a second 
consult in December 2003, which confirmed his preliminary findings 
reported in September. Although initially scheduled to present his 
findings at a February 2004 Advisory Committee meeting-the purpose of 
which was to publicly discuss how the agency should handle the safety 
issues raised in pediatric anti-depressant trials-Dr. Mosholder was 
informed in early January 2004, he would not be presenting at the 
Advisory Committee meeting. It is my understanding that individuals 
within the Neuropharm Division, who incidentally were in charge of this 
February meeting, told Dr. Mosholder-they had ``reached a different 
conclusion'' about the data. As a result of this disagreement, he was 
prevented from presenting his analysis before the FDA Advisory 
Committee.
    The first question this raises is simply: why? Isn't an Advisory 
Committee a panel of experts? Aren't those people capable of hearing 
differing points of view and making decisions? What was the harm in 
allowing Dr. Mosholder an opportunity to present his data, his analysis 
and his opinion to this group of experts? I am looking forward to 
hearing from Dr. Mosholder and some of the other FDA witnesses about 
these issues, to get to heart of this matter.
    On September 13, 2004, the FDA convened another meeting of the 
Advisory Committee to consider the question again: whether there was an 
increased risk of suicide-related behavior in children taking anti-
depressants. This time, at this September meeting, Dr. Mosholder did 
present his data. As I understand it, the FDA also presented another 
analysis, recently completed by Dr. Hammad. Both Dr. Hammad's analysis 
and Dr. Mosholder's December 2003 analysis essentially reached the same 
conclusions-there is an increase in suicide-related behavior with 
children taking anti-depressants. The agency now acknowledges this 
association.
    Where do we go from here? The FDA has now looked at the issue in 
depth and has indicated that they are just about ready to announce a 
final course of action. What that course of action is, and when will it 
be implemented-are two questions I am very interested to know. Will we 
have a ``black-box'' on the drugs? Will we have a new and stronger 
warning label? Will we have a pamphlet, known as a ``Med Guide,'' 
attached to the drug? Will we contraindicate the drug like they did in 
Britain when they banned it from the pediatric population? Will we have 
an informed consent form signed by patient, parent and physician? I 
look forward to getting feedback on these questions and a better sense 
of that direction today.
    One final issue that I want an answer from FDA today: When did the 
FDA first become aware of a potential link between anti-depressants and 
suicidality in children and what did they do to get to the bottom of 
it? Through our investigation, we have learned that as far back as 
1996, a medical reviewer at FDA-a Dr. James Knudsen--raised the 
question of an increase in suicidality in pediatric clinical trials of 
Zoloft. There was also an analysis in 1997 of Luvox-another anti-
depressant-where the reviewer, the same Dr. Mosholder, noted that there 
was an increase in hostility in children versus adults. This issue was 
noted in the Luvox labeling as a result.
    The fact that children taking anti-depressants were experiencing 
psychiatric adverse events-at greater rates than adults-was known at 
the agency as far back as 1996 and 1997. I want to know: What did the 
agency do to respond to these concerns? Did they require that pediatric 
clinical trials conducted pursuant to the Best Pharmaceuticals for 
Children Act be designed to capture these types of safety issues? If 
not-why not? Did the agency alert their medical reviewers to this 
potential issue and tell them to look closely at that type of data the 
companies submitted in pediatric trials? If not-why not?
    I hope that after today we will be able to view the whole picture 
concerning antidepressants and their effect on children, as well as the 
FDA approval process as a whole.
    The FDA's task is quite commendable and not easy. They are 
entrusted with being guardians of our safety. As Members of Congress, 
it is our duty is to ensure through the oversight process that this 
vital agency undertake this task in an earnest and diligent manner. We 
must ensure that FDA fulfills its public health role. The FDA serves 
the American people. We are the client. The mission of the FDA is not 
to protect the FDA, but to promote and protect the public health by 
helping safe and effective products reach the market, by monitoring for 
safety, and by disclosing accurate, science-based information. Is FDA 
accomplishing its mission with anti-depressants used by children?
    At the September 9th hearing concerning the publication of anti-
depressant clinical trial data, I was upset with the FDA's lack of full 
cooperation with the document production process pursuant to the 
Committee's request. Since that hearing, I have met with Acting FDA 
Commissioner Dr. Lester Crawford about the issue of FDA's cooperation 
in this matter, and I would like to note that since that meeting, there 
has been some improvement, in FDA's cooperation and document 
production. I also want to thank Dr. Crawford for his assistance with 
securing the appearances of some of witnesses that will be speaking 
today. Finally, I would like to thank the FDA in their diligence in 
responding to several member questions that were raised at the 
September 9th hearing.
    However, if FDA does not continue this cooperation, I will be 
forced to address this issue again just as I did at the September 9th 
hearing. Nevertheless, I am hopeful that we can continue to move 
forward on improved document production from the agency.
    Once again, I would like to thank the witnesses for appearing today 
and the other members present today, and I look forward to this 
hearing.

    Chairman Barton. I would now like to turn to our ranking 
member, Mr. Deutsch for any opening statement that he wishes to 
make.
    Mr. Deutsch. Thank you, Mr. Chairman, for holding this 
hearing and its counterpart earlier this month.
    The September 9 hearing dealt with the fact that the FDA 
and drug companies withheld from the public the important 
information that all but one of the pediatric trials of anti-
depressants failed to show efficacy in adolescents. Sadly, we 
got no good answers from the FDA witness at that time, Dr. 
Woodcock.
    Today we deal with the critical question of the safety of 
these potent medications in children. Specifically, we need to 
understand if the risk of suicidal behavior of teens taking 
SSRIs is greater than the suicide risk associated with a 
failure to take these anti-depressants.
    That is exactly the kind of straightforward, scientific 
question that the Congress expects FDA to answer for the 
American people. Unfortunately, the FDA has handled the 
decisions involving both the safety and efficacy of these drugs 
in adolescents in such an unscrupulous manner that it is very 
hard for anyone to accept that objective science is the basis 
of the agency's conclusions.
    Consider that the FDA extended the monopoly status of these 
drugs for 6 months, costing American taxpayers and consumers 
over $4 billion, and then decided that the public didn't even 
need to know that all but one of these drugs could not 
demonstrate efficacy.
    The only labeling change was for Prozac, the only SSRI 
shown to work at all in kids. Shockingly, the FDA made a 
deliberate decision to withhold information on the clinical 
failures from parents as well as pediatricians and other 
prescribers. But it gets even worse.
    When Wyeth found evidence of elevated risk of suicidal 
ideation and hostility among adolescents taking its drug and 
tried to change its label to warn parents and providers about 
this increased danger, the FDA said no label change to reflect 
those warnings is permissible.
    It is incredible that this agency charged with protecting 
the public health would stop a company from warning the public 
about risks associated with the use of its products by 
children. But the FDA was far from finished with its cover-up 
at that point.
    As information flooded in from the industry and the British 
authorities who had banned the use of these drugs in kids, the 
FDA began a review of the 15 studies that had been done on 
pediatric use of SSRIs. They turned the project over to a 
scientist, Dr. Andrew Mosholder, a medical doctor, psychiatrist 
and epidemiologist in the Office of Drug Safety.
    Dr. Mosholder's analysis of multiple studies concluded that 
there was indeed an elevated risk of suicidal behavior 
discernible from the pediatric studies. Dr. Mosholder was 
scheduled to present his findings before the Advisory Committee 
charged with recommending action to the FDA on anti-depressant 
drugs in February.
    Someone within the FDA did not want those conclusions to be 
public and ripped his presentation from the program. Perhaps it 
was the same people who thought Wyeth shouldn't warn the public 
either. The FDA excuse was that the underlying data needed to 
be examined more critically before such a sensational 
conclusion could be broached publicly.
    When the San Francisco Chronicle got wind of the story that 
the FDA had squelched its own investigator's report, the real 
cover-up began. Both this subcommittee and the Senate Finance 
Committee chaired by Senator Grassley began inquiries, but even 
as Congress was gearing up, senior officials within the FDA 
decided to conduct a witch hunt.
    They sent criminal investigators to probe the source of the 
leak. It is readily apparent that the probe was not about 
information but, rather, about intimidation. It was a warning 
to Dr. Mosholder and other dedicated epidemiologists at the 
Office of Drug Safety, and the ostensible initiating officer 
was the Director of the Office of Drug Safety.
    When we authorized the Prescription Drug User Fee Act in 
the last Congress, the clear tradeoff for the continuing rapid 
review and approval of new drug applications was that the FDA 
would place a renewed emphasis on post-marketing surveillance 
to detect safety problems with drugs just as soon as they 
emerged.
    The Mosholder investigation is a substantive demonstration 
that drug safety remains a stepchild in the FDA-drug company 
partnership at the Center for Drug Evaluation and Research. But 
it gets even worse.
    To be clear, the events I am about to describe involve 
response to requests from Senator Grassley, although I have no 
doubt that, had this ploy succeeded, false documents would have 
been supplied to this committee as well.
    Andy Mosholder was forced to supply a statement to the 
Office of Internal Affairs regarding the events surrounding the 
decision to remove his analysis from the Advisory Committee's 
agenda and the leaking of that story to the Chronicle. This 
document was apparently in response to a request from Senator 
Grassley.
    Apparently, officials in the FDA Office of Legislative 
Affairs and the Office of Chief Counsel met to decide how to 
respond. They decided that not only should the Mosholder 
affidavit be redacted, but that a new document needed to be 
created to hide the fact that an investigation had even taken 
place.
    Ultimately, Dr. Mosholder on advice of his personal counsel 
declined to sign the phony document suggested and drafted by an 
FDA lawyer. Had Dr. Mosholder not acted to thwart the 
submission of an altered document to a bona fide Congressional 
investigation, a criminal act of obstruction of justice would 
have occurred. As it was, the FDA and its lawyers are only 
guilty of attempting to obstruct justice.
    As you are well aware, Mr. Chairman, the FDA has 
stonewalled lawful requests from this committee regarding 
documents in the past. It has also slow-rolled and stonewalled 
our requests for interviews.
    I applaud the determination that you have shown to get to 
the bottom of this, despite the obstruction that has been 
employed by FDA and its attorneys. As a result of this 
committee's efforts, the Advisory Committee did receive the 
Mosholder analysis last week, as well as subsequent analysis 
done by Dr. Tarek Hammad. That reached the same conclusion.
    As we are all well aware, the Advisory Committee 
recommended that a black box warning of increased suicide risk 
in children be attached to the labels of these drugs, and that 
patients be informed of the increased risk when each 
prescription is dispensed. They also recommended that each drug 
that has failed its efficacy test be so labeled.
    I expect that the FDA will tell us at this hearing that it 
will adopt the recommendations of its Advisory Committee. if 
so, this may be an appropriate result. But for the 
investigations by Congress, specifically this committee, and 
the media, I doubt that we would have reached the level of 
public knowledge and concern that has prompted this result.
    Mr. Chairman, I congratulate you on the witness panel you 
have assembled before us today. I hope that the Secretary will 
provide us with an accurate account of events that were exposed 
today.
    There is something terribly rotten at the FDA. No agency 
charged with protecting the public health should behave with 
such indifference to the public safety as is evidenced in this 
case, and no agency should ever treat Congress with the 
disrespect shown by the FDA during the course of this 
investigation.
    Again, Mr. Chairman, you are to be applauded for your 
determination and commitment to the public interest in pursuing 
this difficult inquiry.
    Chairman Barton. Thank you, Mr. Deutsch, and let me say 
before I recognize our vice chairman: This has been a 
bipartisan effort. Mr. Deutsch has been applauding me, but it 
is actually the entire subcommittee and the staffs on both 
sides. We have worked together on this, and we are finally 
beginning to get the truth out to the American people.
    With that, I would like to recognize the distinguished vice 
chairman of the committee, Mr. Walden, Mr. Greg Walden, for an 
opening statement.
    Mr. Walden. Thank you, Mr. Chairman. I thank you for 
holding this second hearing on the safety and efficacy concerns 
of anti-depressants in children.
    Giving parents and doctors as much information about the 
benefits or lack thereof and the risks associated with drugs 
that are being prescribed for millions, tens of millions, of 
our Nation's children should be at the forefront of FDA's 
mission. I am troubled by issues raised at the last hearing 
about what information is on the label of these drugs and what 
information was publicly presented to doctors and parents about 
these pediatric anti-depressant trials.
    Testimony from certain pharmaceutical companies at the last 
hearing raised two issues that I would like the agency to fully 
discuss today. The first question is about stronger warnings.
    As I understand it, in August 2003, Wyeth Pharmaceuticals 
issued a ``Dear Health Care Provider'' letter to more than 
450,000 health care practitioners warning them of increased 
hostility in children taking Efexir and recommending that it 
not be prescribed to anyone under 18 years of age. Wyeth also 
added a stronger warning to their label reflecting this safety 
issue.
    Approximately 8 months later when the FDA finally decided 
to change the warnings on all the labels of all anti-
depressants, they required Wyeth to remove--to remove this 
stronger labeling. What this tells me is the regulatory agency 
charged with protecting the public health is preventing a 
company from disseminating important safety information to 
parents, the public and physicians.
    I want answers from the folks at the Neuropharm Division at 
FDA that made this decision to explain their rationale for it.
    The second question concerns efficacy. In testimony from 
various pharmaceutical companies at the last hearing, it became 
clear that many companies--in fact, most except Eli Lilly--
conducted anti-depressant clinical trials in kids that showed 
no efficacy. That is why none of the anti-depressants except 
Prozac is approved by the FDA for use in treating depressed 
kids.
    Yet the FDA also decided not to allow the companies' 
product labeling to state that clinical trials conducted in 
kids did not demonstrate efficacy. The question is why? Why 
wouldn't you put that on the label? Why shouldn't the label 
reflect that information?
    I note that the Advisory Committee just recommended that 
this labeling change take place, but the point is that the FDA 
knew about the lack of efficacy in these trials several years 
ago, and nothing has been done to change the label to inform 
doctors, patients and parents of this finding.
    I am also interested to learn more about the FDA Advisory 
Committee process and the recommendations that the Advisory 
Committee made last week concerning how to notify the public 
that clinical trial data indicate that there is an increased 
risk of suicide related behavior in children that take anti-
depressants.
    I was struck by the press release that the FDA sent out on 
September 16, just a few days after their Advisory Committee 
meeting. Now in that release, the FDA states, ``that it 
generally supports''--generally supports--``the recommendations 
of the Advisory Committee.'' Generally supports? To me, that 
sounds like the FDA has some doubts about the Advisory 
Committee's recommendations.
    So I would like to know if the FDA has reservations about 
these recommendations; if so, what they are, and why. I would 
also like to know more about FDA's characterization of the 
Advisory Committee's 15 to 8 vote as, ``a split decision'' on 
whether a black box warning label should be on the labels of 
SSRIs.
    Now it is my understanding that a black box warning will 
alert doctors, patients and parents about the risks of taking 
these drugs without preventing these drugs from being 
prescribed to depressed children. Now here in the House, if you 
get a 15 to 8 vote, a 2 to 1 margin, that is a pretty 
significant vote, not generally described as a split decision.
    So it is my question as to how that is being described and 
why in the FDA's press release. Is the FDA going to follow the 
clear majority recommendation and implement this labeling 
change and, if not, why? It is my understanding that Dr. Temple 
and Dr. Laughren will be able to address these questions.
    Finally, I hope to get some answers from the agency about 
the timeline of events in terms of what they told the public 
about safety concerns raised within the agency about children 
taking these drugs, and then when they told the public.
    As we know, the British drug regulatory agency seemed to 
act much swifter on this than the FDA with the same data. So I 
think it is a fair question to ask this agency: Was the public 
health served by a longer deliberative process in this case?
    I also would like to know why the agency made the decision, 
as you have heard from my colleagues, to prevent Dr. Mosholder 
from presenting the findings from his extensive 6-month 
analysis of data on SSRI clinical trials at the February 2004 
Advisory Committee meeting.
    So I will be interested in hearing Dr. Mosholder's 
perspective on his consult, why he believed the safety signals 
were robust even in December 2003, and how he believes his 
consult would have contributed to the February Advisory 
Committee's deliberative process.
    We have many witnesses from the FDA today, and I am hopeful 
they will provide a more complete picture of this process and 
answer these questions that are on our minds and those of the 
people we represent. I thank them for being here, and I thank 
you, Mr. Chairman.
    Chairman Barton. We thank you, Congressman.
    Now I will recognize the distinguished member from 
Colorado, Congresswoman DeGette, for an opening statement.
    Ms. DeGette. Thank you, Mr. Chairman. I would ask unanimous 
consent to put my full statement in the record.
    Chairman Barton. Without objection, so ordered.
    Ms. DeGette. Thank you. I would just like to make a couple 
of observations.
    When I walked into our last hearing on September 9, I 
didn't know anything about this rampant off-label prescription 
of anti-depressants for kids, and I didn't know about the risks 
about it, and I don't think most Americans did know about it.
    Sometimes when I go out in my district, as I have the last 
few weeks, my constituents say how can you stand doing the job 
that you do; how can you stand it back there? What I have been 
saying the last couple of weeks is, well, let me tell you a 
little story about this hearing we had in Congress where we 
found out that anti-depressants, which have been approved by 
the FDA for adults, are being prescribed for kids in rampant 
off-label use and, furthermore, there was data that showed 
that, at best, those drugs did not work, at worse and quite 
possibly, some of those drugs increase the risk of suicide for 
kids.
    So after we had that hearing, and with all the press 
associated with that hearing and the witnesses, well, lo and 
behold, the FDA's Advisory Committee decided there was an 
increased risk of suicidality, and they recommended a black box 
label.
    So, Mr. Chairman, I guess every so often we do do some good 
in Washington, but I think it is a damn shame that we have to 
have Congressional hearings to make that happen.
    Frankly, the public is desperate. Teen depression, in 
particular, is on the rise. We only have one drug that has been 
approved by the FDA for use in kids, and parents are desperate 
to find some way to treat their kids. But they were unaware how 
the off-label use of anti-depressants could really not only not 
help their kids but could actually kill their kids.
    Now I think that the FDA has to answer a lot of questions. 
They need to answer questions about, for example, why there 
were delays of presentation of data between the links of 
suicide and anti-depressants. The FDA needs to answer what 
steps will be taken to ensure that scientists at FDA are able 
to present their findings to advisory committees. They have to 
answer as to what future actions the FDA is taking for 
pediatric and adult use of anti-depressants.
    The American public and the U.S. Congress rely on the FDA 
to ensure that all approved pharmaceuticals are safe. This is 
the responsibility that is at the very core of the FDA's 
mission, and to fulfill that mission the FDA must conduct 
objective studies with rigorous scientific inquiry, and then 
they must present the results to the public. They can't simply 
just sweep this under the carpet or put it in the back room 
because they are concerned about the rise of teen depression 
and the lack of medications to deal with this.
    So I think--I am really glad we are having this series of 
hearings, but I think the FDA has a lot to answer for. I would 
also like to add that at the last hearing, Mr. Chairman, you 
chastised the FDA for its lack of cooperation with this 
committee, and rightly so. But we are still having difficulty 
getting information from the FDA.
    Some of the documents that we requested were not produced 
until 36 hours before this hearing. The questions posed by the 
Democrats at and after the last hearing, including myself, have 
still not been answered, and the FDA did finally, I heard, 
respond to some questions that Mr. Walden had last night.
    We didn't get Doctors Temple and Mosholder's testimony 
until after 7 o'clock last night, and I don't know if Dr. 
Temple testimony required OMB review, which is why the FDA 
usually says the testimony is tardy, but the delay is certainly 
a burden on the committee and our hard working staff. Some of 
us on this subcommittee were here until after 6 o'clock in a 
different hearing last night, and it makes it very difficult to 
prepare for these hearings.
    So in sum, Mr. Chairman--and I have an extension of remarks 
I will put in the record--we have got to have cooperation in 
this hearing by the FDA and by all the other Federal agencies. 
We are elected as representatives of the American people to 
find the truth, and I know. one of the things I love about this 
subcommittee, we work on a bipartisan basis, as the chairman 
said.
    We intend to get to the bottom of this, and I really want 
to thank the chairman for not relenting, and I would hope these 
agencies would realize they have got to cooperate.
    I yield back the balance of my time.
    Chairman Barton. I thank the distinguished Congresswoman 
from Colorado. You statement is the first I had heard that we 
hadn't had those questions answered. I wish I had known that 
yesterday, because I had a phone conversation with Dr. 
Crawford. But what we might do is do another--maybe another 
meeting and get you and Mr. Dingell and Mr. Deutsch involved, 
and we will get your answers.
    Ms. DeGette. Thank you, Mr. Chairman.
    [The prepared statement of Hon. Diana Degette follows:]
Prepared Statement of Hon. Diana DeGette, a Representative in Congress 
                       from the State of Colorado
    Today's hearing is the second of this series on antidepressant use 
in pediatric populations. Parents, children and physicians seeking 
improved mental health carefully weigh the risks and benefits of taking 
antidepressants. The Committee's investigation has uncovered that the 
risks of taking antidepressants had not been fully shared.
    This hearing is more broadly about the Food and Drug Agency's 
ability and efforts to ensure that all approved pharmaceuticals are 
safe. This responsibility is at the very core of the FDA's mission. To 
fulfill that mission, FDA must conduct objective studies with rigorous 
scientific inquiry. When risks are identified, it is essential that 
they be communicated to the public.
    The FDA staff here with us today must answer to this Committee and 
to the American public. Why were there delays in the presentation of 
data on the link between suicides and antidepressants? What steps will 
be taken to ensure that scientists at FDA are able to present their 
findings to Advisory Committees? What future actions is FDA taking for 
pediatric and adult use of antidepressants?
    This investigation on antidepressant use in pediatric populations 
has revealed that transparency and availability of information may have 
been compromised. I would once again like to remind the FDA of the 
importance of their role. It greatly concerns me that the United 
Kingdom's equivalent to FDA (the MHRA), contraindicated all anti-
depressants for individuals less than 18 years of age in December 2003. 
That was almost one year ago. Why has the FDA not taken similar steps?
    The FDA's recent Advisory Committee meeting has determined that 
there is an increased risk of suicidality in pediatric patients taking 
antidepressants. They have recommended warning labels, but not 
contraindication. But the data has shown that a risk of suicide does 
exist for two antidepressants (Effexor and Paxil). How can we not 
provide that information to physicians and parents?
    I, like many of my colleagues believe that we must balance safety 
concerns with access to medication. I do not believe that this balance 
can exist when the risks are hidden.
    In addition to considerations about analysis of the data, this 
investigation has revealed that post-market surveillance of 
pharmaceuticals has not perhaps been as strict as this Committee would 
like. I hope that the witnesses from the FDA will provide some insight 
on how this monitoring process may be limited and what Congress can do 
to improve it.
    I continue to be concerned about the inadequacy of our mental 
health research and treatment system. While antidepressants have 
greatly improved treatment options, much more must be done. In addition 
to examining the FDA's actions, this hearing highlights the areas of 
improvement needed. While safety of medications is of immediate 
importance, this Committee should not turn a blind eye to the more 
significant shortcomings in our health system.

    Chairman Barton. The Chair would recognize Mr. Rogers for 
an opening statement.
    Mr. Rogers. I will yield.
    Chairman Barton. Would Mr. Bilirakis like to make an 
opening statement, distinguished subcommittee chairman?
    Mr. Bilirakis. Well, thank you, Mr. Chairman, just very 
briefly. Obviously, the recent reports of anti-depressant drugs 
possibly increasing the risk of suicidal thoughts and actions 
in children taking these drugs are certainly extremely 
disturbing. While there are, as I understand it, no actual 
suicides, it is important to recognize any possible adverse 
effects that these drugs may have on adolescents and children.
    Mr. Chairman, I don't disagree with any of the comments 
made by you or any of the other members of the committee up 
here and the fault on the part of the FDA and that sort of 
thing, but I guess, as I understand it also, there have been 
some positive things that have taken place.
    I think we all can agree that the new FDA labeling 
requirements are a step in the right direction. The FDA has 
been closely reviewing the results of anti-depressant studies 
in children since June 2003, and asked that the matter be 
investigated by the Psychopharmacologic Drugs Advisory 
Committee, PDAC, and the Pediatric Subcommittee of the Anti-
Infective Drugs Advisory.
    The Advisory Committee did recommend to the FDA that the 
labeling of these drugs be revised to advise the need to 
monitor patients closely when the anti-depressive therapy 
started and, based on this recommendation, FDA did require 
changes to the labels for anti-depressant drugs used for 
adolescents to include stronger cautions and warnings about the 
need to monitor patients for worsening of depression and the 
emergence of suicidality.
    I don't know that this will solve the problem, Mr. 
Chairman, and certainly things like delays and not being 
apparently cooperative and all that are concerns, but I suppose 
that this is a step in the right direction. And thanks to you 
and Mr. Walden, the ranking members in the committee, 
hopefully, this brings it out to the fore, and these matters 
will be solved on an adequate basis, and I look forward to 
hearing from all the witnesses.
    Thank you, Mr. Chairman.
    Chairman Barton. Thank the distinguished subcommittee 
chairman. We now recognize Mr. Allen for an opening statement--
Congressman Allen, I mean.
    Mr. Allen. Thank you, Mr. Chairman, and thank you for 
calling this second hearing to examine concerns surrounding the 
safety and efficacy of anti-depressant use by children.
    This committee must closely examine the FDA's role in 
reviewing clinical trial data indicating serious side effects 
associated with certain prescription drugs. The FDA's mission 
is to protect public health and, therefore, it has the 
responsibility to alert physicians and the public to safety and 
efficacy concerns associated with various medical treatments.
    I do find it very troubling that FDA officials appear to 
have attempted to suppress information indicating that SSRI 
anti-depressants may increase the risk of certain suicide 
related thoughts and/or behaviors in children. I am disturbed 
that Dr. Mosholder's full report on this issue conducted at the 
behest of the FDA was not allowed to be presented at FDA's 
February Advisory Committee meeting on this issue.
    I look forward to hearing from Dr. Mosholder about the 
directive under which he conducted his review on clinical trial 
data of SSRIs and the conclusions of his report.
    Clearly, there is debate among the scientific community 
about whether episodes of attempted suicide while taking SSRIs 
are attributed to the underlying depression of an individual 
patient or to the taking of SSRIs. However, disagreement about 
clinical trial data does not mean that the studies and 
conclusions of specific researchers should be dismissed or 
suppressed. Rather, vigorous debate in the scientific community 
should be encouraged and conclusions challenged in order to 
arrive at the best determination of what information should be 
disseminated to physicians and their patients.
    The increasing rate of clinical depression in children is a 
serious public health issue. Children diagnosed with depression 
are clearly at an increased risk for suicidal thoughts and 
behaviors. Each year, more than 500,000 children and 
adolescents attempt suicide, and approximately 2,000 young 
people die as a result of suicide.
    I had the opportunity to discuss the link between SSRI use 
and the possible increase in suicidal thoughts and behavior 
with a pediatric physiatrist in Maine. He said that there is a 
solid agreement among physicians that they need better clinical 
data on the side effects of anti-depressants and not just 
studies financed by the drug manufacturers.
    He also stressed that physicians need to have a variety of 
drugs available to them in order to make the best choice for 
their patients. Research indicates that between 30 and 40 
percent of children and adolescents with depression will not 
respond to the first medication. The debate surrounding this 
issue clearly indicates a need for greater post-marketing 
studies on prescription drugs.
    I am interested in learning from Dr. Temple about the 
recent recommendations of the Psychopharmacologic Drugs and 
Pediatric Advisory Committee, including the suggestion of 
requiring the black box warning on all anti-depressant drugs, 
indicating an increased risk for suicidality in pediatric 
patients.
    Certain drugs prescribed to children can be ineffective or 
dangerous. It is FDA's responsibility to investigate the risks 
associated with prescription drug use in order to protect the 
safety of our Nation's children. FDA has a critical role in 
ensuring that doctors and consumers receive balanced 
information.
    I look forward to hearing the testimony of all of you on 
this very important topic. Mr. Chairman, I yield back the 
balance of my time.
    Chairman Barton. Thank the distinguished member for that 
statement.
    Does the gentleman from New Hampshire wish to--Okay. Does 
the gentleman from California, Congressman Waxman, wish to make 
an opening statement? Mr. Stupak is not a member of the 
subcommittee.
    Mr. Waxman. Thank you very much, Mr. Chairman. I want to 
commend you for holding this hearing. I am pleased with the 
bipartisan way the committee has operated, and this is an 
important issue, the question of anti-depressant use in 
children.
    The issue has a lot of different implications. Certainly, 
we ought to learn how FDA oversees the safety and effectiveness 
of drugs, both in the approval process and after the approval 
process when drugs are used for an off-label use, and 
especially when we are talking about children.
    The issue also has implications for how the pharmaceutical 
industry shares data on its products with the public, and 
especially the medical community.
    The subcommittee's investigations have revealed that all 
too often the drug industry has concealed data from physicians 
and patients. In the case of anti-depressants, the data that 
was concealed would have shown that the drugs failed to work in 
children.
    Concealing these negative results had very serious 
consequences. It now appears that many children taking these 
potentially ineffective drugs were put at an unnecessary risk, 
because the drugs they were given may have actually increased 
the likelihood that they might commit suicide.
    Today the FDA is going to respond to allegations that the 
agency failed to act quickly enough when the risk of suicide as 
first brought to light. I am very interested in hearing what 
they have to say, and hearing their responses.
    In the weeks and months to come, I hope that the 
subcommittee will continue to examine the broader issue of how 
information about pharmaceuticals is made in general, so that 
we can better protect patients from serious drug risks in the 
future. I think FDA has a lot to answer to today, and I am 
pleased that we have them here and under oath, so that the 
questions may be asked of them and that we can pursue the 
matter fully.
    I am disturbed to hear that perhaps they had not given the 
committee all the information that has been requested. I have 
very little patience, and I know the chairman feels this way as 
well, that when we request information from any government 
agency in order to do our job of oversight--and it is an 
important constitutional function to do that job--we need to 
given all the information that is requested so that we can make 
a better evaluation of the matter before us.
    So I commend you, Mr. Chairman, again for holding these 
hearings, and I look forward to the testimony today and working 
with the members of this committee to figure out what actions 
we need to take thereafter.
    [The prepared statement of Hon. Henry Waxman follows:]
    Prepared Statement of Hon. Henry A. Waxman, a Representative in 
                 Congress from the State of California
    I'd like to thank the Subcommittee for holding this series of 
hearings on anti-depressant use in children. This is an extremely 
important issue, which has implications for how the FDA oversees the 
safety and effectiveness of drugs. The issue also has implications for 
how the pharmaceutical industry shares data on its products with the 
public.
    The Subcommittee's investigations have revealed that all too often 
the drug industry has concealed data from physicians and patients. In 
the case of anti-depressants, the data that was concealed would have 
shown that the drugs failed to work in children. Concealing these 
negative results had very serious consequences. It now appears that 
many children taking these potentially ineffective drugs were put at 
unnecessary risk, because the drugs that they were given may have 
actually increased the likelihood that they might commit suicide.
    Today, the FDA will respond to allegations that the agency failed 
to act quickly enough when the risk of suicide was first brought to 
light.
    I am very interested in learning the response of the FDA to these 
allegations.
    In the weeks and months to come, I hope that the Subcommittee will 
continue to examine the broader issue of how information about 
pharmaceuticals is made public in general, so that we can better 
protect patients from serious drug risks in the future.

    Chairman Barton. We thank the gentleman from California.
    The gentleman from New Jersey, Congressman Ferguson, is 
recognized for an opening statement.
    Mr. Ferguson. Thank you, Mr. Chairman. I thank you for 
holding this important hearing, continuing the committee's 
investigation of adverse effects of anti-depressants in 
children.
    Two weeks ago, we discussed how vital it is that doctors 
receive all the latest relevant study data and results so they 
can make the most informed decisions possible on the safety of 
the drugs that they are prescribing. The drug makers discussed 
steps that they are taking to make their trials available to 
doctors so they can have all the information they need to 
confidently prescribe medicines to patients.
    I commend the work of the committee and, most importantly, 
the parents of children who have suffered unspeakable pain 
because of the adverse reactions to some of these anti-
depressants.
    In the last hearing 2 weeks ago, I spoke about a 
constituent and friend of mine, Lisa Van Sickel. Lisa is here 
with us again today. I spoke about Lisa and her daughter, 
Michelle, as well as other constituents of mine who have 
suffered in this way. Lisa, as I say, is with us again here 
today.
    I am told that Michelle, who is away at college, will be 
watching via the committee's webcast today. If that is the 
case, hello, Michelle.
    Since our last hearing, there have been developments from 
the FDA regarding their recommendations for doctors prescribing 
anti-depressants to children. Last week the FDA's Psycho-
pharmacological Drugs and Pediatric Advisory Committees met and 
made their recommendations on the prescribing of anti-
depressants to children.
    I am interested to hear today what the panel has to say 
about the recommendations and whether or not the FDA plans on 
fully implementing the Advisory Committee's recommendations, 
but also of particular interest is the path that the FDA took 
to come to the conclusions that they have decided upon.
    I look forward to hearing the testimony of Dr. Mosholder 
today, and then the testimony of the second panel about how we 
have arrived at the point that we are at now.
    Question: Why was Dr. Mosholder's work not presented to the 
FDA's February 2004 advisory committee, and when did the 
Neuropharm Division first become aware of an increase in 
psychiatric adverse events occurring in pediatric randomized 
controlled trials of anti-depressants as compared with the 
adult population?
    My constituents and I and members of this panel are looking 
forward to hearing the answers to these and a number of other 
questions from today's panels of witnesses.
    Thank you again, Mr. Chairman, for holding this hearing, 
and I yield back.
    Chairman Barton. Thank the gentleman from New Jersey. The 
gentlelady from Illinois, Ms. Schakowsky, is recognized for an 
opening statement.
    Ms. Schakowsky. Thank you, Chairman Barton, for recognizing 
me for the purpose of making an opening statement and for 
agreeing to hear the opening statement of a Member of Congress 
not on this subcommittee, Mr. Stupak. I hope that the tradition 
of opening statements will continue going forward.
    I look forward to hearing the testimony of the members of 
the panel who took part in reviewing the safety of anti-
depressants in children over the past 1\1/2\ years. We need to 
get some straightforward answers as to why specific concerns 
regarding the safety of those medications were kept not just 
from the public and from the medical community, but from the 
Advisory Committee whose job it is to advise the FDA on these 
issues.
    The process of reviewing the safety and efficacy of 
medications is complex. What is not complex is that the 
findings of someone who is charged at taxpayers' expense with 
the review should not be hidden from sight. This is a 
particular concern when we talk about the health and safety of 
our children.
    I would like to hear an explanation today as to why, after 
spending months examining the connection between anti-
depressant use in children and increased suicidal ideation at 
the request of his superiors, an FDA medical examiner would be 
prevented by those same superiors from presenting his 
conclusions to the FDA's Advisory Committee.
    I find this apparent suppression of information appalling, 
particularly when it serves to hide information that could have 
a significant impact on how medications are used by children.
    In order for an advisory committee to come up with well-
informed and accurate recommendations, it is absolutely crucial 
that they are provided with the most comprehensive, up-to-date 
and accurate information available. When this does not happen 
and the committee is prevented from hearing the conclusions of 
those who actually conducted the reviews, the recommendations 
of the committee inevitably will fail to reflect the best 
interests of children and their families. This not only leads 
to continued misuse of medications by misinformed parents and 
physicians, it results in a serious breach of trust of the FDA 
in its role of protecting the public from unsafe foods and 
medications.
    There already exists a great deal of misunderstanding and 
mistrust within our society regarding the diagnosis and 
treatment of mental health disorders. Incidents such as these 
only serve to add fuel to the fire and increase the anger and 
frustration on all sides.
    Over the past weeks, we have heard from many mental health 
professionals and parents who are convinced that these 
medications can be effective in the treatment of major 
depression in their children if they are used in an appropriate 
manner and under the right circumstances. Many parents are also 
very concerned about the possible negative impact of these 
drugs on their children. All of them, however, deserve to know 
that the decisions about these drugs are based on a full, fair 
and independent analysis, and that critical information has not 
been denied them. Thank you.
    Chairman Barton. The Chair would now recognize the 
distinguished member of the full committee, Congressman Stupak 
of Michigan, for an opening statement.
    Mr. Stupak. Thank you, Mr. Chairman, and thank you once 
again for allowing me to take part in this series of hearings 
concerning the safety and effectiveness of anti-depressants 
used by children.
    Two weeks ago, this committee heard the FDA repeatedly 
claim the jury was still out about the safety of anti-
depressants. Just 4 days later before an advisory committee in 
Bethesda, the FDA finally admitted what they had known for a 
year: There is an increased risk of suicidal thoughts and 
behavior in children who take anti-depressants.
    I am appalled but, frankly, not surprised by the systematic 
efforts of the FDA to suppress information that could have 
prevented the senseless deaths of too many children.
    I believe these anti-depressants should be banned until the 
jury comes back with proof that they are safe and that they 
work. They are not effective to treat depression. Increased 
risk, no matter how large or small, is still an increased risk 
for suicidal behavior.
    The American people have a right to demand the FDA to look 
out for their interests and not the interests of the drug 
companies. When safety is questioned, FDA should err on the 
side of caution.
    The tragedies experienced by the families in the audience 
today may have been prevented. The jury is no longer out. 
Congress at a minimum should demand that the FDA to immediately 
and completely implement all the Advisory Committee 
recommendations made last week. Those recommendations included 
warnings on all anti-depressants, black box labeling, and easy 
to understand warnings on the packaging where parents and 
patients can see it.
    What many here may not realize is the FDA is under no 
obligation to implement those recommendations. There are many 
instances when the FDA has ignored or scaled back Advisory 
Committee recommendations, caving to drug company pressure.
    I know from my own experience that the FDA has repeatedly 
ignored for the past 4 years advisory committee recommendations 
concerning the acne drug, Accutane. I am particularly concerned 
the FDA might back away from the recommendation of package 
labeling that parents and patients can see and understand. The 
FDA should require that information about the safety and 
efficacy of these drugs be dispensed with every prescription 
and on the package labeling.
    The FDA should also require parents to sign an informed 
consent before treatment can begin. The FDA cannot ignore these 
recommendations like they ignored Dr. Mosholder's analysis. 
They can't drag their feet on implementing the recommendations 
as they dragged their feet on posting these studies on their 
website.
    Congress and the American people have had enough of the 
stonewalling and excuse making. It is time to take action. 
Let's be clear. Package labeling is the least the drug 
companies can do.
    In 1997 Congress passed a law beginning a system where the 
drug companies get patent extensions worth billions of dollars 
to study these drugs in children. Children, the most vulnerable 
members of our society, are the only group that we grant patent 
extensions to drug companies in exchange for studies.
    We don't grant patent extensions to drug companies to study 
the effect of drugs in women. We just demand it, and the drug 
companies do it. We don't grant patent extensions worth 
billions of dollars to drug companies to study drugs in 
minorities. We just demand it, and drug companies do it.
    Patents are extended once pediatric studies are turned in 
to the FDA. There is no requirement that the studies were 
actually well done or actually show whether the drug worked or 
was safe, and there is no requirement that the packaging label 
on these drugs are actually changed before the patent extension 
is granted.
    At the very least, parents should get the facts in exchange 
for these billions in profits. It is clear today that they are 
not.
    Mr. Chairman, thank you again for calling these hearings 
and for your leadership on this issue. This hearing illustrates 
a larger problem at the FDA where too often drug companies 
trump parents where medical evidence is suppressed and where 
expert opinion is silenced, and it illustrates that our system 
to study the effects of drugs on children is broken.
    It is a system that gives billions of dollars to drug 
companies and asks little in return. The FDA is failing to live 
up to its responsibility to the American people.
    I yield back the balance of my time.
    Chairman Barton. We thank the distinguished gentleman from 
Michigan.
    The Chair would now recognize the gentleman from Florida 
for an opening statement, Mr. Stearns.
    Mr. Stearns. And good morning and thank you, Mr. Chairman, 
for holding this hearing.
    I think, as Mr. Stupak and others who are parents of 
children are very much interested in this, 2 weeks ago we 
explored the measures to make the results of clinical drug 
trials more accessible to doctors and parents, and I think that 
goes without saying.
    You know, in our society today there seems to be a pill for 
everything that ails you and, of course, this is especially 
true for depression where millions of American children are 
being prescribed anti-depressants. It is probably 
unquestionable that anti-depressants have improved the quality 
of life for many children and their families, and may have even 
saved some lives. But for years now, we have heard anecdotal 
evidence that some of these same anti-depressants increase 
suicidal behavior in some children.
    Lately, the evidence has become less anecdotal and more and 
more compelling. In March 2004 the FDA issued a warning that 10 
popular anti-depressants can cause deeper depression, 
agitation, and other forms of violent behavior, including 
suicide.
    A month later, it was reported that the number of American 
children being treated with anti-depressants has soared over 
the past decades--it has been in all the press--even though the 
vast majority of clinical trials have failed to prove that the 
medicines even help--even help children at all.
    Now we have also heard that the agency's own drug safety 
analyst found a link between some anti-depressants and suicidal 
behavior in children. Yet, my colleagues, these findings were 
suppressed, and his analysis deemed unreliable.
    Finally, a recent FDA commission study by Columbia 
University researchers have confirmed the adverse results, and 
we are forced to admit finally the truth that there is indeed 
an increase in suicide and suicidal thoughts and behavior for 
some children who are prescribed certain anti-depressants.
    Mr. Chairman, the FDA is responsible for protecting the 
public health by assuring the safety and efficacy of these 
prescription drugs. We all know that. The widespread use of 
these anti-depressants should provide even more incentive for 
this FDA to fulfill its stated mission. At the very least, the 
drugs in question should contain strong warning labels to help 
physicians and parents evaluate the risks.
    So truly, all of us here hope that this hearing will help 
us get to the bottom of these disturbing findings and that we 
will have a chance to fully explore the findings with the 
panel.
    So I look forward to this hearing and to learning more 
about the FDA's role in making sure anti-depressants used by 
children are safe and do what they are supposed to do.
    Thank you, Mr. Chairman.
    Chairman Barton. We thank the distinguished gentleman from 
Florida for his opening statement. Seeing no other members of 
the subcommittee on either side of the aisle present, the Chair 
would ask unanimous consent that all members of the 
subcommittee not present have the requisite number of days to 
put their formal opening statement in the record. hearing no 
objection, so ordered.
    [Additional statement submitted for the record follows:]
   Prepared Statement of Hon. Edward J. Markey, a Representative in 
                Congress from the State of Massachusetts
    Thank you Mr. Chairman for calling this important hearing.
    As we continue the Subcommittee's examination of how the FDA and 
the pharmaceutical industry evaluated, reported, and responded to data 
linking certain anti-depressants to an increased risk of suicide in 
children and adolescents, I think it is important to recognize that 
these drugs have played a very positive role in expanding the treatment 
options for so many people around the country who have been struggling 
with depression. For them and their families, anti-depressant 
medications have been a real life line.
    However, we have learned that until very recently we did not have 
the whole truth about the impact of these drugs on our children. 
Today's hearing will help the Subcommittee understand how this could 
have occurred.
    Based on what I have heard and read so far, it seems to me that our 
current system for informing the public about potential risks 
associated may be broken. It failed to inform the public about 
potential risks of anti-depressants at two points. The first failure 
was when the pharmaceutical companies did not disclose the negative 
results of their clinical trials. Congressman Waxman and I will soon 
introduce legislation to address this issue. We are proposing the 
creation of a federal registry of clinical trials. This will ensure 
that companies cannot pick and choose what information they want to 
share with the public.
    The second failure was when the pharmaceutical companies told the 
FDA about negative trials, the FDA did not move quickly and 
aggressively to fulfill its role as the watchdog for public health. 
After conducting their own study and confirming the risk, the Agency 
hesitated, suppressed their own data and left the public in the dark 
for months. Meanwhile, regulators in Great Britain were already taking 
action to protect their citizens from the same risks revealed by the 
data.
    The public absolutely needs to know about the risks associated with 
the drugs that they are taking. Even if Dr. Mosholder's conclusions 
were wrong (which does not appear to be the case) it was completely 
inappropriate for the FDA to suppress his findings. Instead, the he 
should have been allowed presented his findings and conclusions to the 
FDA's Advisory Committee and allowed the experts to evaluate the data, 
question the study and have a complete discussion of the available 
information. Instead the FDA hid the data, got embarrassed when the 
public found out about their actions from the press, and initiated an 
internal criminal investigation that appears aimed at scaring its own 
employees into silence.
    Today we are going to examine the nature of the FDA's failure. The 
FDA plays a critical role in protecting the public health so I am very 
concerned about the maintaining the integrity of the FDA process. It is 
my hope that in the future the FDA will provide a fair, thorough 
evaluation of the risks associated with drugs and promptly inform the 
public of those conclusions in a timely fashion. I am looking forward 
to hearing what steps the FDA is taking to restore the public's trust. 
I look forward to hearing the testimony of today's witnesses.

    Chairman Barton. The Chair would now call forward our first 
witness, the distinguished representative from the Food and 
Drug Administration, Dr. Andrew Mosholder. Would you please 
come forward and be seated.
    Welcome, Dr. Mosholder. You are aware that the committee 
has the tradition of taking all testimony under oath. Do you 
object to testifying under oath?
    Mr. Mosholder. Thank you. As a member of the Religious 
Society of Friends or Quakers, I would prefer to affirm rather 
than swear.
    Chairman Barton. We have the oath so that you can affirm 
rather than swear. But you don't oppose to affirming under 
oath?
    Mr. Mosholder. That is correct.
    Chairman Barton. Thank you. You also have the right as a 
citizen of the United States of America under the Constitution 
of our great Nation to be advised by counsel during your 
testimony. Do you wish to be so advised during your testimony?
    Mr. Mosholder. No, I do not.
    Chairman Barton. Would you please stand and raise your 
right hand.
    [Witness sworn.]
    Chairman Barton. Be seated. Dr. Mosholder, we welcome you 
to the subcommittee. Your testimony in its entirety is in the 
record. We would recognize you for 7 minutes to elaborate on 
that formal testimony.

 TESTIMONY OF ANDREW D. MOSHOLDER, FOOD AND DRUG ADMINISTRATION

    Mr. Mosholder. Thank you. I have a brief oral statement 
which I can read now.
    Mr. Chairman and members of the subcommittee, I am Dr. 
Andrew Mosholder, a medical officer in the Office of Drug 
Safety at FDA's Center for Drug Evaluation and Research. My 
statement will briefly summarize my role in FDA's review of 
suicidality in pediatric anti-depressant drug trials.
    Before joining the Office of Drug Safety, or ODS, I was 
medical officer in the Division of Neuropharmacological Drug 
Products, DNDP, where I reviewed a number of submissions of 
pediatric data for anti-depressant drugs, including Paxil. In 
my review of the Paxil pediatric data, I noted that some of the 
clinical trial adverse events classified as emotional ability 
involved suicidal behavior or ideation.
    So DNDP requested clarification from the manufacturer, 
GlaxoSmithKline. In May 2003, GlaxoSmithKline provided new 
analyses showing an increase in suicidal thoughts and behaviors 
with paroxetine compared to placebo. Dr. Russell Katz, the 
Director of DNDP, requested my assistance in the evaluation of 
these data, and my managers in ODS agreed.
    In July, DNDP asked the sponsors of other anti-depressant 
drugs to reproduce GlaxoSmithKline's analysis of suicidal 
events for Paxil by applying the same method to their own 
pediatric trial data bases.
    By September 2003, I had completed an analysis of the 
paroxetine data and a preliminary analysis of pediatric data on 
seven other anti-depressant drugs. I presented these analyses 
at a briefing for CDER management September 16, 2003.
    DNDP forward responses from the other manufacturers to me 
for review. I completed the first written draft of my report in 
December 2003. DNDP apparently was reaching a conclusion that 
these data were not adequate for definitive analysis. DNDP 
requested additional data from each sponsor, and also arranged 
for the possible suicidal events in these trials to be 
reclassified by outside experts.
    On December 18, 2003, at a planning session for the 
February 2 Advisory Committee meeting on this issue, I shared a 
proposed outline of my Advisory Committee presentation. I noted 
that suicidal events designated as serious in pediatric 
clinical trials for major depressive disorder were 1.9 times 
more frequent with anti-depressant drug treatment than with 
placebo, and that this was statistically significant. There was 
some discussion of the pros and cons of my analysis.
    On January 6, Dr. Katz informed me by telephone that 
someone else would present the clinical trial data at the 
February 2 meeting, since I had a different view of the data 
from that of DNDP.
    News of my analysis and the fact that it would not be 
presented at the February 2 AC meeting reached Mr. Rob Waters, 
a reporter for the San Francisco Chronicle. The Chronicle ran 
the story on February 1, 1 day prior to the AC meeting.
    On February 18, I completed my written report. In it I 
recommended discouraging off-label pediatric use of the anti-
depressant drugs. When my report received supervisory signoff 
March 19, Dr. Mary Willy concurred, and Doctors Anne Trontell 
and Mark Avigan attached cover memoranda indicating their areas 
of disagreement.
    On March 3, 2004, two special agents from the FDA Office of 
Internal Affairs interviewed me regarding the disclosure of my 
findings in the February 1 San Francisco Chronicle article. I 
later provided the Office of Internal Affairs with a written 
statement about the matter. I indicated that I was not the 
source of the disclosure.
    On March 22, FDA issued a public health advisory stating in 
part, ``health care providers should carefully monitor patients 
receiving anti-depressants for possible worsening of depression 
or suicidality.''
    In mid-July Dr. Tarek Hammad of DNDP shared the results of 
his analysis of the clinical trial events as reclassified by a 
panel of suicide experts convened by Columbia University. The 
new analysis confirmed the previous finding: Definitive 
suicidal behaviors and ideation in short term pediatric trials 
were 1.8 times more frequent with anti-depressant drug 
treatment compared to placebo, and this was statistically 
significant.
    Shortly thereafter, data from a new study of paroxetine, 
the treatment of adolescent depression study or TADS, became 
available. The TADS data indicated a therapeutic effect of 
fluoxetine, but also showed an excess of suicidal events among 
those receiving fluoxetine compared to patients who received 
placebo, which was a new finding for fluoxetine.
    On September 13 and 14, FDA held an AC meeting to consider 
this issue. I was among the presenters, and I provided a 
comparison of my analysis to the current analysis. The Advisory 
Committee members voted 15 to 8 in favor of a boxed warning to 
the labeling of anti-depressant drugs.
    Thank you.
    [The prepared statement of Andrew D. Mosholder follows:]
 Prepared Statement of Andrew D. Mosholder, Medical Officer, Office of 
             Drug Safety, U.S. Food and Drug Administration
    Mr. Chairman and Members of the Subcommittee: I, Andrew D. 
Mosholder, am a licensed physician and board certified in child and 
adolescent psychiatry. I obtained my medical degree from the University 
of Virginia. I also have a Master of Public Health degree from Johns 
Hopkins University.
    I am currently employed by the U.S. Food and Drug Administration 
and have been so employed since 1992. During my employment, I have been 
a medical officer with the Center for Drug Evaluation and Research 
(CDER) for twelve years. For about the past 20 months, I have worked as 
an epidemiologist in the Division of Drug Risk Evaluation, Office of 
Drug Safety (ODS). Prior to that, I was a medical officer in CDER's 
Division of Neuropharmacological Drug Products (DNDP) for over 10 
years.
    In this statement, I will briefly summarize my role in FDA's review 
of pediatric use of antidepressant drugs, with particular attention to 
recent concerns about the effects of these drugs on suicidal thoughts 
and behaviors in children and adolescents.
    As a medical officer in DNDP, I reviewed a number of submissions of 
pediatric data for antidepressant drugs, including pediatric data 
submitted for Paxil (paroxetine), manufactured by GlaxoSmithKline. In 
my review of the Paxil pediatric supplement, I noted that a number of 
clinical trial adverse events designated as ``emotional lability'' 
involved suicidal behavior or ideation. Accordingly, DNDP requested 
clarification regarding such behavioral adverse events from 
GlaxoSmithKline. In May of 2003, after I had transferred to ODS, DNDP 
received new data analyses from the manufacturer, indicating an 
increase in suicidal thoughts and behaviors with paroxetine compared to 
placebo in pediatric clinical trials. A consultation request from DNDP 
to ODS signed June 6, 2003 by Dr. Russell Katz stated: ``Since the 
original review of the Paxil supplement, as well as the reviews of most 
other pediatric supplements for SSRIs, was done by Andrew Mosholder, 
M.D, . . . we ask that this consult be assigned to him. We seek his 
advice on further analysis and interpretation of the Paxil results, as 
well as more general advice on what might be done to re-evaluate the 
risk of suicidality in the pediatric databases for other SSRIs . . .''
    My managers in ODS agreed to Dr. Katz's request and assigned me to 
this consultation on June 9, 2003. To determine whether the apparent 
increase in suicidal events applies to pediatric use of other 
antidepressant drugs as well, I started to review FDA's pediatric data 
for other antidepressant drugs. DNDP ultimately decided that the best 
way to proceed would be to ask the sponsors of other antidepressant 
drugs to reproduce GlaxoSmithKline's analysis of suicidal events for 
Paxil, with each sponsor applying the same method to their own 
pediatric trial databases. In July of 2003, DNDP sent requests for such 
analyses to other antidepressant drug sponsors.
    By September of 2003, I had completed an analysis of the paroxetine 
data and a preliminary analysis of pediatric data on seven other 
antidepressant drugs. At the request of management, I presented these 
analyses at a CDER Regulatory Briefing for upper level management on 
September 16, 2003. During the briefing, I presented the paroxetine 
pediatric data, along with preliminary findings for other 
antidepressant drugs. As noted in the briefing minutes, there was 
discussion about the clinical significance of some of the events in the 
analysis: ``We need to get a better sense of what the events from these 
studies really are, i.e., are they legitimate, suicide-associated 
thoughts/actions or self-mutilation acts that are becoming increasingly 
common in the adolescent population today and are not generally 
associated with a sincere intent to die.''
    The Federal Register on October 31, 2003 contained this 
announcement to the public regarding an Advisory Committee meeting 
scheduled for February 2, 2004: ``The Psychopharmacologic Drugs 
Advisory Committee and the Pediatric Subcommittee of the Anti-Infective 
Drugs Advisory Committee will discuss reports of the occurrence of 
suicidality (both suicidal ideation and suicide attempts) in clinical 
trials for various antidepressant drugs in pediatric patients with 
major depressive disorder (MDD). The committee will consider optimal 
approaches to the analysis of data from these trials, and the results 
of analyses conducted to date, with regard to the question of what 
regulatory action may be needed pertinent to the clinical use of these 
products in pediatric patients. The committee will also consider 
further research needs to address questions on this topic.''
    As DNDP received responses from the other manufacturers to the July 
information requests, those responses were forwarded to me for review. 
I then worked on my analysis of these responses over the next couple of 
months and completed the first written draft of my results in December 
of 2003.
    DNDP apparently was reaching a conclusion that the responses from 
the sponsors to the July requests were not going to be adequate for a 
definitive analysis. In October of 2003, DNDP sent requests to the 
manufacturers asking for patient level data sets, to permit a more 
sophisticated statistical analysis than what I could accomplish using 
only the responses to the July requests. DNDP also decided that all of 
the possible suicidal events in these trials should be reclassified by 
outside experts in suicidology.
    On December 10, 2003, the U.K.'s Medicines and Healthcare products 
Regulatory Agency issued their statement, ``Use of Selective Serotonin 
Reuptake Inhibitors (SSRIs) in children and adolescents with major 
depressive disorder (MDD)--only fluoxetine (Prozac) shown to have a 
favourable balance of risks and benefits for the treatment of MDD in 
the under 18s.''
    On December 18, 2003, we held one of our planning meetings for the 
February 2 Advisory Committee (AC) meeting. A draft agenda distributed 
for the December 18 planning meeting included a 45-minute presentation 
by me entitled, ``Limited Overview of Paxil Controlled Trials and 
Controlled Trials of Other Antidepressants.'' At that meeting, I shared 
a proposed outline of my presentation, which included my finding that 
suicidal events designated as ``serious'' in pediatric clinical trials 
for major depressive disorder were 1.9 times more frequent with 
antidepressant drug treatment than with placebo, and that this was 
statistically significant. I recall some discussion of the pros and 
cons of my analysis.
    On January 6, 2004, Dr. Katz sent me an email asking to speak with 
me by phone regarding my presentation at the February 2 AC meeting. In 
our subsequent telephone conversation on that date, he told me that 
someone else would present the clinical trial data at the February 2 AC 
meeting since I had reached a different view of the clinical trial data 
from that of DNDP. On January 7, 2004, I sent an email to the team 
members planning the February 2 meeting, confirming that I would not be 
giving the presentation as originally planned and attaching a draft of 
my slides for their use and interest.
    On January 12, 2004, the Agency issued a Federal Register notice 
with a revised agenda for the February 2 meeting. The notice stated, 
``The committee will not be considering options for definitive 
regulatory action at this meeting because definitive analyses of the 
data have not been completed. This topic will be covered in a second 
meeting to be scheduled by summer 2004.''
    News of my analysis, and the fact that the findings would not be 
presented at the February 2 AC meeting, reached Mr. Rob Waters, a 
reporter for the San Francisco Chronicle. I was not the source of this 
information, however, and in the course of a number of contacts from 
Mr. Waters I did not disclose to him any confidential information. 
Nonetheless, his story about this matter ran on February 1, 2004 in the 
San Francisco Chronicle, one day prior to the AC meeting.
    At the February 2, 2004 AC meeting, I delivered a presentation 
entitled, ``Office of Drug Safety Data Resources for the Study of 
Suicidal Events Associated with Pediatric Use of Antidepressants.'' 
This presentation emphasized postmarketing surveillance (MedWatch) data 
regarding suicidal events with pediatric use of antidepressants, but it 
did not include findings from my analysis of the pediatric clinical 
trial data. Dr. Anne Trontell, the Deputy Director of ODS, instructed 
me to prepare brief remarks regarding my analysis of the pediatric 
clinical trial data, to be used if any members of the Advisory 
Committee inquired about it. No AC members asked any questions about 
this, however, and so I did not deliver the brief remarks that I had 
prepared.
    Subsequent to the February 2 AC meeting, I completed my written 
consultation memorandum regarding suicidality in pediatric clinical 
trials of antidepressants, dated February 18, 2004. In it, I 
recommended discouraging off-label pediatric use of antidepressant 
drugs, chiefly because the one drug that appeared to have the least 
risk of suicidal adverse events from the data available at that time 
was also the only drug to have won approval for pediatric depression, 
i.e., fluoxetine. I had extensive discussions with my management in ODS 
regarding my findings and their interpretation, and when my report 
received final supervisory sign-off on March 19, Dr. Mary Willy 
concurred, while Drs. Anne Trontell and Mark Avigan wrote separate 
cover memoranda indicating their areas of disagreement. That 
essentially ended my involvement with this project until mid-July when 
the results of the Columbia University reclassification analysis became 
available.
    On March 3, 2004, two Special Agents from the FDA Office of 
Internal Affairs interviewed me regarding the disclosure of my findings 
in the February 1 San Francisco Chronicle article. I was also asked to 
produce a written statement regarding this matter for the Office of 
Internal Affairs, and in that statement I indicated that I was not the 
source of the disclosure.
    On March 22, 2004, FDA issued a public health advisory which 
included the following statement: ``Health care providers should 
carefully monitor patients receiving antidepressants for possible 
worsening of depression or suicidality, especially at the beginning of 
therapy or when the dose either increases or decreases. Although FDA 
has not concluded that these drugs cause worsening depression or 
suicidality, health care providers should be aware that worsening of 
symptoms could be due to the underlying disease or might be a result of 
drug therapy.''
    During the spring and summer of this year, I had several meetings 
with investigative staff of this Committee and of the Senate Finance 
Committee, as part of each committee's examination of this issue. FDA's 
written response to this Committee, dated April 14, 2004, summarized 
the rationale for withholding the results of my analysis at the 
February 2 AC meeting as follows: ``. . . given the Agency's concerns 
regarding the limitations of the data and the plans to pursue case 
reclassification and more in-depth analyses, CDER decided that having 
Dr. Mosholder present his conclusion to the Advisory Committee, with 
the appearance that it was an Agency determination, would be 
potentially harmful to the public health as it might lead patients who 
were actually benefiting from the use of these drugs to inappropriately 
discontinue therapy.''
    My next involvement with the analysis of the clinical trial data 
came in mid-July, when Dr. Tarek Hammad was completing the DNDP 
analyses of suicidal adverse events as reclassified by a panel of 
suicide experts convened by Columbia University. The reclassification 
of potential suicidal events by the panel of experts had apparently 
confirmed the finding; definitive suicidal behaviors and ideation in 
short-term pediatric trials were 1.8 times more frequent with 
antidepressant drug treatment compared to placebo, and this was 
statistically significant. I was asked by my management to work with 
Dr. Hammad to prepare a comparison of his analysis to my previous 
analysis. We both participated in an August 9 briefing for CDER 
management on this issue, during which I presented such a comparison.
    Subsequently I prepared a memorandum summarizing this comparison, 
along with some additional supplemental topics, and this memorandum 
received supervisory sign-off August 16.
    Shortly after this, Dr. Hammad obtained data from a new study of 
fluoxetine (Prozac), called the Treatment of Adolescent Depression 
Study (TADS). The TADS data indicated a therapeutic effect of 
fluoxetine, as seen in the previous fluoxetine pediatric depression 
trials, but TADS also showed an excess of suicidal events among those 
receiving fluoxetine compared to patients who received placebo. The 
latter was a new finding, since there did not appear to be such an 
excess in previous fluoxetine trials.
    On September 13 and 14, FDA held an AC meeting to consider this 
issue. The consult document signed March 19 and the follow-up 
memorandum dated August 16 were both included in the briefing materials 
for the AC meeting, and in fact FDA posted these documents on its web 
site several weeks in advance of the meeting. At the first day of the 
AC meeting, I was among the presenters and provided a comparison of my 
previous analysis to the current analysis, this time including the new 
findings from the TADS data, which were not included in the August 16 
memorandum. The following day, the AC members voted 15-8 in favor of a 
boxed warning for the labeling of antidepressant drugs, to note the 
observed increase in suicidal behavior and ideation among pediatric 
patients treated with antidepressant drugs in clinical trials.

    Chairman Barton. Thank you, Dr. Mosholder.
    The Chair would recognize himself for the first series of 
questions, and we will set the clock at 10 minutes.
    Before I ask questions, I want to commend you for your work 
on behalf of the American people. I want to thank you for your 
perseverance. I want to applaud you for insisting on honesty 
and integrity in the review process. My guess is it has not 
been easy. So on behalf of at least this subcommittee and the 
full committee, and I would think I can say on behalf of the 
American people, just let me say thank you. We appreciate you 
being here today.
    Mr. Mosholder. Thank you very much.
    Chairman Barton. My first question to you is: Do you feel 
that you have been pressured in any way at the FDA to suppress 
or change your conclusions regarding your consult or consults--
I think there were two of them--with regard to the efficacy of 
anti-depressant drugs being prescribed off-label for children 
in this country?
    Mr. Mosholder. With regard to efficacy, not per se, but as 
far as the suicidality issue, at the time of finalizing the 
March consult document I had considerable discussion with my 
managers in the Office of Drug Safety about my interpretation 
of the data and the recommendation, and at one point 
alternative conclusions were offered to me which I declined to 
incorporate into my written document. Accordingly, we had the 
document finalized with cover memoranda which in our system 
indicated disagreement between the manager signing the document 
and the original author of the document.
    Chairman Barton. Okay. What are your thoughts on why you 
were refused to participate in the February 2004 Advisory 
meeting?
    Mr. Mosholder. Well, I would describe that as lack of 
confidence in the data and the meaning of the data on the part 
of those who made the decision to remove my presentation from 
the agenda. My understanding is that that lack of confidence 
centered around concern about whether the cases that I had 
counted in my analysis were really bona fide suicidal events or 
were perhaps events that were more clinically trivial or not 
meaningful.
    Chairman Barton. My understanding is that you are a medical 
doctor, an M.D. Is that correct?
    Mr. Mosholder. Yes, that is correct.
    Chairman Barton. And it is pediatric psychiatry. Is that 
correct?
    Mr. Mosholder. Child and adolescent psychiatry. Yes.
    Chairman Barton. Okay. So you feel that you are qualified--
because of your medical training and your background, you are 
professionally qualified in the medical field to make some of 
the judgments and decisions that you had to make in the 
analysis of this data. Nobody has questioned your credentials. 
Is that correct?
    Mr. Mosholder. Not as far as my clinical background, no.
    Chairman Barton. So there was no--It is not one of the 
reasons you were not allowed to participate in the February 
Advisory, because somebody questioned your credentials or 
anything like that?
    Mr. Mosholder. Not to my knowledge.
    Chairman Barton. Okay. Do you agree with the British 
decision to prohibit the use of these anti-depressant drugs in 
children?
    Mr. Mosholder. Well, my comment there is--well, of course, 
in the sequence of events, that came shortly before I was 
completing my own report, and I am sure it had some influence 
on my thinking.
    A close reading of the British contraindication actually 
would suggest that, under certain circumstances, physicians 
might choose to use the drugs for children. So that the term 
contraindication means something a bit different on either side 
of the Atlantic perhaps.
    In the U.S. a contraindication basically means never, that 
the risk is never justified. So that I did support the British 
action with the understanding that their term contraindication 
is not an absolute and recognizing the fact that there might be 
selected circumstances where a clinician and patient might 
choose to use the drug.
    Chairman Barton. This is a personal question. You don't 
have to answer it if you don't want to. Do you have children?
    Mr. Mosholder. I have one step-son who is married, grown 
and married.
    Chairman Barton. If you did have young children, would you 
prescribe these anti-depressant drugs for them if they 
exhibited some of the symptoms of depression and suicidality?
    Mr. Mosholder. Well, my own opinion would be that, based on 
the evidence we have, the so called evidence based approach to 
clinical practice would be that fluoxetine appears to have the 
best data for depression as far as its efficacy.
    We now have data that indicate, even with fluoxetine, there 
could be an increase in the suicidal events. So that that would 
have to be weighed, the risk and the benefit. So I would think 
that fluoxetine would sort of emerge as the default choice 
among the drugs for depression. But even there, it would have 
to be with careful attention to the potential risks.
    Chairman Barton. So I take that, if you personally had a 
child, what I heard you say is the best of a bad choice is this 
fluoxetine, but you really didn't say whether you would 
recommend that it be prescribed or not.
    Mr. Mosholder. Well, in certain circumstances--I think my 
view of the data that we have now is that we should think more 
carefully about the place of medication in the broader 
treatment of juvenile depression. And just again on a personal 
note, I trained long enough ago in psychiatry where we did not 
have Prozac or any of the other SSRIs, and in those days using 
medication was something that was not necessarily the first 
choice.
    So I would say I would not never use it if it was my child 
or my patient, for that matter, but I would do it with careful 
attention to all the risks and benefits.
    Chairman Barton. Why do you think that the FDA, in spite of 
all these studies and all the evidence and all of the analysis 
that you have done, has been so reluctant to withdraw or more 
firmly encourage the medical community to stop prescribing 
these drugs off-label? Why wouldn't our FDA, which is viewed as 
the gold standard of the world, given the studies that have 
been done and your work--why do you think they haven't followed 
the lead of the British? Why have they continued to, even after 
last week--you know, this 51 to 8 decision which has just put a 
black box warning--It just seems to me that the cautious, 
prudent, conservative approach would be to strongly indicate to 
the medical prescribing community that these drugs shouldn't be 
used in children.
    What has caused this reluctance at the FDA which, in my 
view, is quite contrary to their normal procedure, which is to 
be totally cautious?
    Mr. Mosholder. Well, I'm not sure I can give a complete 
explanation, but I think, on the other hand, there is some 
concern with abandoning the utility of these drugs perhaps to 
quickly--there's concerns about whether the studies which 
failed to show efficacy, whether that is due to the drug not 
being effective or whether the trial was not done properly, and 
it is often difficult to tell.
    Another limitation is that we don't have good data on long 
term effects of these drugs. All of the studies that I looked 
at and that Dr. Hammad looked at were just a matter of several 
weeks. So there is also the possibility there could be long 
term benefits but short term risks. We just don't know.
    So I think those are the caveats that perhaps the other 
people in the agency are looking at.
    Chairman Barton. Well, my time has expired. The Chair 
recognize the distinguished gentlelady from Colorado, Ms. 
DeGette, for 10 minutes.
    Ms. DeGette. Thank you, Mr. Chairman. Dr. Mosholder, you 
told the chairman that after you presented your initial 
findings, alternative conclusions were offered to you. I wonder 
if you could tell us what those alternative conclusions were.
    Mr. Mosholder. Well, this was, as I recall, an e-mail from 
Dr. Trontell, one of my supervisors who wrote a cover 
memorandum to the report. As I recall, the difference was 
whether to take the step of channeling patients toward 
fluoxetine, as I said, as sort of a default choice or----
    Ms. DeGette. That is Prozac, which has been approved for 
pediatric use.
    Mr. Mosholder. Yes, for both depression and obsessive 
compulsive disorder--whether to sort of actively advise people 
that that looks like the best choice or to be more cautious and 
just say sort of to use the drugs with caution.
    Ms. DeGette. And they were recommending that you change it 
to say just use the drugs with caution?
    Mr. Mosholder. That is my recollection, yes.
    Ms. DeGette. And you said you rejected that. Right?
    Mr. Mosholder. Yes, and the reason was I thought we had 
some good reasons to sort of point toward fluoxetine as 
perhaps----
    Ms. DeGette. To take the stronger position, saying this is 
the drug that's been approved for pediatric use, this is what 
you should be prescribing. Right?
    Mr. Mosholder. Yes.
    Ms. DeGette. Okay. I want to ask you, Doctor, in layman's 
terms what did you consult reveal about the link between 
suicidality and anti-depressants?
    Mr. Mosholder. Well, to put it simply, in the short term 
studies events which involved suicidal thoughts or behaviors 
were almost twice as frequent among the children and 
adolescents who received drug compared to the placebo or sugar 
pill control.
    Ms. DeGette. So, basically, what your research showed: Kids 
are twice as likely to commit suicide on anti-depressants, at 
least in the short term, than on placebo?
    Mr. Mosholder. Well, I don't think I would say suicide, 
because, of course, there were no actual suicides. So suicidal 
thoughts and behavior.
    Ms. DeGette. Okay. Thanks. Now did these conclusions apply 
to all anti-depressant drugs?
    Mr. Mosholder. That is a very good question. That is the 
conclusion from putting all of the studies together. When you 
break that apart by individual drug, the numbers become much 
smaller, and it is harder to have the same level of confidence 
that you have when you combined all the studies, as I did to 
get that figure.
    So--But it is certainly true that in almost all of the 
drugs that have been looked at individually, there is at least 
an excess of such events with the drug versus the placebo.
    Ms. DeGette. It would probably be helpful to have 
additional research, wouldn't it? More data?
    Mr. Mosholder. There is no question about that. Yes.
    Ms. DeGette. That is what I think, too. Were any of your 
conclusions or findings about increased risk of suicidality 
ever disproved by the FDA, by the Columbia data review, or by 
Dr. Hammad's reanalysis?
    Mr. Mosholder. In general, I think Dr. Hammad's analysis 
and mine were consistent.
    Ms. DeGette. Did anybody else disprove your findings?
    Mr. Mosholder. Not that I am aware of.
    Ms. DeGette. Okay. Now I am curious about the February 2 
Advisory Committee meeting that you testified about. I am 
wondering, if you know, why they decided not to let you present 
your findings at that meeting?
    Mr. Mosholder. Well, it was explained to me by Dr. Katz 
that I had reached a different point of view about the data 
from the Neuropharm Division, and by that I understood that I 
felt the data were of sufficient quality to perform an 
analysis, which I did, while the Neuropharm Division felt that 
any analysis should await the Columbia University 
reclassification project.
    Ms. DeGette. So they felt like your data was not as 
conclusive as you thought it was? Would that be a fair 
characterization?
    Mr. Mosholder. Yes, you could characterize it that way.
    Ms. DeGette. Okay. Let me ask you this. The chairman was 
asking you about some of your background, and you have been at 
the FDA quite sometime. Is that right?
    Mr. Mosholder. Twelve years.
    Ms. DeGette. And how long have you been in your current 
position?
    Mr. Mosholder. Just over 1\1/2\ years.
    Ms. DeGette. And before that, what did you do at the FDA?
    Mr. Mosholder. I was a medical officer in the Neuropharm 
Division.
    Ms. DeGette. And part of your job, as I understand, is you 
were a reviewer of adult anti-depressants in that job. Correct?
    Mr. Mosholder. Yes, that was part of my assignments. Yes.
    Ms. DeGette. In your 12 years at the FDA, I am wondering if 
you have ever been in a situation like this before where you 
were asked to do a medical consult, where you completed the 
consult, where you presented the findings to your supervisors 
and got approval, and then where ultimately the FDA said, well, 
don't worry about it, just keep your conclusions to yourself?
    Mr. Mosholder. Well, certainly, disagreements are not an 
uncommon event. Personally, I had never had the experience of 
having my presentation removed from an Advisory Committee 
meeting agenda.
    Ms. DeGette. Have you ever known that to happen at the FDA?
    Mr. Mosholder. Not by direct knowledge, but I have heard 
reports of other types of events like that.
    Ms. DeGette. Is it your impression that it is a rare or a 
common occurrence at the FDA?
    Mr. Mosholder. Well, it is hard to give an exact frequency, 
I guess, but I would say I have heard of several such 
circumstances, just incidentally.
    Ms. DeGette. And how often is it that people are asked to 
do consults like this and make presentations as to their 
finding? I mean, you said you have heard of people being told 
they can't do their presentations a couple of times. I am 
wondering how often that happens, how often we have these types 
of presentations at the FDA.
    Mr. Mosholder. Advisory Committee meetings, I think, are 
fairly frequent, probably on a monthly basis. There's probably 
other people who can give you real figures.
    Ms. DeGette. So the Advisory Committee meetings happen 
fairly often. How many cases do they review at the meetings?
    Mr. Mosholder. Typically, one issue or one drug per 
meeting.
    Ms. DeGette. Okay. So your view would be it has been 
infrequent that people have been told that they can't--and 
again it is anecdotal, I know, because this only happened to 
you this one time.
    Mr. Mosholder. That is correct.
    Ms. DeGette. Okay. Now is it--I think that you--now you did 
present at the February 2 meeting, but you didn't present on 
your findings from the analysis of the pediatric clinical trial 
data. Is that right?
    Mr. Mosholder. That is correct.
    Ms. DeGette. What did you testify about?
    Mr. Mosholder. I did a presentation which looked at the 
Office of Drug Safety's resources to evaluate this issue, the 
chief resource being, of course, the post-marketing reports, as 
we call them, or reports obtained through the MedWatch program 
from patients and doctors about adverse experiences with 
drugs--that is outside of clinical studies--along with 
examining some other potential sources of information, the 
conclusion being that the best source of information was the 
actual clinical studies.
    Ms. DeGette. But you didn't testify about your latest 
consult?
    Mr. Mosholder. No, that is correct.
    Ms. DeGette. Mr. Chairman, I have more questions. I will 
ask them during the next round. Thank you.
    Mr. Walden [presiding]. I assume we will have one. Dr. 
Mosholder, thank you for being here. Thank you for your good 
work on all these issues.
    I would like you to turn to Tab 1 in that giant notebook in 
front of you there, and I would ask unanimous consent to be 
able to put the binder with all the data in our official 
record. Without objection, so ordered.
    This is an e-mail, and I will read it or parts of it at 
least, to you and then your response to Dr. Katz. It is an e-
mail from Rusty Katz to you, and then your response. Can you 
tell us--Well, let me read part of it, and then maybe you can 
respond to it, sir. This is dated June 2, 2003, and Dr. Katz 
says:
    ``We have recently become aware of a presumed association 
between Paxil and suicidality in pediatric patients. We 
received a call from the EMEA a little over a week ago. Dr. 
Raines told us the company, GSK, had submitted data that 
demonstrated that use of Paxil in kids was associated with 
increased suicidality compared to placebo and that the company 
proposed labeling changes. I believe she also said that it was 
in the news, and it was a big issue. Tom and I told her that 
the company had not informed us of any of this, and we agreed 
to look into it.''
    Then it goes on to talk about some things, and it says: 
``The sponsor has not proposed labeling changes and makes a 
feeble attempt to dismiss the finding. We are also awaiting the 
submission of what the sponsor submitted to UK. We want to move 
quickly to evaluate this signal. We are planning to look at the 
NDAs for other SSRIs to see whether or not similar events are 
being hidden by various inappropriate coating maneuvers.''
    Then they want to compare other things. Then they go on to 
say to you: ``Given your history with this application and this 
general issue, we think you would be the right person to help 
us think about the best approach to the data in the other NDAs 
and their sponsors, as well as to provide ideas for further 
sources of potential relevant data and possible approaches to 
better evaluate this signal study.''
    They go on to say, you know, we want to know if you want to 
do this, basically, and want to move soon.
    Can you tell us, basically, what you were tasked to do as a 
result of this?
    Mr. Mosholder. Well, I approached my own management, and 
they agreed to assign me to this issue, and it involved, 
initially last summer, a review of the Paxil submission that 
was referred to, and then a preliminary search of submissions 
for the other drugs, looking for any kind of similar pattern 
with these events.
    Mr. Walden. So you looked at all the drugs, similar drugs 
being prescribed to kids for anti-depression?
    Mr. Mosholder. All the ones that we had the pediatric 
supplement NDA applications for.
    Mr. Walden. And you were specifically looking at 
suicidality among adolescents? Wasn't that----
    Mr. Mosholder. That is correct. Children and adolescents, 
yes.
    Mr. Walden. When did you first report the results of your 
consult to your superiors?
    Mr. Mosholder. As I recall, I completed a written consult 
in early September 2003, and then there was a briefing for CDER 
management also in September.
    Mr. Walden. I believe it was September 16, our records 
would indicate, of 2003, that the regulatory briefing took 
place.
    Did you attend an internal regulatory briefing then in 
September 2003, and at that briefing did you present the 
results of your first consult to FDA's Neuropharm Division?
    Mr. Mosholder. Yes, I did.
    Mr. Walden. And was Robert Temple and Tom Laughren and 
Russell Katz among those who attended the briefing?
    Mr. Mosholder. As I recall, they were.
    Mr. Walden. What were your general conclusions about the 
pediatric suicidality data you reviewed and your September 2003 
consult in Tab 3, if you need to refer to it--or excuse me, Tab 
8, if you need to look at that? What were your general 
conclusions about suicidality?
    Mr. Mosholder. Well, I need to refer to my summary here.
    Mr. Walden. Sure. Absolutely.
    Mr. Mosholder. Well, basically this had two components. One 
was a thorough look at the Paxil data, and then a preliminary 
look at the data for the other drugs. Basically, I was saying 
that there did seem to be a risk with Paxil based on the data 
the company had submitted and that a first look at the other 
drugs showed that it was not limited necessarily to Paxil. That 
was the question at the time, and it might be what we call a 
class effect, which means that it applies to all of the drugs 
in a particular type of drug.
    Mr. Walden. So am I correct then in understanding that what 
you were saying in that document is that Paxil definitely 
showed potential suicidality increase in adolescents, and that 
the others may also show that in a whole class?
    Mr. Mosholder. Yes, and I recommended looking further at 
the other drugs, which was already underway at that time.
    Mr. Walden. And that was September 16, 2003?
    Mr. Mosholder. Yes. The briefing presentation basically 
mirrored the written document.
    Mr. Walden. When this consult was first given to you and 
you had experience previously in looking at some of these 
pediatric anti-depressant trials, did you have any sense of 
what the conclusion would likely be?
    Mr. Mosholder. No, I did not.
    Mr. Walden. What type of data did you review from the other 
SSRIs to come to the conclusion you did come to?
    Mr. Mosholder. For this work, it involved a manual review 
of the reports from those pediatric trials.
    Mr. Walden. That would be the adverse event reports?
    Mr. Mosholder. Right, as written up in the clinical trial 
reports for those drugs.
    Mr. Walden. And at that time, were you waiting to receive 
more data from the pharmaceutical companies. So, therefore, 
this was a preliminary consult?
    Mr. Mosholder. Yes, and I think, as I mentioned earlier, 
what GlaxoSmithKline did was they had an electronic search of 
their clinical trial data base, looking for certain key words 
that had been used to describe adverse events, and that is how 
they produced the data which yielded the signal for Paxil.
    So what DNDP had done in July was ask all the other 
sponsors to reproduce that, using the same methods that GSK had 
used for Paxil, so that we had, you know, a reasonable 
comparison between the drugs. Then that was still being awaited 
at the time--I think those data were just arriving at the time 
I was finishing this September report.
    Mr. Walden. And were you the one who was going to review 
those data?
    Mr. Mosholder. Yes.
    Mr. Walden. Okay. And did anyone at that meeting express to 
you that your work was done and not to continue with it?
    Mr. Mosholder. No, although there was considerable 
discussion about how to pursue it and how to classify the 
events, but nobody thought it was finished, although there 
wasn't--there was a lot of discussion about what the next steps 
should be.
    Mr. Walden. Incidentally, who signed off on this consult, 
because I see that the last page of it only has signature 
blocks for you and Dr. Willy. Did you need to get anyone else's 
approval to finalize the September consult?
    Mr. Mosholder. Let's see. In my copy, if you turn to 
another couple of pages, you will see that Dr. Avigan, who is 
my Division Director, signed it electronically, which is our 
system for sign-off.
    Mr. Walden. All right. But not Anne Trontell?
    Mr. Mosholder. No. Dr. Trontell did not.
    Mr. Walden. Okay. So it was finalized shortly after you 
completed it, and there was not a significant lag time between 
you completing it and getting it signed off?
    Mr. Mosholder. Well, let's see. The date I have is 
September 4, and then it looks like it was signed off September 
5.
    Mr. Walden. Okay. If you would turn to Tab 10 then, this is 
an e-mail from Russell Katz to you dated September 17, 2003 in 
which he stated you had done a superb job. Is this in reference 
to the presentation you made about the signal of suicidality in 
children taking anti-depressants?
    Mr. Mosholder. This was in reference to that September 
briefing.
    Mr. Walden. Okay. But on that issue. Right?
    Mr. Mosholder. On this issue. Correct.
    Mr. Walden. Did he or any other person in an advisory role 
express any concerns with your conclusion at this time? That 
is, did anyone take the position that your analysis was wrong?
    Mr. Mosholder. Not wrong per se, but there was a lot of 
discussion about whether the events could be more appropriately 
classified and whether--which--that is the concern that led 
ultimately to the Columbia reclassification project.
    Mr. Walden. But one more question. Then I will yield to my 
colleagues. Were there any concerns expressed by anyone within 
Neuropharm or the agency at that time that the method in which 
you approached the data and your analysis was incorrect or 
problematic?
    Mr. Mosholder. As I recall, there was--I had some 
suggestions from the statisticians about how to improve the 
methodology from that standpoint.
    Mr. Walden. But did you ever think that--I mean, yes, how 
confident were you in that consult in your methodology? Was it 
any different than what Columbia ended up when they 
reclassified the data?
    Mr. Mosholder. Well, I mean, I would say I was reasonably 
confident. People may have different opinions about that, you 
know. The Columbia project was--their involvement was to 
classify the events into whether they were definitive suicidal 
behaviors or not, basically, and they had a more refined 
methodology than what I had used.
    Then the other part of that is that Dr. Hammad's analysis 
from a statistical standpoint is more sophisticated than what I 
did. So----
    Mr. Walden. But the outcome was the same, wasn't it?
    Mr. Mosholder. The results were very similar.
    Mr. Walden. Thank you. I now recognize the gentleman from 
Michigan, Mr. Stupak, for questions.
    Mr. Stupak. Thank you, Mr. Chairman. Doctor, Ms. DeGette 
asked a question about not being allowed to testify at the 
Advisory Committee. Is it your understanding that Dr. Graham 
has not been allowed to testify at the Accutane Advisory 
Committees?
    Mr. Mosholder. I am not--I don't have direct knowledge of 
the Accutane Advisory Committees.
    Mr. Stupak. Okay. When we talk about these anti-
depressants, Paxil, Zoloft, Prozac, etcetera, we are talking 
about SSRIs, which is selective serotonin reuptake inhibitors. 
Correct?
    Mr. Mosholder. Correct. There are also--in the group of 
drugs that were looked at, there are some so called atypical 
anti-depressants which are not SSRIs.
    Mr. Stupak. Sure. Let me show you a document. We will give 
the doctor one and the rest of the committee members a copy of 
this document. I am going to show you three of them, but the 
first one is a September 19, 2001, FDA pharmacology/toxicology 
consultation.
    In there, they are reviewing three previously unreported 
Accutane studies, and a pharmacologist reported--and I am on 
page 3, the last paragraph, sort of the conclusions. It is a 
seven or nine-page document there, but on page 3 there are 
conclusions, and I am quoting now. I think it is the second to 
last line. ``Although possible psychiatric correlates of 
excessive serotonagenic function cannot be ruled out, it should 
be noted that increased serotonagenic function is presumed to 
be the mechanism of action of a major class of anti-
depressants, the SSRIs, i.e., selective serotonin reuptake 
inhibitors.''
    Since the excessive serotonic function discovered with 
Accutane use mimics the SSRIs of these anti-depressants, I as 
you then: Do you believe that this relationship between 
Accutane and the SSRIs warrant the same type of notification to 
patients, to the parents, consisting of an informed consent, a 
clear and concise package warning, a Med Guide, and a 
certification of the physician and the registry of all 
patients, as is recommended for Accutane? Do you think we 
should have that same kind of notice, if we are talking about 
SSRIs which somehow, some are similar to function we find in 
Accutane?
    Mr. Mosholder. That is a good question. As I understand it, 
you are suggesting that a risk management program----
    Mr. Stupak. That has been recommended for Accutane, which 
Accutane, according to this consult 3 years ago, talks about 
SSRIs and the mechanism which is similar--it is the same thing 
we are talking about right here with Paxil and Zoloft and 
Prozac.
    So if we are going to have that kind of a recommended 
warning for Accutane, shouldn't we have that kind of 
notification or warning to patients who are using these anti-
depressants that again have the SSRI function in them?
    Mr. Mosholder. That is something I haven't really thought 
about. I guess that would be going beyond the boxed warning and 
more----
    Mr. Stupak. Sure, it is.
    Mr. Mosholder. The real issue being how can we be sure that 
patients----
    Mr. Stupak. Have the full information before they make this 
decision. Right? As you said earlier talking to Mr. Chairman, 
the benefits and the risks have to be known before you can have 
had the whole thing--before a parent should make that decision. 
Correct?
    Take a look at the second document I showed you there. This 
document, if you look, is a PET scan of the orbital frontal 
cortex in the area of the brain that mediates depression. The 
PET scan is of a 17-year-old, and the brain starts--17-year-old 
brain. It starts with baseline of the orbital frontal cortex, 
and then it shows this area of the brain after 4 months on 
Accutane. Please note the changes. As demonstrated in color, 
the brain after 4 months on Accutane, there's some clear 
differences.
    The PET scan clearly shows changes in the brain after 4 
months. The researcher took PET scans of Accutane patients and 
patients who received a different oral antibiotic. The 
researcher took a baseline PET scan of all the patients' brains 
and then again at the 4 month stage of their Accutane or oral 
antibiotic treatment.
    Some of the Accutane patients showed a pronounced 
difference in the brain's metabolism in the area that we 
recognize causing depression.
    Since the FDA in their previous memo has equated Accutane 
with SSRIs, and we know from this research that, while 
metabolic changes are occurring in the brain of Accutane user, 
then my question is this. Is the FDA, by allowing anti-
depressants be used in young people, creating another situation 
like we have in Accutane where these drugs are destroying part 
of the brain, destroying young people, but the evidence is 
ignored as not being scientifically established and, therefore, 
the drug manufacturer continues to market their products, 
despite the research which suggests that the drugs are actually 
destroying a person's brain, causing depression, and is doing 
more harm than good? Based on the PET scan, research of this 
metabolism that is going on in the brain may or may not be 
reversible. Can the brain regenerate itself to repair the 
damage done by the SSRIs? What are we telling parents whose 
children have not improved after taking the anti-depressants? 
That the drug their children are taking may have actually 
destroyed part of the brain?
    You and I don't have the answers to this, but in summation: 
Since there appears to be an established link, at least in one 
research project, by giving our children Accutane and these 
SSRIs, Prozac, Zoloft and Paxil, we may actually be causing 
more harm than good in the brains of young people.
    Should the FDA--and here is my question. Should the FDA 
prevent the use of these drugs in children until these very 
serious questions are answered? I think it is the same 
question--maybe we have a little bit of evidence here that Mr. 
Barton didn't have--that Mr. Barton asked you about the risk 
versus benefits, and I think in response you said to him, risk 
is never justified in dealing with suicidal behavior.
    So if we have some evidence here showing changes in the 
brain in Accutane, which is equated to the previous documents 
SSRIs, should we not be very cautious on continuing to 
prescribe these SSRIs to young people under the age of 18 until 
we answer these questions?
    Mr. Mosholder. Well, I would say that the findings from--
actually from the clinical trial data--you know, without 
turning to even neuroimaging, one can look at the clinical 
trial data, and that would certainly give one pause about the 
usefulness of these drugs for children and adolescents for 
depression.
    It is also true that we don't know nearly enough about the 
long term effects of these anti-depressant drugs or other drugs 
on children and adolescents who are growing and developing.
    Mr. Stupak. Well, as you said, we don't know enough about 
it. So as I said in my opening statement, shouldn't we really 
err on the side on caution? You know, suicide is final, and we 
have had a number of suicides related to these SSRIs and, say, 
with Accutane. I mean, if there is a question here as to the 
safety, and to date this is probably the only evidence we have 
showing a change in the brain in some of these Accutane 
patients which equate to your SSRIs--if we have brain changes, 
until we answer these questions, if it is reversible, can the 
brain rehabilitate itself, grow new cells, shouldn't we really 
be very, very cautious in how we use these drugs, and should we 
not even consider not prescribing to young people under age 18?
    I asked that same question of the drug manufacturers 2 
weeks ago, and they really wouldn't give me an answer. They 
thought it was still okay to prescribe drugs to people under 
18, even though the jury is still out, as they wanted to say. 
Shouldn't we err on the side of caution here?
    Mr. Mosholder. Well, my own opinion is, as I said before, 
that we should be mindful of the fact that the best data, the 
best evidence for benefit is limited to the single drug, 
Prozac, at least in terms of depression. Obsessive compulsive 
disorder is a different story, but for depression.
    So that faced with the question of possible harm, on the 
one hand, and then lack of evidence of benefit, on the other, 
that should certainly be part of the evaluation of whether or 
not to use the drugs.
    I am not prepared to say that the drugs shouldn't be used 
in children.
    Mr. Stupak. I believe you got one more document there. My 
time has almost run out. Let's go to that. In dealing with 
pediatric studies, and again we are still in question here, 
dosage is usually a question as to the proper amount that 
should be given, of the amount, the percentage, things like 
that.
    For example, in Accutane we know that the dosage is way too 
high, and in one FDA source--in fact, it is there with you--it 
states that the Accutane formula dose may be 240 times more 
than necessary for safe treatment, and that was followed up 
with discussions to have Hoffman La Roche do a dosage study 
and, as far as I know, it was never done.
    So my question is: Since these anti-depressants and 
Accutane have sort of been linked here today, has there been 
shown to be--has the FDA given any thought to determine whether 
proper dosage is given to children and adolescents with these 
anti-depressants, because they were developed for adults. So 
are we dealing with the proper dosage when we are dealing with 
young people and adolescents?
    Mr. Mosholder. Well, that is a very good question, and 
unfortunately, to the best of my recollection, the clinical 
trials that we have for the anti-depressants in children were 
done with what we call flexible dosing where it is left up to 
the clinician/investigator to determine the dose within a 
certain range.
    So there might have been one or two exceptions to that, but 
what is really needed is a study in which patients are assigned 
to a specific dose, and then both the benefits and the side 
effects can be compared to get a judgment of what the best dose 
is.
    So there is clearly--apart from even figuring out if the 
drugs are effective in children, there is clearly more need for 
data on the proper dosage.
    Mr. Walden. I want to thank the gentleman.
    Mr. Stupak. Thank you. Mr. Chairman, I ask that those three 
documents referred to by Dr. Mosholder and given to the 
committee be made part of the record.
    Mr. Walden. Without objection.
    [The documents referred to follow:]
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    Mr. Stupak. Thank you.
    Chairman Barton. Thank you.
    Mr. Walden. Dr. Mosholder, given the new TAD study on 
fluoxetine, do you believe that that raises any issues parents 
and physicians should be concerned about relative to 
suicidality?
    Mr. Mosholder. My opinion is that it does raise some 
concerns about that, and as I was saying earlier, when I did my 
initial--well, actually, the March consult document didn't have 
the TADS study, and it looked at sort of conveniently the one 
drug that had the best efficacy for depression, also didn't 
seem to have this risk of increasing suicidal events, which 
made a certain amount of sense. But I think now it is a little 
different picture that, although the TAD study again showed 
that Prozac is effective in ameliorating the symptoms of 
depression, it suggests there is a certain number of patients 
who have an increased risk of suicidal behaviors or thoughts at 
the same time.
    So there is both a risk and a benefit, in other words.
    Mr. Walden. Do you recall what the suicidality rate was in 
the TAD study and how that compares to the other studies?
    Mr. Mosholder. As I recall from Dr. Hammad's analysis, the 
relative risk, as we call, which is--or risk ratio is between 4 
and 5. I can look that up.
    Mr. Walden. And what does that mean to a layperson like me?
    Mr. Mosholder. Well, one way that we measure these risks is 
to do what we call a risk ratio, and that is--I guess the 
simplest way to explain would be with a brief example. A study 
with 100 patients on drug, 100 on placebo, if one had 10 
suicidal events on drug and 5 on placebo, the ratio would be 10 
out of 100 to 5 out of 100, or 2.
    So we would say that that relative risk is 2, and that is--
and as I recall, in the TAD study it's actually higher than 
that.
    Mr. Walden. And is that a--is 4, if that was the number, is 
that one that should raise a flag? I mean, you do this work all 
the time.
    Mr. Mosholder. Well, I think it raises a flag, and it has 
to be judged against the benefit. so that there is a study in 
which in the same study, you can look at the benefits and the 
risks simultaneously.
    Mr. Walden. All right. The question is: Does it suggest a 
point of underreporting in the other studies?
    Mr. Mosholder. No, I'm not sure that is the--I'm not sure 
the answer is as simple as that. There are some differences 
between the TAD study and the other studies that might or might 
not account for the different in the data. It is kind of hard 
to tell after the fact.
    Mr. Walden. Could you turn to Tab 11 in our notebook there. 
This is an e-mail dated October 2, 2003. Mary Willy who is your 
direct supervisor--correct?--in the Office of Drug Safety at 
that time, suggests to the Neuropharm Division and others that 
you should present your Paxil suicidality conclusions that were 
first presented in September to a Pediatric Advisory 
Subcommittee meeting that was meeting in October.
    Then Russell Katz writes back to her and states: ``We 
recognize that some folks outside the Division have concluded 
there is enough of a signal already established to make some 
sort of a meaningful statement about the data, but we haven't, 
and we think that publicly presenting part of the data in its 
current state has the great potential to be misleading and 
uninformative.''
    Do you agree with Dr. Katz' statement that publicly 
presenting your data and conclusions you reached at that time 
has the great potential to be misleading and uninformative?
    Mr. Mosholder. Well, my opinion was--and that of Dr. Willy 
at the time was that we thought it could be done and might have 
been useful, which is why she proposed it. But as you see, 
there was a difference of opinion about that.
    Mr. Walden. You know, it strikes me that when word came 
over from Europe that there may be a problem here, they went 
right to you quickly and said we have to act quickly.
    I guess what is troubling to us is it appears there was a 
fairly long delay between the time you did your quick review, 
your consult, came back and said I see some problems here, if I 
am characterizing that correctly, and then when it finally gets 
presented up the chain. It seems like somebody put a brake on 
somewhere. Did you ever feel that way?
    Mr. Mosholder. You know, it is really hard to be specific 
and say that--I'm not sure I have much of an answer to that, 
really.
    Mr. Walden. All right. Did you present at that October 
Pediatric Advisory Committee meeting?
    Mr. Mosholder. No.
    Mr. Walden. Throughout the fall of 2003, did you continue 
to work on this consult and, if so, can you briefly describe 
what you were looking at?
    Mr. Mosholder. During that fall, what I was doing was an 
analysis of the responses from the other anti-depressant 
manufacturers. As you recall, in July they had been asked to 
reproduce GSK's methods that found the problem with Paxil. So 
we wanted to--for comparability purposes, we wanted to have 
that reproduced by each of the other manufacturers.
    We received that information in the late spring/early fall 
of 2003, and that is what I was working on.
    Mr. Walden. You were reviewing all those data?
    Mr. Mosholder. Yes.
    Mr. Walden. Would those data have been ready for the 
October presentation? Were you ready?
    Mr. Mosholder. For the October presentation, it would not 
have been the--what we would have had at that point would have 
paralleled the regulatory briefing that I had given in 
September to CDER management.
    Mr. Walden. Okay. So at the end of October, the FDA noticed 
a public Advisory Committee meeting for February 2 and 3, 2004. 
Was it your understanding that you were going to present at 
this meeting on the topic of your consult and what your 
findings were regarding suicidal behavior in these pediatric 
clinical trials?
    Mr. Mosholder. Yes, that was my understanding.
    Mr. Walden. That's what you were going to go do. Did the 
fact that in October 2003 Neuropharm decided to involve 
Columbia University in reclassifying the events provided by the 
companies mean that you were to stop working on your consult?
    Mr. Mosholder. I remember wondering that and discussing it 
with Dr. Willy, my team leader, and we decided that at that 
point I had gone far enough and had devoted a lot of time to 
this project that it made most sense just to have me finish 
with my analysis, which was the one that I completed the draft 
in December.
    Mr. Walden. So it was your understanding, both your consult 
and any work that Columbia did would be pursued simultaneously?
    Mr. Mosholder. Correct, although the timeline--it seemed 
obvious that the Columbia--it seemed obvious pretty early that 
the Columbia data would not be ready for analysis and 
presentation by February 2.
    Mr. Walden. But it was important enough that you wanted to 
get answers sooner than that?
    Mr. Mosholder. Yes, which is not to say that it had to be 
either one or the other, but both efforts were continuing full 
speed, you know, as far as I was concerned.
    Mr. Walden. Were you involved in the planning meetings for 
the February 2 Advisory Committee meeting?
    Mr. Mosholder. Yes, I was.
    Mr. Walden. When did you complete your final meta analysis 
of all the data from the SSRI pediatric clinical trials?
    Mr. Mosholder. As I recall, my draft was turned in to my 
management around mid-December.
    Mr. Walden. Of 2003?
    Mr. Mosholder. Of 2003. I made some refinements to it in 
the subsequent couple of months.
    Mr. Walden. And basically--correct me if I am wrong, but 
didn't those data, or didn't your findings show a 1.9 or 1.89 
times more likely serious suicide-related event on drug than 
placebo?
    Mr. Mosholder. Yes.
    Mr. Walden. Across the trials. Right?
    Mr. Mosholder. That's correct, yes.
    Mr. Walden. All right. And didn't you recommend interim 
measures?
    Mr. Mosholder. Yes. I recommended--I wasn't very specific, 
I realize, but I had in mind some kind of interim measures to 
announce that there could be a problem.
    Mr. Walden. Did you feel a sense of urgency?
    Mr. Mosholder. Yes, I did.
    Mr. Walden. To get this information and your findings out?
    Mr. Mosholder. Yes, I thought it was--and that was one of 
the points I made at the September regulatory briefing, that 
these drugs are widely used in this population, and so that it 
was an important public health issue.
    Mr. Walden. Did you reclassify any of the events that the 
sponsor gave? That is, did you change the classification from 
serious to nonserious or discount it completely?
    Mr. Mosholder. What I did for my meta analysis, I took the 
events which had been identified by each sponsor, using GSK's 
method, and then the result that I emphasized was the subgroup 
of those events which also met a regulatory definition for 
seriousness. That is a definition that--it is in the Code of 
Federal Regulations. It is something that each sponsor 
designates when they report the studies to the FDA as to 
whether or not a particular adverse event is serious or not.
    Mr. Walden. And didn't your consult focus on serious 
suicidal events?
    Mr. Mosholder. Yes, it did.
    Mr. Walden. Including the famous girl slapping face?
    Mr. Mosholder. Well, that was not a serious event which 
was----
    Mr. Walden. So that wasn't----
    Mr. Mosholder. Well, that was the rationale that, without 
being able to do anything as elaborate or sophisticated as the 
Columbia University project, as a first cut to eliminate some 
of the questionable cases, I took the subgroup that met the 
criteria for seriousness, which in this case is mostly either 
life threatening or resulting in hospitalization.
    Mr. Walden. Okay. So the girl slapping face scenario was 
not even included in your data that resulted in a 1.9 times----
    Mr. Mosholder. No.
    Mr. Walden. I mean, you were pushing the upper end here in 
terms of suicidality issues then. Is that right? My reading as 
a layperson.
    Mr. Mosholder. Well, it was an attempt to hone in on the 
events that were clinically meaningful.
    Mr. Walden. But it also says there are other events below 
that, including the girl slapping face situation that--I guess 
my point is, that could be occurring out there in adolescents--
--
    Mr. Mosholder. Yes.
    Mr. Walden. [continuing] are not even in your data. That is 
not a criticism. I am just trying to get the range here.
    Mr. Mosholder. Well, I did look at it with the broader 
category, too, but I thought the more important result was with 
the subgroup of the serious events.
    Mr. Walden. Indeed. My time has long since expired. I turn 
to my colleague from Colorado.
    Ms. DeGette. Thank you, Mr. Chairman. Dr. Mosholder, if you 
could turn to Tab 67 of the notebook in front of you, do you 
see that statement? It is entitled Written Statement.
    Mr. Mosholder. Yes.
    Ms. DeGette. Was this statement prepared by you?
    Mr. Mosholder. Yes, it was.
    Ms. DeGette. Can you tell me how you came to prepare that 
document?
    Mr. Mosholder. I was--well, this is a statement that I 
provided to the Office of Internal Affairs, and this was 
pursuant to an interview that I had with two Special Agents of 
the Office of Internal Affairs regarding the San Francisco 
Chronicle story about my analysis of the suicidal events.
    Ms. DeGette. Did those agents ask you to prepare that?
    Mr. Mosholder. Yes, subsequent to the interview they asked 
me to provide a written statement.
    Ms. DeGette. And that is how you came to prepare that?
    Mr. Mosholder. Yes.
    Ms. DeGette. Okay. And that statement was under oath. 
Correct?
    Mr. Mosholder. It was given----
    Ms. DeGette. It was an affidavit?
    Mr. Mosholder. Right. That's correct, yes.
    Ms. DeGette. And what it was about was the circumstances 
surrounding the removal of your analysis of the incidence of 
pediatric suicidality in clinical studies of anti-depressants 
from the agenda of the Advisory Committee meeting that we 
talked about, and also the conversations that you had with the 
San Francisco Chronicle reporter about that analysis and the 
decision to omit it from consideration by the Advisory 
Committee. Is that right?
    Mr. Mosholder. That is correct.
    Ms. DeGette. And so what this written statement was 
attempted to be was an accurate account of the events as you 
knew them about the presentation and the decision to cancel 
that presentation, and also about your contacts with the 
reporter. Right?
    Mr. Mosholder. That is correct, and importantly, to include 
the statement that I did not divulge the information to the 
reporter.
    Ms. DeGette. Right, and you wanted to--so part of what you 
wanted to do was set out a chronicle of the events, including 
how and why and in what way you communicated with this 
reporter. Right?
    Mr. Mosholder. That is correct. And that was part of the 
request that they gave me to include in the statement.
    Ms. DeGette. Okay. Now when did you provide that statement 
to the OIA?
    Mr. Mosholder. I believe it was--it was middle of March, I 
think maybe March 15.
    Ms. DeGette. That is the information I've got as well. Did 
there come a time when the U.S. Senate Finance Committee made 
inquiries regarding the events described in your statement?
    Mr. Mosholder. Yes, that's correct.
    Ms. DeGette. And when did you know about that? How did you 
find out about that?
    Mr. Mosholder. I believe I saw a news report in late March 
of this year.
    Ms. DeGette. And then were you contacted by the Office of 
Legislative Affairs?
    Mr. Mosholder. Yes, I was, when the Senate Finance 
Committee investigators wanted to arrange an interview.
    Ms. DeGette. So it was sometime after March 15?
    Mr. Mosholder. That's correct.
    Ms. DeGette. Okay. Did you meet with folks from the Office 
of Legislative Affairs subsequent to the TV report that you saw 
or the media report?
    Mr. Mosholder. Yes. We had a couple of preparatory 
meetings, as I recall, to prepare me for the Senate Finance 
Committee interview.
    Ms. DeGette. Okay. Was that with Patrick McGarry and Karen 
Meister?
    Mr. Mosholder. I believe they were some of them.
    Ms. DeGette. And there were others as well as them?
    Mr. Mosholder. Yes. We had a series of meetings, and I am 
not entirely clear on who precisely was at which meeting, but 
there was a number of them.
    Ms. DeGette. Okay. Doctor, take a look at Exhibit 64, which 
is an e-mail from Ms. Meister to you regarding a May 3, 2004, 
meeting in Mr. McGarry's office. Do you see that memo, Tab 64?
    Mr. Mosholder. Yes.
    Ms. DeGette. There are some people who are copied on that 
e-mail: Ann Hennig, Donna Katz, and Kim Dettlebach. Do you see 
those names?
    Mr. Mosholder. Yes.
    Ms. DeGette. Do you know those individuals?
    Mr. Mosholder. Yes, I do.
    Ms. DeGette. Do you know who they are?
    Mr. Mosholder. Ms. Hennig works with the CDER Office of 
Executive Programs, as I believe it is called. Ms. Katz and Ms. 
Dettelbach are, as I understand, with the Office of Chief 
Counsel at FDA.
    Ms. DeGette. Okay. Now can you tell me what the subject of 
that meeting was?
    Mr. Mosholder. As I recall, it was a preparatory meeting 
for my Senate Finance Committee interview.
    Ms. DeGette. And after that meeting, were there exchanges 
of various revisions to the written statement that you talked 
about a little while ago that you had prepared earlier that was 
to be provided to the Senate Finance Committee?
    Mr. Mosholder. Yes. That became an issue, and I can explain 
it this way. Having given the statement under penalty of 
perjury, as we said, I had a legal interest, and my attorney 
confirmed this, in being consistent with that statement. So 
that----
    Ms. DeGette. And telling the truth, because you were under 
oath.
    Mr. Mosholder. Yes. And also not even inadvertently 
contradicting a previous statement. So----
    Ms. DeGette. A previous statement made by you?
    Mr. Mosholder. Right. So to ensure my own consistency and 
knowing that the Senate Finance Committee would be asking about 
the same sequence of events, it was to my advantage to make use 
of that statement for the Senate Finance Committee 
investigation as well.
    So I wanted to provide them with a copy of the statement as 
sort of my official record.
    Ms. DeGette. Right, your take on what happened, to the best 
of your recollection.
    Mr. Mosholder. The issue was that at that time the Internal 
Affairs investigation, as I understand it, was still an open 
investigation, and apparently FDA's policy or the executive 
branch policy is not to reveal the existence of such 
investigations. So that I was advised to redact the statement 
so that it didn't have any reference to the Internal Affairs 
investigation.
    Ms. DeGette. And they also wanted you to take the names 
out?
    Mr. Mosholder. Right. The other issue was personal privacy 
of not revealing the names of other people who were subject of 
an Internal Affairs investigation. So although I was free to 
reveal my own involvement, but that it wouldn't be appropriate 
to divulge other people who were subject to that same 
investigation.
    Ms. DeGette. And were you willing to make those redactions?
    Mr. Mosholder. I said that I was uncomfortable redacting 
the document in a way that it wasn't transparent that it had 
been redacted.
    Ms. DeGette. So you didn't mind taking out the names or the 
reference to the internal investigation, but you wanted the 
document to reflect that it had been altered. Correct?
    Mr. Mosholder. That is correct.
    Ms. DeGette. And they wanted to alter it so that there 
would be no record of the redactions. Correct?
    Mr. Mosholder. That is my understanding. That is how I 
understood it, yes.
    Ms. DeGette. Now ultimately you decided not to sign the 
revised document that they had sent you. Correct?
    Mr. Mosholder. Well, I said that, when I went to the 
Finance Committee for my interview, that I preferred to use my 
version, which indicated that the document had come from a 
previous document, and in the--actually, what happened was in 
the interim the Internal Affairs investigation was closed. So 
that that made that issue moot. So I was able to ultimately 
provide the Finance Committee with my affidavit, only minus the 
names for personal privacy.
    Ms. DeGette. Okay. Take a look at Exhibit 57. That is an e-
mail from Donna Katz to you with copies to various people. Do 
you see that there?
    Mr. Mosholder. Yes.
    Ms. DeGette. Now attached to that e-mail is a copy of the 
written statement, your written statement, with lines through a 
number of sentences, and a copy where the deletions had been 
made. Do you see that?
    Mr. Mosholder. I see the--I only have the copy with the 
deletions indicated.
    Ms. DeGette. All right. We are going to hand it to you. 
Apparently, it is not attached in the notebook, but do you 
recall seeing a draft of a document that Ms. Katz wanted you to 
look at?
    Mr. Mosholder. Yes. That is actually the situation I just 
described.
    Ms. DeGette. Right, and here it is.
    Mr. Mosholder. Thank you.
    Ms. DeGette. Is that the document?
    Mr. Mosholder. Well, this is the document showing where the 
lines have been dropped. Yes.
    Ms. DeGette. Right, where she wanted to redact it, and in 
fact, her e-mail to you says, ``Andy, I have taken a look at 
your written statement and made some suggested edits. Given 
this will be a new document created to give to the Senate 
Finance Committee, albeit based on an earlier document, I think 
it is cleaner to make this a stand-alone document, i.e., to 
include everything in it that is current and you would like to 
include, and just delete out anything you would like to leave 
out. I don't think it is necessary to indicate that this 
document represents a version of the earlier one by noting that 
the things that have been omitted. This simply invites the 
Committee to ask further questions about what was omitted in 
the earlier document. Please let me know if you have any 
questions, etcetera. Thanks, Donna.''
    Is it your understanding that, had you signed the revised 
statement, it would have been submitted to Senator Grassley and 
probably also this committee without notation regarding its 
alteration?
    Mr. Mosholder. Well, it wasn't a matter of signing it, but 
the plan was that I would provide this to the Committee at the 
start of my interview with them. So----
    Ms. DeGette. Right. So if you had gone alone with this, 
this redacted document without the--I mean the lines would have 
been taken out. It would have been cleaned up, and that is what 
would have been given to the Senate and also probably to us, 
without notation of the things that had been taken out. Right?
    Mr. Mosholder. That is my understanding of what was 
proposed.
    Ms. DeGette. And that is what you objected to?
    Mr. Mosholder. Yes. I said I was not comfortable with that.
    Ms. DeGette. Okay. Now take a look at Tab 58. What that is, 
your reply to Ms. Katz the same day, which says, attached is a 
version of the statement that you say you would have been 
comfortable with. Right?
    Mr. Mosholder. Yes, that's correct.
    Ms. DeGette. And the e-mail reads: ``Thanks very much, 
Donna. Your version is actually very similar to the one I came 
up on my own this a.m. See attached. Although it might be 
cleaner to do so, as you say, I am uncomfortable with 
concealing from the Committee the fact this is not a new 
document. Accordingly, I prefer to use the version I edited as 
in the attached e-mail which otherwise incorporates all the 
edits we have discussed. Thanks, Andy.'' Right?
    Mr. Mosholder. Yes.
    Ms. DeGette. And it is clear that you chose against the 
wishes of Ms. Katz and, I assume, the other lawyers to revise 
that document in such a way as to put the interest of 
Congressional committees on notice the document had been 
altered. Right?
    Mr. Mosholder. Well, that was my intent.
    Ms. DeGette. Right. Thank you very much, Mr. Chairman.
    Mr. Walden. The Chair recognizes the gentleman from 
Michigan, Mr. Stupak, for 10 minutes.
    Mr. Stupak. Thank you. Did you incur legal expenses while 
you were doing all these interviews with your Internal Affairs 
and all this?
    Mr. Mosholder. I did obtain legal representation. In point 
of fact, I have a Federal employee liability policy which 
provided for that. So my only expense was the insurance 
premium.
    Mr. Stupak. I can see an internal investigation on 
something about some newspaper leak or something, but sounds 
like here, and I think Ms. DeGette was being much too polite, 
you were being squeezed here to change your testimony. Correct?
    Mr. Mosholder. I'm not sure I would----
    Mr. Stupak. I was police officer for 12 years. I would have 
squeezed you and got it, too, you know. I mean, look, let me 
ask you this. Go to Tab 89.
    Mr. Mosholder. I'm sorry. Eighty?
    Mr. Stupak. Eighty-nine, please. It is a June 16 letter 
from Representative--I guess it is Senator Grassley to the FDA, 
and on the fourth page the letter states--it is on Tab 89. It 
says on page 4: ``Perhaps most troubling, however, was the fact 
that the OND attempted to have Dr. Mosholder present reporting 
rates of suicidal thoughts rather than the available clinical 
trials data on anti-depressants in children which form the 
foundation of his analysis.''
    Can you please clarify the difference between the reporting 
rates of suicidal thoughts and available clinical trials data? 
Which is more reliable and relevant?
    Mr. Mosholder. A reporting rate is a term we use when we 
have spontaneous reports obtained through the MedWatch program, 
and as the enumerator. Then that is divided by some measure of 
the number of prescriptions in the U.S.
    The problem with reporting rates is that it is usually 
assumed we only have only a small fraction of the number of 
events that are actually occurring in the population.
    Mr. Stupak. Well, clinical trial data is far more reliable 
than reporting rates. Right?
    Mr. Mosholder. That is correct. When----
    Mr. Stupak. And isn't it true that you were asked to 
present the reporting rates instead of the clinical trial rates 
or clinical trial data?
    Mr. Mosholder. You could put it that way. That is true, 
yes.
    Mr. Stupak. Okay. Then why did you choose not to present 
the reporting rates instead of your clinical trials data?
    Mr. Mosholder. Well, this was an issue we had considerable 
internal discussions about in preparation for the February 2 
meeting. Ultimately, we in the Office of Drug Safety felt that, 
given that suicidal behaviors are part of the reason why the 
patients would be receiving the drug in the first place, giving 
a rate of such events really is not very useful information, 
and that the better data is done from trials where there could 
be comparisons.
    Mr. Stupak. So the better data is from the clinical trials 
data, and they were requesting, pressuring you--whatever word 
you want to use--to use the reporting rates and not the 
clinical trials data. OND asked you to present reporting rates 
instead of the clinical trials data. They wanted you to soften 
your conclusions.
    Mr. Mosholder. Well, at that point I was not presenting the 
clinical trials data at all.
    Mr. Stupak. But it was in your paper, your affidavit, if 
you will. So you had it. Correct?
    Mr. Mosholder. In my presentation to the Advisory Committee 
February 2 I presented simply a number of reports, as I recall, 
without the reporting rates in the end.
    Mr. Stupak. Right, but you used clinical trials data, 
because it is more reliable.
    Mr. Mosholder. Yes. My opinion is that is better data. Yes.
    Mr. Stupak. And OND wanted you to use reporting rates 
instead of clinical trials data. Correct?
    Mr. Mosholder. That is correct that they asked for that.
    Mr. Stupak. Correct. And the reason for that is it softens 
your conclusions that you put down in this paper, the 
affidavit. Isn't that correct?
    Mr. Mosholder. I'm not----
    Mr. Stupak. Let me put it this way. The numbers look better 
if you use reporting rates as opposed to the more reliable 
clinical trials data. Isn't that correct?
    Mr. Mosholder. My own opinion--well, that was a concern of 
the Finance Committee investigator. My own opinion is that the 
reporting rates simply are not informative. You can interpret 
it as an attempt to--I wouldn't go----
    Mr. Stupak. I'm not trying to put words here, but look it, 
we established that the clinical trials data is more reliable 
than the reporting rates. You were asked to change your 
clinical trial data to reporting rates, which is not as 
reliable. The reason to do that is then your affidavit, your 
conclusions are not as firm and solid. It is a softening of 
your conclusions, is it not? Softening is my word, not yours.
    Mr. Mosholder. Well, I would say that the reporting rates 
are inconclusive. There are no conclusions that you can draw 
from reporting rates, in my opinion. So----
    Mr. Stupak. Then why would OND want you to use reporting 
rates, if they are not as solid, not as reliable?
    Mr. Mosholder. Well, again there was difference of opinion 
about that. My understanding was that it was for completeness, 
because ordinarily this had been done and----
    Mr. Stupak. How do you get completeness if you don't use 
the most reliable data?
    Mr. Mosholder. Well, that was----
    Mr. Stupak. Completeness is the conclusion that one wishes 
to draw from the report that you did, completeness in the eye 
of the beholder. Right?
    Mr. Mosholder. Well, my own preference would have been to 
present the clinical trial data. Yes.
    Mr. Stupak. Correct. Okay. Reporting rates--to your 
knowledge, how many other instances were reporting rates 
provided when more reliable data was available? Is this a 
common thing? You medical officers do your reports. You look at 
the most reliable evidence, which may be your clinical trials 
data, and then you are told, well, geez, don't use that, let's 
look at the reporting rates, and let's use reporting rates as 
opposed to clinical data? Does that occur fairly often at the 
FDA?
    Mr. Mosholder. Not that I can recall, for just those 
reasons, that situations where reporting rates are useful are 
for very rare events that wouldn't necessarily be part of the 
reason why the patient was receiving the drug. So that it----
    Mr. Stupak. Absolutely. I agree with 1000 percent. Clinical 
trial data is always better than reporting rates. My question 
is: In the past, to your knowledge, has the FDA pressured 
medical review officers who review the drugs and deal with the 
data all the time to change from clinical trial data to 
reporting rates?
    Mr. Mosholder. I am not aware of any comparable situations, 
personally.
    Mr. Stupak. Your statement you gave here today--did the FDA 
have to approve your statement you are giving here today before 
the committee, your written statement?
    Mr. Mosholder. No, they did not.
    Mr. Stupak. Okay. If we do this labeling, packaging 
labeling that was suggested in the Advisory Committee, will you 
be involved in that process?
    Mr. Mosholder. Not to my knowledge.
    Mr. Stupak. I think someone may have asked you this, but 
let me just clarify this.
    What is your impressions of Dr. Hammad's study?
    Mr. Mosholder. Well, I think the important point is that it 
is very consistent with the findings I had in my analysis.
    Mr. Stupak. That was my second question.
    Mr. Mosholder. You know, it lends strength to the finding.
    Mr. Stupak. So you would--Dr. Hammad's study is good work, 
and you would agree with it?
    Mr. Mosholder. Yes, and in many respects it is more 
sophisticated than my first crack at the data.
    Mr. Stupak. And it confirmed what your initial findings 
were? Dr. Hammad's report confirmed what your initial 
preliminary report showed. Correct?
    Mr. Mosholder. That is my--my own biased opinion is that it 
did confirm it, yes.
    Mr. Stupak. Someone, I think, asked you this one, too, on 
Tab 15 in which Dr. Avigan writes on your consult, ``Andy, 
great job.'' If Dr. Avigan thought you did a great job with 
your analysis, why did he later issue a dissenting memo to your 
consult? It is in Tab 15.
    Mr. Mosholder. Yes. I believe Dr. Avigan did not feel that 
the data were ready to make the--or was sufficiently conclusive 
to make the recommendations that I made in my consult.
    Mr. Stupak. So you went from great job to being 
inconclusive?
    Mr. Mosholder. Well, to be fair, he did say that--at the 
time of the first draft, I remember him telling me that we 
would have to think about the recommendations some, but in the 
end he felt that the data were not persuasive enough to endorse 
my recommendations.
    Mr. Stupak. Thank you, Mr. Chairman.
    Mr. Walden. Thank you. Dr. Mosholder, I want to refer you 
to Tab 78, if you would, sir, and go to--this is a memo. You 
were the medical officer on review and evaluation of clinical 
data. It is dated 12/13/96, received 12/16/1996, to Sulvay 
Pharmaceuticals regarding Luvoxamine maleate.
    Mr. Mosholder. Maleate, yes.
    Mr. Walden. Thank you.
    Mr. Mosholder. Or Luvox.
    Mr. Walden. Thank you. That is even easier. I want to refer 
you, though, to the second page, and it says: ``it's of 
interest that in the adult studies the incidence of agitation 
was 2 percent and 1 percent for fluoxomine and placebo, 
respectively, while the pediatric study, the corresponding 
incidences were 12 percent and 3 percent. That is, the risk 
ratio for adults was two and for children was four. It is 
possible this reflects a real difference in adverse reactions 
between adults and children. There is an emerging literature 
pointing to behavioral reactions to SSRI drugs in children.'' 
Then you make some references there or some references are made 
here. ``It may be that this is a reaction to SSRIs that is more 
prominent in children than adults. Further data would help 
clarify this.''
    Now I think what is interesting about this, this is a 
December 1996 memo. The review was completed in February 1997. 
Was this a flag you were raising in 1997?
    Mr. Mosholder. Well, as I said, this was one of the very 
first pediatric clinical trials we had seen with this class of 
drugs, and although there had been some other reports, 
apparently--I don't recall that reference at this point, but it 
seemed to be raising the question of whether the behavioral 
adverse effects might be different for kids versus adults.
    Mr. Walden. Right. And you also said this is also reflected 
in Pfizer's recently submitted study of Certraline in the 
treatment of juvenile OCD as well in that reference. I guess 
the reason I asked is it looks like from this documentation, 
perhaps others, that this was sort of coming up as an issue 
back in 1996-1997.
    I wonder, as we go into these pediatric clinical trials, 
could they have been designed better to go look at this issue 
of suicidality in children and adolescents? Should we have 
picked up on that sooner?
    Mr. Mosholder. Well, that is a good question. Historically, 
these two, as I recall, were the first actual studies we had 
with this class of drugs in kids. So it suggests that a pattern 
was starting to emerge. We, of course, didn't get more data 
until several years later, but the----
    Mr. Walden. But should the FDA have sought more data in the 
way they designed the clinical trials for children?
    Mr. Mosholder. Well, the question being, as we were writing 
the request for pediatric studies, part of the pediatric 
exclusivity, could we have done more to get at this issue. 
Well----
    Mr. Walden. In retrospect.
    Mr. Mosholder. Yes, in retrospect, you know, perhaps more 
attention could have been given to that. On the other hand, 
these trials had done nothing special to look for this type of 
event, and it seemed to be turning up. So that would be on the 
side of saying routine adverse event monitoring was sufficient 
to turn up this possibility.
    Mr. Walden. Were you aware that apparently Dr. Knudsen also 
had some warnings that go back to 1996?
    Mr. Mosholder. I recall the----
    Mr. Walden. For Zoloft.
    Mr. Mosholder. [continuing] something about that at the 
time. Then, of course, in preparation for this hearing I've 
been reminded of that. Yes.
    Mr. Walden. I guess that the question we keep going back to 
is: Should this signal have been spotted sooner?
    Mr. Mosholder. Well----
    Mr. Walden. Because it raises the issue, are there other 
signals that are bouncing around out there on other drugs being 
prescribed off-label for people that we are not catching. How 
do we fix the system, I guess, is part of it. Should we have 
spotted this one sooner? Should FDA?
    Mr. Mosholder. Well, one always wants to spot a problem as 
soon as possible, of course. The issue here, I think, at least 
in my own mind, was that we were lacking clinical trials in 
children until the past few years, that the Luvox and Zoloft 
studies were really sort of on the forefront of that, and so it 
was more just a plain lack of data rather than lack of any 
specific attention to it.
    Mr. Walden. Okay. And I guess--but if we designed trials 
right, you would have the data. You would have had the data. 
Right?
    Mr. Mosholder. And in fact, that is what we have currently.
    Mr. Walden. And I guess what I also want to make sure of is 
that, when we do have the data and they are evaluated by people 
of your credibility, that those data then are applied 
appropriately and the results are put out there appropriately.
    I am troubled by an article that appeared in the August 7, 
2004, British Medical Journal, and it states that Dr. Thomas 
Laughren reported the relative risk ratios of all the anti-
depressants evaluated at the Pediatric Drug Advisory Committee 
meeting, and that it was--``it was Dr. Mosholder's conclusions 
and not the data that were withheld.''
    Do you agree with Dr. Laughren's reported 
characterizations?
    Mr. Mosholder. Is this what was----
    Mr. Walden. This is the article. He also says--you will see 
in the second graph on this particular page--I'm sorry, second 
column, the last paragraph on the page, both the raw data and 
Dr. Mosholder's interpretation ``were imperfect,'' said Dr. 
Temple, adding that some of the behaviors labeled suicidal were 
highly suspect and could have been accidents, such as a child 
``who hit her head with her hand.'' FDA officials acknowledged, 
however, that some cases classified as accidental injury could 
be suicide related. Because of this, they have gone on then to 
Columbia University.
    That is why I raise that issue about whether or not your 
study included the incident of the girl slapping her head, 
because it didn't include that, did it?
    Mr. Mosholder. I included it in one analysis but not the 
result that I----
    Mr. Walden. But not in the results, not in your 
conclusions.
    Mr. Mosholder. Yes.
    Mr. Walden. And so why would then Dr. Temple tell this, 
allegedly, I suppose--it is printed here--say that that may be 
part of the problem here, that it is imperfect. Did you think 
your conclusions were imperfect?
    Mr. Mosholder. Well, I'm not sure I can give an unbiased 
answer to that. I think there was----
    Mr. Walden. Well, do you think--let me ask this. Do you 
think his characterization of your consult is correct?
    Mr. Mosholder. I think we have had some--perhaps some 
communications issues where I am not sure that it was--I 
perhaps could have done more to make it obvious that I was 
trying to get away from the question of the clinically trivial 
events, if you will, such as the slapping in the face.
    Mr. Walden. And I know we are putting you in a tough spot 
here with some of these folks that are, you know, your 
superiors sitting right behind you. I mean, I don't envy that 
position. Trust me. But these are critically important issues 
we have to get to.
    Was your data analysis fully and fairly presented at the 
February 2004 Advisory Committee meeting and, if not, what 
should have been presented? What was presented, first of all, 
since you didn't do the presentation?
    Mr. Mosholder. As far as the clinical trial data, Dr. 
Laughren gave the presentation of that.
    Mr. Walden. Was it full and fair?
    Mr. Mosholder. It did not include all of the results or 
data that I had in my draft presentation.
    Mr. Walden. I guess the point is did it include the most 
important recommendations?
    Mr. Mosholder. Well, it didn't include--well, apart from 
the recommendations, the data I think that I would have 
included--let me put it that way--would----
    Mr. Walden. If you had been there presenting it, what would 
you have included that wasn't included?
    Mr. Mosholder. I would have included the analysis of the 
serious subgroup of suicidal events and the meta analysis where 
the data was combined across studies. I think that--if I were 
doing or if I had a chance to do the presentation, that is what 
I would have included.
    Mr. Walden. So the way you would have presented it would 
have painted a much more serious situation to that Advisory 
Committee than the way it was painted, when it comes to the 
risk of suicidality in adolescents and children? Is that 
accurate?
    Mr. Mosholder. I guess we will never know what the Advisory 
Committee might have made of----
    Mr. Walden. No, no, no. The difference in the two 
presentations.
    Mr. Mosholder. I think, if I had been doing it, it would 
have perhaps been more obvious.
    Mr. Walden. The chairman at the outset of this hearing 
thanked you on behalf of the committee for your work, and I 
think our country feels the same way. I know you have been 
honored many ways.
    Somebody told me you had been selected, too, to be the ABC 
Person of the Week. Is there any truth to that?
    Mr. Mosholder. I was told that I was nominated, but I did 
not run.
    Mr. Walden. Well, there is always next week, I guess.
    All right. We are going to add, without objection, this 
newspaper article from the British Medical Journal, August 7, 
2004, to the record. Without objection, so ordered.
    [The newspaper article follows:]
    [GRAPHIC] [TIFF OMITTED] T6099.011
    
    Mr. Walden. Do you have further questions? We have been 
called to votes on the House floor, and it would--Mr. Stupak, 
do you have anymore questions for this witness at this time?
    Mr. Stupak. No. I just thank Dr. Mosholder for being here.
    Mr. Walden. Thank you. And, Dr. Mosholder, we would like 
you to stay with us, even though we probably won't have you on 
the next panel. We would like to have you available, should 
there be some questions that we need to seek your expert advice 
on. So if you could stay with us.
    We are going to recess the committee until after these 
votes. There are four of them, which probably tells me it will 
be 45 minutes before we are back here. So it is a good time for 
everyone to go grab a quick bite, and we will reconvene the 
committee immediately after those votes have concluded.
    The committee is in recess.
    [Brief recess.]
    Mr. Walden. I am going to call this hearing back to order 
and ask our next panel of witnesses to come up: Dr. Robert 
Temple, Food and Drug Administration; Dr. Paul Seligman, Food 
and Drug Administration; Dr. Thomas Laughren, Food and Drug 
Administration; Dr. Tarek Hammad, Food and Drug Administration; 
and Dr. James Knudsen, Food and Drug Administration. Please 
come up to the witness table, if you would.
    You are aware the committee is holding an investigative 
hearing and, when doing so, has the practice of taking 
testimony under oath. Do you have any objection to testifying 
under oath? Do any of you have an objection?
    Let the record show they all indicated they have no 
objection.
    The Chair then advises you that, under the rules of the 
House and the rules of the committee, you are entitled to be 
advised by counsel. Do you desire to be advised by counsel 
during your testimony today? Mr. Knudsen? Could you turn on 
your mike, sir, and then we will need you to identify your 
counsel. Dr. Knudsen.
    Mr. Knudsen. My name is Dr. James Knudsen.
    Mr. Walden. Okay. Yes, you actually have to get kind of 
close to that. Sorry. If you could identify for the record, Dr. 
Knudsen, your counsel, please.
    Mr. Knudsen. My counsel?
    Mr. Walden. Oh, I thought you said you wanted to be 
represented by counsel.
    Mr. Knudsen. No, I did not.
    Mr. Walden. Okay, fine. No? Okay. Dr. Temple? Dr. Laughren?
    Mr. Laughren. No, sir.
    Mr. Walden. Dr. Seligman?
    Mr. Seligman. No.
    Mr. Walden. Okay. So let the record show, none of them is 
being represented by counsel.
    In that case then, would you please rise and raise your 
right hand, and we will take your testimony under oath. Let the 
record show, they all indicated yes.
    [Witnesses sworn.]
    Mr. Walden. Thank you. You may be seated.
    You are now under oath, and you may now give a 5-minute 
summary of your written statement, and we will start with Dr. 
Knudsen.
    Mr. Walden. Dr. Hammad? No opening statement. Dr. Temple? 
Actually, I am not sure your mike is on yet.
    Mr. Temple. Now?
    Mr. Walden. There it is, sir, yes. Thank you, and welcome.

   TESTIMONY OF JAMES KNUDSEN, FOOD AND DRUG ADMINISTRATION; 
  ACCOMPANIED BY ROBERT TEMPLE, FOOD AND DRUG ADMINISTRATION; 
 PAUL SELIGMAN, FOOD AND DRUG ADMINISTRATION; THOMAS LAUGHREN, 
 FOOD AND DRUG ADMINISTRATION; AND TAREK HAMMAD, FOOD AND DRUG 
                         ADMINISTRATION

    Mr. Temple. Mr. Co-Chairman, I guess, and members of the 
committee, I am Robert Temple, CDER's Associate Director for 
Medical Policy. I welcome the opportunity to participate in 
this hearing on FDA's regulation of pediatric uses of anti-
depressants.
    My colleagues and I recognize that the entire discussion of 
the past year has been very painful and difficult for people--
both for people whose loved ones have committed suicide while 
on an anti-depressant and for people whose family members are 
seriously depressed and are uncertain as to what they can do 
for them.
    Today I will briefly review the importance of detecting and 
treating depression in children, the available treatments and 
recent efforts to encourage studies of drugs in children, the 
history of the concern, the subject of this hearing, about the 
possibility that anti-depressants might provoke suicidal 
thinking or behavior, and FDA's evaluation and data--of the 
data from the pediatric depression studies.
    Throughout my testimony and later, I will want to emphasize 
an important concern that we had from the beginning of this. We 
were concerned that overemphasis or premature conclusion about 
an increased risk of suicidality related to anti-depressant use 
could discourage treatment of serious pediatric depression, 
which is a potentially life threatening condition.
    At the same time, failure to take adequate note of the risk 
could lead to inattention to the possibility for emerging 
suicidality or to too casual use of the anti-depressants.
    We dealt with this concern by making the public fully aware 
of the issue and of the data that led to our concern, but we 
thought it was responsible to withhold an agency conclusion 
about what the data showed until it had been fully evaluated.
    Depression in children is a serious mental illness that 
affects up to 2.5 percent of children and 8 percent of 
teenagers. In the U.S. there are about 1600 suicides in 
teenagers per year, many of them in people who are diagnosed as 
having depression.
    The difficulty of obtaining good data on the effectiveness 
and safety in drugs in children is well recognized. A provision 
of the Food and Drug Administration Modernization Act which was 
renewed in the Best Pharmaceuticals for Children Act in 2002 
provides 6 months of patent extension to sponsors who carry out 
pediatric studies that have been requested by the FDA.
    This provision has enormously stimulated the conduct of 
these studies, and it was FDA's analysis of the depression 
studies submitted under these laws that led to the question of 
whether the drugs could cause suicidality in children.
    Specifically, review by Dr. Mosholder of adverse effects 
collected under the term emotional lability in five Paxil 
studies that were submitted under the Act detected an excess of 
such cases, some of which appeared to represent suicidal 
thinking or behavior in patients.
    I can't emphasize too strongly that, although as you will 
hear there were some disagreements on our part with some of Dr. 
Mosholder's conclusions or whether they were right, this 
discovery, this observation was of immense value and has kicked 
this whole thing off. So let there be no question about whether 
that was an important observation.
    A request for a more focused analysis of the Paxil 
suicidality data led to a further suggestion of an increased 
rate of suicidality in the Paxil treated patients, and this was 
more credible because the analysis was better than their 
initial one.
    FDA issued a Public Health Advisory on June 19, 2003, 
describing the results of the Paxil evaluation and stating 
that, although FDA had not completed its evaluation, we 
recommended that Paxil not be used in children and adolescents 
to treat major depressive disorder.
    Subsequently, the Review Division asked all manufacturers 
of newer anti-depressants for an analysis that was similar to 
what GlaxoSmithKline had done for Paxil, and this was provided 
by late September 2003. These reports were sent to Dr. 
Mosholder and were also considered by the Review Division.
    On October 27, 2003, FDA issued an updated Public Health 
Advisory, again noting the suggestion of excess suicidality in 
anti-depressant treated patients and the need for further data 
and analysis.
    The Review Division had been examining the data submitted 
by the sponsors, too, as had Dr. Mosholder, and had significant 
concerns about it. It, therefore, began in September-October 
2003 to make arrangements to have the reported suicidality 
events reviewed and reclassified by the Columbia Department of 
Psychiatry.
    Our concern was that the companies had cast a wide net in 
seeking cases of suicidality, of suicidal thinking or instances 
of self-harm, but not all such cases--for example, a 
superficial cutting--represent attempted suicide.
    I also want to say that I am somewhat embarrassed about my 
BMJ quote from before, because at least by the time that came 
out, I was well aware that Dr. Mosholder had excluded cases 
like that. I think that reflected an earlier conversation. So 
there is no question that he did exclude many such things, and 
the banging of the head. So I feel bad about that. However, 
remained concerned that the cases themselves needed close 
evaluation, and I can talk later about how those data were 
collected and why we thought they needed that.
    Given our conclusion that they needed to be looked at 
closely, we concluded that a blind expert classification of the 
cases was needed.
    In addition, we sent the Columbia reviewers narrative 
descriptions of additional adverse reaction cases that had not 
been included by the companies, because we thought there might 
be excess--might be cases of suicidal behavior or thinking in 
there, and that proved to be correct.
    It is worth emphasizing that we had no idea what the 
results of the reclassification would be. We didn't know 
whether it would strengthen the findings or weaken the 
findings. We had no way of knowing and no expectation, and not 
to state the obvious, no preference. We just wanted to get at 
what the right answer was.
    At a February 2, 2004, Advisory Committee meeting we 
presented the results of the company submissions, as you have 
heard before, study by study, in part to make the point that 
the results were very variable from one study to another, and 
from one drug to another. But many of the drugs clearly showed 
an increased risk of suicidality. That's the sum of suicidal 
behavior and suicidal thinking.
    We noted to the committee our concerns with the data 
submissions and explained why we considered additional review 
by Columbia necessary.
    We also acknowledged that some in the agency thought the 
results were, in fact, definitive and could be a basis for 
change in labeling to discourage use of the drug, except for 
Prozac, in children.
    Although no specific question was put about this to the 
committee, discussion indicated that they clearly understood 
the agency's reservations, and they in fact expressed doubt 
that anything arising from this kind of data collection would 
be useful, a conclusion that they modified at the most recent 
Advisory Committee.
    The Advisory Committee recognized that, whatever the 
relationship of anti-depressants to suicidality, it was 
perfectly clear even then that the period after initiation of 
treatment for depression was of great concern and that 
physicians needed to be warned about this, the need to be 
careful and make close observations.
    On March 22, we asked manufacturers of anti-depressants to 
add warning language to their labeling and issued a third 
Public Health Advisory describing our request. The new warning 
emphasized the critical importance of observing newly treated 
patients for emerging suicidality or other problems.
    All manufacturers added this warning to their labeling by 
late summer. We have no received the reclassified cases from 
Columbia and analyzed the data.
    The analysis by Dr. Hammad was presented to the Advisory 
Committee on September 13, 2004. The analysis included the 
study you have heard about, the TAD study, a new study of 
Prozac carried out by the National Institutes of Mental Health.
    The analysis showed that, as a group, the anti-depressants 
studied, both SSRIs and the so called atypicals, increased the 
risk of suicidality. There was variation from drug to drug and 
variation from study to study, but the roughly twofold 
increased risk was reasonably consistent across drugs. As has 
been pointed out, there were no actual suicides in these 
trials.
    At the September 13-14 Advisory Committee meeting, the 
combined Pediatric and Psychopharm Drugs Advisory Committees 
agreed with FDA's conclusions that the data in aggregate 
indicated an increased risk of suicidality in pediatric 
patients, and made several critical recommendations.
    First, they believed the conclusion should apply to all of 
the studied drugs, even though it was more prominent in some 
than others. They also strongly urged that we apply it to any 
new anti-depressant and to the older anti-depressants, 
including the tricyclics. They thought that partly because the 
logic seemed to be that this is a property of anti-depressants, 
and they were quite concerned that people would be driven to 
the tricyclics, which are rather more dangerous.
    They did not believe the anti-depressants, other than 
fluoxetine,should be contraindicated in children, and 
repeatedly expressed concern that these drugs may be valuable 
even if that has not been shown, and they were quite aware that 
it had not yet been shown.
    They strongly supported a patient and family directed Med 
Guide which we had suggested to them, and two-thirds of them 
thought the new warning information should be boxed.
    On September 17 we announced publicly that we generally 
support the recommendations and had begun working on new 
labeling to reflect that. The term generally applies only to 
the thought that we are going to read closely what they said 
collectively about the boxed warning, and think about it.
    Obviously, two-thirds of them thought that was reasonable, 
but the discussion indicated concern that over-discouraging use 
was potentially very dangerous, too, and they wanted a balance. 
So we are going to be thinking about that.
    I appreciate the opportunity to present these remarks, and 
I look forward to your questions.
    I am aware that you have also invited Dr. Russell Katz to 
appear here this morning. Unfortunately, he is not able to 
attend because a member of his family is having surgery today. 
He will be happy to answer any questions you have for him in 
writing or speak with your staff at a later date. Thank you.
    Mr. Walden. We appreciate that, Dr. Temple. We were aware 
of that, obviously, too, and did not want to interfere in his 
very difficult time.
    [The prepared statement of Robert Temple follows:]
   Prepared Statement of Robert Temple, Director, Office of Medical 
  Policy, Center for Drug Evaluation and Research, U.S. Food and Drug 
                             Administration
                              introduction
    Mr. Chairman and Members of the Subcommittee, I am Dr. Robert 
Temple, Director, Office of Medical Policy for the Center for Drug 
Evaluation and Research (CDER) at the U.S. Food and Drug Administration 
(FDA or the Agency). We appreciate the opportunity to discuss FDA's 
review of the safety and efficacy concerns in anti-depressant drugs for 
use in pediatric populations.
                        background on depression
    Depression is a serious mental illness that affects the way nearly 
19 million adult Americans feel, think, and interact. While everyone 
experiences occasional sadness, particularly in response to loss or 
adversity, a person with depression has persistent symptoms that can 
significantly interfere with their ability to function. People with 
depression cannot merely ``pull themselves together'' and get better. 
Depression cannot be willed or wished away.
    The two most severe types of clinical depression are major 
depressive disorder (MDD) and bipolar depression, which is the 
depressed phase of bipolar disorder. Within these types, patients 
experience variations in the severity and persistence of mental 
symptoms associated with these disorders. A person experiencing MDD 
suffers from, among other symptoms, a depressed mood or loss of 
interest in normal activities that lasts most of the day and nearly 
every day, for at least two weeks. Such episodes may occur only once, 
but more commonly occur several times in a lifetime. People with 
bipolar disorder cycle between episodes of major depression, similar to 
those seen in MDD, and highs known as mania. In a manic phase, a person 
might act on delusional grand schemes that could range from unwise 
business decisions to romantic sprees. Both MDD and bipolar disorder 
can lead to suicide. The treatment of the two conditions is quite 
different. In general, anti-depressants alone are not an appropriate 
treatment for bipolar disorder.
           depression in the pediatric/adolescent population
    According to a 2000 National Institute of Mental Health (NIMH) Fact 
Sheet on Depression in Children and Adolescents, depression affects up 
to 2.5 percent of children and about eight percent of adolescents in 
the United States. These disorders often go unrecognized by families 
and physicians because behaviors associated with depressive disorders 
may be seen as normal mood swings typical of a particular developmental 
stage. In addition, health care providers may be reluctant to 
prematurely ``label'' a young person with a mental illness diagnosis.
    At the February 2, 2004, meeting of FDA's Psychopharmacologic Drugs 
Advisory Committee (PDAC), Dr. Cynthia Pfeffer of Cornell University 
addressed the issue of pediatric depression and its treatment. She 
noted that pediatric depression is very common and often recurrent, is 
often accompanied by very poor psychosocial outcomes for children and 
adolescents, and is associated with high risk for suicide and substance 
abuse. She reported that in 2001, about 1,600 15 to 19-year-olds 
committed suicide in the U.S. Suicide is the third leading cause of 
death in the U.S. in this age group and accounts for more deaths in 
this age group than all other major physical conditions combined.
    At that meeting, Dr. David Shaffer of Colombia University reported 
on rates of suicidal ideation (thinking about suicide) and suicide 
attempts. He obtained his information from large community studies, 
particularly the Youth Risk Behavior Study (YRBS), a study carried out 
by the National Center for Health Statistics. In this study, officials 
from the National Center interviewed a broad population of between 
15,000 and 20,000 high school students every two years using self-
reporting measures. Based on this data, it was determined that suicidal 
ideation in high school students is extraordinarily common. Almost 20 
percent of American high school students think about suicide. Suicide 
attempts are also very common. Experts report that the overall rate is 
about nine percent. Only about a quarter of these attempts are brought 
to medical attention. It is widely recognized that adolescents are 
frequently reluctant to disclose suicidal thoughts or even suicide 
attempts to parents or others. There are about 4,000 female suicide 
attempts for every female suicide death, and about 400 male attempts 
for every male death.
    Dr. Shaffer also showed rates of pediatric suicide over several 
decades. The rate has fallen by about 25 percent over the last decade, 
the period in which the use of anti-depressants has grown steadily. 
This association does not prove that the increasing use of anti-
depressants is the cause of the decline in suicide, but it is at least 
suggestive.
                     drugs for treating depression
    Existing anti-depressant drugs influence the levels of one or both 
of two neurotransmitters in the brain: serotonin and norepinephrine. 
Older medications--tricyclic anti-depressants (TCAs) and monoamine 
oxidase inhibitors (MAOs)--affect the activity of both of these 
neurotransmitters. The disadvantage of the older medications is that 
they can be difficult to tolerate due to significant side effects. MAO 
use may also be subject to dietary and medication restrictions. TCAs 
and MAOs are of limited value in the pediatric population because of 
serious, potentially life-threatening adverse events. These include 
tachycardia, convulsions, and shock-like coma. Moreover, TCAs are a 
potential tool for adolescents attempting to commit suicide because 
overdose can cause serious and protracted cardiac arrhythmias.
    Newer medications, such as the selective serotonin reuptake 
inhibitors (SSRIs), have fewer side effects than the older drugs, 
making it easier for people to continue treatment. They have become 
very widely used to treat depression, especially in the pediatric 
population. FDA approved Prozac, the first SSRI, for adults, in 
December 1987, and for children in January 2003. Experts believe that 
SSRI drug products work by increasing the level of the hormone 
serotonin in the brain. There were no approved drugs for the treatment 
of depression in children before the January 2003 Prozac approval.
               anti-depressant treatment and suicidality
    Suicidality in the context of treating patients with depression and 
other psychiatric illnesses has been a genuine concern and a 
longstanding topic of debate. In fact, for many decades, anti-
depressant labeling carried the following standard language under the 
``Precautions'' section of the label alerting clinicians to the need to 
closely monitor patients during initial drug therapy due to concern for 
the possible emergence of suicidality:
          Suicide: The possibility of a suicide attempt is inherent in 
        major depressive disorder and may persist until significant 
        remission occurs. Close supervision of high-risk patients 
        should accompany initial drug therapy. Prescriptions for [name 
        of drug] should be written for the smallest quantity of tablets 
        consistent with good patient management, in order to reduce the 
        risk of overdose.
    This standard precaution statement did not explicitly warn of the 
possibility that anti-depressant drug products have a causal role in 
the emergence of suicidality early in treatment. Several mechanisms 
have been proposed to explain the clinical observation that some 
depressed patients being treated with anti-depressants, particularly 
early in treatment, have an increase in suicidality. In September 1991, 
FDA convened a meeting of the PDAC to discuss this issue. At that 
meeting, Dr. Martin Teicher, a psychiatrist from Harvard Medical 
School, proposed various mechanisms to explain the emergence of 
suicidality early in treatment of depression:

 Roll back phenomenon: anti-depressants with prominent energizing 
        effects might actually increase suicidal behavior in severely 
        depressed patients who are suicidal but also have psychomotor 
        retardation and are thus inhibited from acting on their 
        suicidal thoughts.
 Paradoxical worsening of depression: in rare cases, the patient's 
        depressed mood might actually worsen as a result of anti-
        depressant treatment.
 Akathisia (inability to sit still): some anti-depressants are 
        associated with akathisia, which might lead to suicidal 
        behavior in certain depressed patients.
 Induction of anxiety and panic attacks: some anti-depressants may 
        induce anxiety and panic attacks, and these might lead to 
        suicidal behavior in certain depressed patients.
 Stage shifts: anti-depressants may lead to switching the patient from 
        depression into mixed states in bipolar depressed patients, 
        possibly leading to suicidality.
 Insomnia: insomnia associated with certain anti-depressants might 
        lead to suicidal behavior in certain depressed patients.
    While all of these theories have some plausibility, it is difficult 
to know whether these mechanisms are real. In addition, proposing a 
mechanism is quite different from actually demonstrating that there is 
a causal association between anti-depressant use and suicidality. It 
might be possible to demonstrate that anti-depressants cause an 
increase in suicidality through randomized clinical trials, but these 
trials would need to be quite large because suicidality is not common. 
It might be possible to pool results of many trials, but if this 
involves results from studies of different drugs, the question remains 
whether some drugs could behave differently from others. Furthermore, 
assessing this risk in uncontrolled data is particularly difficult 
because depression itself causes suicidality. In any given case, one 
cannot usually distinguish whether the suicidality occurred because of 
the drug or despite it.
             anti-depressant-induced suicidality in adults
    Thus, the question of whether anti-depressants can provoke 
suicidality has been the subject of considerable discussion. With 
regard to the adult population, the debate intensified in 1990 when Dr. 
Teicher and several colleagues published a paper describing six adult 
patients with depression who, in their view, became suicidal because of 
treatment with Prozac. This paper and subsequent discussions led Eli 
Lilly, the manufacturer of Prozac, to conduct new analyses of data from 
their controlled trials for Prozac to look for suicidality. These 
events also led FDA to fully re-evaluate its spontaneous reports 
database to determine whether we could observe a signal of increased 
risk.
    During a September 1991 PDAC meeting, family members raised 
concerns about suicide by loved ones whose deaths they attributed to 
Prozac. Representatives from FDA, NIMH and Lilly also gave 
presentations. FDA gave an update on the very substantial number of 
spontaneous reports of suicidality in association with Prozac use, but 
also noted the marked increase in reporting following the publication 
of the Teicher paper and the publicity about the paper. A 
representative from NIMH gave their perspective on the issue, 
essentially making the case that depression is a serious disorder that 
itself is associated with suicidality, and arguing that the data 
available to date did not support the view that anti-depressants 
further increase the risks of suicidality in this population. Finally, 
Lilly presented the results of its analysis of data pooled over its 
extensive clinical trials, revealing no signal of increased suicidality 
in association with the use of Prozac. Following these presentations, a 
majority of the Advisory Committee members concluded that there was no 
clear evidence of an increased risk of suicidality in association with 
Prozac, and did not recommend any changes to Prozac labeling.
    Over the next several years, researchers accumulated additional 
data as new anti-depressant drugs came to market. All of these 
additional data related to the treatment of adults. In recent years, 
several groups have conducted pooled analyses of data on completed or 
attempted suicides from these studies in an effort to identify a 
possible signal of risk from active treatment. They have also searched 
for risk signals from patients assigned to a placebo group, since some 
have challenged the use of placebo controls in a disease with 
potentially serious outcomes. Arif Khan, a psychiatrist from the 
Northwest Clinical Research Center, and other researchers published a 
paper in 2000 based on adult data obtained from FDA reviews. Dr. Khan 
concluded that the risk of completed suicide was the same, regardless 
of treatment assignment. A similar study reached the same conclusion. 
FDA researchers also analyzed completed suicides in 234 randomized 
controlled depression trials of 20 anti-depressant drug products. Based 
on all our analyses to date of these data, we reached a similar 
conclusion: there does not appear to be an increased risk of completed 
suicide associated with assignment to either active drug or placebo in 
adults with MDD.
         anti-depressants and suicidality in pediatric patients
    Whether anti-depressant drug use causes suicidal thinking or 
behavior in pediatric patients (or adults) is a critically important 
question that we must answer in a careful, thoughtful manner. A 
premature conclusion or emphasis in either direction could have adverse 
consequences for those who are suffering from depression. Missing or 
understating a signal of increased risk of suicidality could result in 
greater reassurance than is warranted about the safety of these drugs, 
insufficient attention to the patients being treated, and perhaps too 
casual use of the drugs. On the other hand, overstating the risk could 
result in overly conservative use of these drugs or excluding their use 
for the pediatric population, and inadequate treatment of a potentially 
fatal condition. Below we discuss the origins of the concern that anti-
depressants could provoke suicidal ideation in children.
          use of anti-depressants in the pediatric population
    Many people have expressed concern about pediatric use of products 
approved for MDD in adults where clinical trials in children were 
negative. Prozac is the only product for which efficacy has been 
established sufficiently to meet FDA's standards for approval in the 
pediatric population. To date, clinical trials evaluating six other 
current generation anti-depressants approved for adults have not met 
FDA's standards for establishing efficacy in the child/adolescent 
population. Nevertheless, there is widespread belief among treating 
physicians that these products do in fact work and that the 
``negative'' results are in fact inconclusive. Negative trials are not 
necessarily informative in MDD trials because they may be an indication 
of inadequate trials rather than evidence of benefit.
    Because Prozac is the only product for which efficacy has been 
establish for treatment of pediatric/adolescent MDD, it is often the 
first product prescribed by a physician. However, in 30-40 percent of 
cases, Prozac does not work for the patient. In such cases, it is 
standard care for physicians to prescribe one of the other current 
generation anti-depressants approved for adults. The older medications, 
tricyclic anti-depressants (TCAs) and monoamine oxidase inhibitors 
(MAOIs), have not been approved for use in pediatric/adolescent 
population. Moreover, as noted previously, they are of limited value in 
the pediatric population because of serious, potentially life-
threatening adverse events. They may cause life-threatening arrhythmias 
in overdose or even at normal doses in individuals who are unable to 
efficiently metabolize these drugs.
        fdama and bpca stimulate new pediatric suicidality data
    The question of suicidality arose in the course of FDA's review of 
clinical trials of anti-depressants in children. When Congress enacted 
the FDA Modernization Act (FDAMA) in 1997, it provided incentives to 
manufacturers to conduct pediatric clinical trials. Section 111 of 
FDAMA authorized FDA to grant additional marketing exclusivity (known 
as pediatric exclusivity) to pharmaceutical manufacturers that conduct 
studies of their drugs in pediatric populations. To qualify for 
pediatric exclusivity, sponsors must conduct pediatric studies 
according to the terms of a Written Request from FDA and submit the 
results of those studies in a new drug application or supplement. 
Congress renewed this authority in 2002, in the Best Pharmaceuticals 
for Children Act (BPCA).
    BPCA contains important, new disclosure requirements. For studies 
other than those submitted under the BPCA, the Agency generally may not 
publicly disclose information contained in investigational new drug 
applications, unapproved new drug applications, or unapproved 
supplemental new drug applications. Only after a new drug application 
or supplemental new drug application is approved can the Agency make 
public certain summary information regarding the safety and 
effectiveness of the product for the approved indication. However, 
section 9 of BPCA regarding the dissemination of pediatric information 
gives the Agency additional disclosure authority and differs from FDA 
regulations that generally preclude the Agency from disclosing to the 
public information in an unapproved application. BPCA requires that, no 
later than 180 days after the submission of studies conducted in 
response to a Written Request, the Agency must publish a summary of 
FDA's medical and clinical pharmacology reviews of those studies. 
Moreover, we must publish this information regardless of whether the 
action taken on the pediatric application is an approval, approvable, 
or not-approvable action. Thus, although under FDAMA information on 
pediatric studies conducted in response to Written Requests is not 
available until after the supplemental application is approved, under 
BPCA, a summary of FDA's medical and clinical pharmacology reviews of 
pediatric studies, conducted in response to a Written Request issued 
under BPCA, is publicly available irrespective of the action taken on 
the application.
               bpca written requests for anti-depressants
    Prior to the enactment of BPCA, under the pediatric exclusivity 
authority of FDAMA, FDA issued seven Written Requests to manufacturers 
of drugs approved for the treatment of depression (Prozac, Zoloft, 
Remeron, Paxil, Celexa, Serzone, and Effexor). The sponsors of three of 
these drugs (Prozac, Zoloft, and Remeron) performed the studies and 
submitted the reports of their studies before FDAMA expired on January 
1, 2002 (and thus, before BPCA took effect). The manufacturers of two 
of these drugs, Prozac (which has been approved for the treatment of 
pediatric depression) and Zoloft (which was studied but not approved 
for the treatment of pediatric depression) received pediatric 
exclusivity for having conducted studies. The third sponsor, the 
manufacturer of Remeron, did not receive pediatric exclusivity. Under 
FDA's general disclosure provisions regarding the availability of data 
and information in approved applications, information on the approved 
pediatric use of Prozac is publicly available at: http://www.fda.gov/
cder/foi/nda/2003/18936s
064_Prozac.htm. Just as it has for other product approvals, FDA posted 
this information because we granted approval for Prozac for use in 
treating pediatric depression. The pediatric data for Zoloft and 
Remeron would not normally be available for public disclosure because 
their pediatric supplements have not yet been approved. However, FDA 
nonetheless asked the sponsors to allow us to make summaries of these 
studies public. The sponsors agreed to our request and summaries are 
now available on FDA's website at: http://www.fda.gov/cder/pediatric/
Summary
review.htm.
    Following enactment of BPCA in January 2002, FDA determined that 
the provisions of this new law should apply as broadly as possible to 
outstanding Written Requests for which studies had not yet been 
submitted. In a July 2002 letter, the Agency notified drug sponsors 
with outstanding Written Requests issued under FDAMA that FDA 
considered those Written Requests to be reissued under BPCA. In its 
July 2002 letter, FDA further advised manufacturers that any studies 
submitted in response to the reissued Written Requests would be subject 
to the terms of the BPCA, including, among other things, the provisions 
governing public availability of study summaries. However, the Written 
Requests for three anti-depressants (Paxil, Celexa, and Serzone) were 
not considered as reissued under BPCA in July 2002 because the 
manufacturers had already submitted their pediatric studies to the 
Agency before FDA issued its July 2002 letter (albeit after BPCA was 
enacted). Therefore, FDA considered the studies for Paxil, Celexa, and 
Serzone, to have been submitted under FDAMA; did not consider their 
Written Requests to be reissued, and did not apply the public 
disclosure provisions of BPCA to these studies. Nonetheless, the Agency 
has received permission from the sponsors of these drugs to post 
summaries of the safety and effectiveness reviews of their pediatric 
studies on FDA's website, and this information appears at: http://
www.fda.gov/cder/pediatric/Summaryreview.htm.
    Only one of the outstanding and reissued Written Requests under 
BPCA was for studies relating to the treatment of pediatric depression. 
This Written Request was for Effexor. FDA granted pediatric exclusivity 
for this product and posted the study summaries on the FDA Pediatric 
Summary Review website, according to the requirements of BPCA. No new 
Written Requests for anti-depressants have been issued since the 
passage of the BPCA.
    We want to emphasize that although these anti-depressants have all 
been shown to be effective in adults, in its Written Requests FDA asked 
manufacturers to conduct two pediatric studies because we knew from 
experience that it is very difficult to show the effectiveness of anti-
depressants in children. In all studies submitted in response to 
Written Requests, no completed suicides occurred in the trials. 
Nonetheless, FDA reviewers of these Written Requests identified a 
suicidality concern during the course of their review.
                  results of the paxil written request
    FDA has been reviewing the results of anti-depressant studies in 
children since June 2003 after an initial report on studies with 
paroxetine (tradename, Paxil) appeared to suggest an increased risk of 
suicidal thoughts and actions in the children given Paxil, compared to 
those given placebo. During the review of the supplemental new drug 
application submitted by GlaxoSmithKline (GSK) for the use of Paxil in 
children, FDA reviewers noted a greater number of adverse events coded 
under the term ``emotional lability'' in patients treated with Paxil 
compared to the placebo group. FDA reviewers in the Division of 
Neuropharmacological Drug Products (DNDP) of FDA's CDER noted this in 
some, but not all, of the Paxil studies. The reviewers also noted that 
the actual events coded under this term included suicidal thoughts and 
attempts as well as a wide range of other events.
    In an effort to better understand these events and to focus on 
suicidal thoughts or behavior, DNDP asked the sponsor to reanalyze its 
data and better characterize the adverse events identified under the 
term ``emotional lability.'' This FDA request resulted in additional 
work by GSK and a report on suicidality, submitted first to the UK 
(UK), and, shortly thereafter, to FDA.
            gsk approach to accumulating paxil summary data
    GSK's re-analysis of the Paxil data focused exclusively on placebo-
controlled trials (of which there were six). This has been FDA's focus 
as well. As noted earlier, in their original pediatric supplement, GSK 
classified adverse events suggestive of suicidality (as well as various 
other behavioral events) under the general term ``emotional lability.'' 
In response to our request for a separate approach to better identify 
events that suggested suicidality, GSK conducted searches to find 
events of potential interest. GSK's adverse event data was in an 
electronic file that allowed them to search for text strings that 
suggested suicidality, e.g. ``overdose,'' ``suic,'' ``hung,'' ``cut,'' 
etc. The company conducted a blind evaluation of all events detected by 
this text search to select those considered possibly suicide-related. A 
subset of these events that could represent self-harm was then 
classified by GSK as suicide attempts. GSK's examination of events was 
limited to those occurring within 30 days of the patient's last dose.
    GSK submitted its report to FDA on May 22, 2003. This report 
suggested an increased risk (Paxil vs. placebo) of various thoughts and 
behaviors coded as events considered ``possibly suicide related.'' In 
addition, there was a suggestion of increased risk for the subgroup of 
events that met the sponsor's criteria for ``suicide attempts.'' The 
signal for increased risk was clearest in 1 of the 3 trials involving 
pediatric patients with MDD.
    It is important to note that these analyses were difficult because 
investigators used a large variety of terms to describe what might have 
been suicidal behavior and provided variable amounts of detail when 
identifying these events. The standard assessments of depression used 
to evaluate effectiveness all had an item indicating suicidal thoughts, 
and an evaluation of these scales showed no increased suicidality 
compared to placebo. However, the trials were not designed to focus on 
the question of suicide risk with drug treatment. To address this 
concern, we plan to develop guidance for subsequent trials that will 
lead to a standard nomenclature and assessment by investigators.
 initial response to signal of increased risk of suicidality for paxil
    The reaction to the GSK report by the Medicines and Healthcare 
Regulatory Agency (MHRA) in the UK was to issue a public statement 
explicitly stating that Paxil ``should not be used in children and 
adolescents under the age of 18 years to treat depressive illness,'' 
and to institute a labeling change contraindicating Paxil in pediatric 
MDD.
    On June 6, 2003, Dr. Russell Katz, the director of DNDP, asked the 
Office of Drug Safety (ODS) to perform a consult review of the newly 
submitted GSK safety data.
    Dr. Katz requested that ODS assign Dr. Andrew Mosholder as the 
primary reviewer for the consult because Dr. Mosholder had previously 
been involved in reviewing data on the safety and efficacy of anti-
depressants and had generated the original request to GSK. On June 19, 
2003, FDA issued a public health advisory stating that: ``Although FDA 
has not completed its evaluation of the new safety data, FDA is 
recommending that Paxil not be used in children and adolescents for the 
treatment of [major depressive disorder].''
    FDA also requested data similar to that submitted by GSK from the 
manufacturers of eight other anti-depressant drugs that were studied in 
children. On July 22, 2003, the Agency sent requests for data to the 
manufacturers of the following drugs: Prozac, Zoloft, Luvox, Celexa, 
Wellbutrin, Effexor, Serzone, and Remeron. In those letters, we asked 
manufacturers to identify suicide-related events for their pediatric 
studies in a blinded manner using two search strategies. We modeled our 
request to these manufacturers on the approach used by GSK, and asked 
manufacturers to conduct an electronic search for text strings relevant 
to suicidality similar to the approach employed for Paxil. We also 
asked manufacturers to blindly search narrative summaries for any 
serious adverse events to identify additional instances of ``suicide-
related events.''
    fda re-review of data from pediatric supplements for other anti-
                              depressants
    While waiting for the various manufacturers of anti-depressants 
other than Paxil to respond, we went back to the adverse event data in 
the pediatric supplements for the other eight drugs to re-examine the 
question of suicidality. Our major question was whether there were 
other anti-depressants with possible signals of increased risk for 
suicidality, as was observed for Paxil.
    There were several limitations to this re-examination. First, the 
methods for detecting and coding events were not standard across these 
studies. Second, because we wanted to have categories similar to those 
used for the Paxil data for purposes of comparison across drug 
programs, we classified events described in the adverse event listings 
for these drug programs into two categories: ``possibly suicide-
related'' and ``suicide attempt.'' One obvious flaw in this approach 
was that FDA's reviewer was not blinded during this reclassification 
process. Nevertheless, we believed this re-examination of summary data 
might shed some light on the possibility of signals emerging from other 
anti-depressant programs. We discovered that there were signals of 
increased risk of suicidality for patients assigned to drugs other than 
Paxil. We also found that the findings were not consistent across the 
studies, even for individual drugs.
         august 2003 effexor labeling change and fda's response
    While we were beginning to receive responses to our requests for 
summary data from the sponsors for the other anti-depressants, Wyeth 
Pharmaceuticals, the manufacturer of Effexor and Effexor XR, decided to 
make labeling changes for its products to address reports of 
suicidality and hostility. Sponsors have the authority to make changes 
to strengthen labeling to address safety issues without prior FDA 
approval. This action was based on the company's re-analyses of data 
from the Effexor pediatric trials. The labeling change was the addition 
of a statement to the ``Usage in Children/Pediatric Use'' section in 
the ``Precautions'' section of the label to note increased reports of 
hostility and suicidality. This labeling change was accompanied by an 
August 22, 2003, ``Dear Health Care Professional'' letter noting the 
findings and noting that these products are not recommended for use in 
pediatric patients.
    In September 2003, the UK MHRA issued a regulatory response on 
Effexor similar to its response to the report on Paxil suicidality 
data. It issued a public statement advising prescribers against the use 
of Effexor for the treatment of pediatric MDD. This statement was 
accompanied by a labeling change to contraindicate the products for 
that pediatric indication. FDA did not take any specific regulatory 
action on Effexor because we viewed the data as preliminary. Like data 
for other anti-depressant drug products, it required a more detailed 
review.
            september 2003 fda internal regulatory briefing
    An important milestone in our consideration of the pediatric 
suicidality data was the September 16, 2003, internal briefing for 
upper level CDER management. This briefing occurred at a time when we 
only had a preliminary review of the summary data for Paxil and a crude 
internal re-analysis of suicidality data from the other pediatric 
supplements. We had not yet received and reviewed the requested new 
analyses from all the sponsors of pediatric drugs.
    There were several agreements reached at this meeting, including 
two that were of particular importance for our further plans to address 
this issue. We recognized that we had cast a very broad net to attempt 
to capture events of potential interest for possible suicidality. This 
was appropriate, but it meant that individual cases needed closer 
examination to determine what they actually represented. Our first 
conclusion was that it would be useful to try to have all events of 
potential interest blindly reclassified by outside experts in 
suicidality in order to have greater confidence in what the signals 
represented. This conclusion eventually led to the Columbia 
Classification Project, described in greater detail below. Second, 
because it was apparent that there was inconsistency in the signals of 
suicidality among the individual studies of the various drugs, we also 
concluded that it would be useful to attempt to obtain patient-level 
data sets for all of these trials. This would permit analyses that are 
more refined and allow adjustments for potentially important 
covariates. These agreements strongly influenced the subsequent course 
of our efforts to better understand these data.
 responses to fda's request for summary data for other anti-depressants
    The responses to FDA's request for summary data for all of the 
anti-depressants arrived by late September 2003. These responses were 
received within DNDP and forwarded to Dr. Mosholder in ODS as they 
arrived, over roughly a six-week period. Unfortunately, as we began 
reviewing these responses, it became clear that different sponsors had 
interpreted the July 22, 2003, request differently. This caused us to 
doubt whether all eight manufacturers used similar approaches in 
selecting, classifying, and presenting cases of suicidality for review. 
There was also a concern, due to the methods used by the manufacturers 
to search their database, about the possibility that manufacturers had 
not captured all adverse events of potential interest.
    This impression was confirmed when we spoke to individual 
manufacturers about their approach to our request. In retrospect, the 
algorithm we had provided to search for potential events and select 
patients experiencing those events was not sufficiently detailed to 
result in a common understanding. This discovery presented a major 
hurdle in our evaluation of these data, because we needed to have 
confidence in the thoroughness and uniformity of the methods used to 
gather and classify these cases. We realized that we would need to be 
more certain that manufacturers captured all relevant cases, and that 
the relevant cases were appropriately classified.
    Greater certainty on this point was necessary to accurately assess 
the ability of these drugs to provoke suicidality. For example, we did 
not receive complete descriptions of how manufacturers conducted 
searches or why manufacturers included or excluded individual cases. In 
at least one case, the search for and classification of cases was not 
conducted in a blind manner to avoid bias. In another case, what 
appeared to be a strong signal in our preliminary analysis of the 
previously submitted data became a weak signal on re-analysis by the 
manufacturer. In all, we concluded that we needed to better understand 
the classification and analysis process.
         fda decision on independent reclassification of cases
    FDA also was concerned about case definition and selection by 
manufacturers in response to our July 22, 2003, letters. We noted 
substantial differences across different drug products in the selection 
of cases included as suicide attempts. Some sponsors decided to include 
essentially all captured events as suicide attempts, even though there 
was clearly not enough information in some of the cases to justify such 
a classification.
    For example, there was concern about a number of the adverse events 
classified under the category ``possibly suicide related.'' In one 
case, a young girl slapped herself on the face and researchers coded 
this as a suicide attempt. A number of other events coded as ``suicide 
attempts'' involved children who had engaged in superficial cutting 
behavior and children who had ingested small numbers of pills in sight 
of parents. Such events, while of concern in their own right, would not 
necessarily be an indication of suicidal behavior.
    This confirmed the view reached tentatively at our September 2003 
internal regulatory briefing of the need to have potential events 
blindly reclassified by an independent group. Although we briefly 
considered doing this internally, we rejected this idea because FDA did 
not have the expertise in suicidality to conduct such a large 
reclassification effort. Furthermore, most employees who might 
logically participate in such an effort had already seen many of the 
cases. These reviewers could also be biased because they were aware of 
the treatment assignment (drug or placebo).
       further requests for data/initiate the ``columbia'' study
    Thus, we began to look outside the Agency and initiated a series of 
discussions with outside experts. Although we found several experts 
interested in such an effort, there remained the problem of who could 
coordinate this work and establish methods and criteria for 
reclassification.
    Columbia University not only had well-recognized expertise in 
adolescent suicidality, but also had developed an approach to 
classifying events that possibly were representative of suicidality, 
and this approach precisely fit our needs. We conducted extensive 
discussions with this group in order to establish a contract to 
accomplish this reclassification of cases and to work out the details 
of a standard approach to finding all relevant cases and setting up 
categories for the reclassification effort that would meet our needs.
    Additionally, as we reviewed the summary data provided by the 
various sponsors in response to our July 22, 2003, letters, we again 
noted an inconsistency in results across trials, even within individual 
programs, that we had observed in our re-review of the pediatric 
supplements. To further address this issue, on October 3, 2003, DNDP 
requested patient-level data sets from all manufacturers of the nine 
anti-depressant drugs. The availability of these more detailed data has 
permitted FDA to perform a more refined analysis, taking into 
consideration possible imbalances across study groups in these trials. 
In order to ensure that we had a complete capture of all relevant 
events that might possibly be related to suicidality for these trials, 
we issued follow-up requests to our
july 2003 letters; these requests were made on november 24 and december 
                                9, 2003.
    This complete set of narratives was sent to Columbia University for 
review by a panel of international pediatric suicidality experts. This 
group was assembled to undertake a blinded review of the reported 
behaviors using a rigorous classification system.
    fda's october 2003 updated public health advisory and talk paper
    FDA issued an updated Public Health Advisory and Talk Paper on 
October 27, 2003, based on our assessment of the pediatric suicidality 
data at that time. Although we indicated that preliminary data 
suggested an excess of reports of suicidality for several anti-
depressant drugs, we noted the need for additional data and analysis. 
We also noted that we intended to bring this issue to an advisory 
committee meeting. We advised caution in the use of any of these drugs 
in treating pediatric MDD, and reminded prescribers of the standard 
language already in anti-depressant labeling alerting clinicians to the 
need for close supervision of high-risk patients, particularly during 
initial onset of drug therapy.
december 2003 uk mhra action on anti-depressant treatment of pediatric 
                                  mdd
    The UK MHRA made a public announcement on December 10, 2003, 
indicating that, in addition to its earlier statements regarding the 
contraindications of Paxil and Effexor in pediatric MDD, it was now 
also contraindicating all SSRI anti-depressants except Prozac for this 
condition. This announcement noted that the risk to benefit profile 
could not be assessed for Luvox, and that, the risk to benefit profile 
is favorable in pediatric MDD for Prozac only. Serzone and Wellbutrin 
are not approved drug products in the UK. Remeron is an approved 
product in the UK, but MHRA has offered no specific comment on the 
pediatric data for this drug.
           fda's february 2, 2004 advisory committee meeting
    FDA uses advisory committees to gain expert advice about scientific 
and public health issues and/or regulatory decisions. In preparing for 
an advisory committee meeting, scientific team leaders, supervisors and 
managers--seasoned regulatory scientists with drug development and 
public health expertise--exercise scientific judgment in synthesizing 
issues to be brought before advisory committees. This process is 
designed to ensure that an advisory committee considering an issue is 
provided with sufficient data and information to fully discuss the 
issues.
    While CDER was conducting its more in-depth review of the data from 
the pediatric clinical trials, planning was also under way to hold a 
meeting of the PDAC on
    February 2, 2004. Because the BPCA mandates a review of the post-
marketing safety data for products that have been granted pediatric 
exclusivity, this meeting was convened to review the post-marketing 
safety reporting for a number of products (not limited to anti-
depressants). One of the drugs scheduled for discussion at the February 
2, 2004, Advisory Committee meeting was Paxil.
    In planning for the discussion of the safety of the use of Paxil in 
children, the Agency initially intended to broaden the PDAC meeting to 
include a discussion of the Agency's review of the safety concerns 
arising from the data on the use of anti-depressants in children, as 
these concerns were clearly of public interest. However, as the reviews 
and meeting planning progressed, it became clear that the additional 
analyses of the data from the clinical trials of anti-depressants in 
children, particularly the Columbia analysis, would not be completed in 
time to present the Agency's final assessment of these data at the 
Advisory Committee meeting.
    The Agency decided to proceed with the plans to discuss the post-
marketing safety data for Paxil at the meeting, to brief the Advisory 
Committee on the Agency's progress in evaluating data from the clinical 
trials of anti-depressants in children, and to solicit advice and 
comment regarding the Agency's plans for further analyses. The plan 
included returning to the Advisory Committee for another meeting once 
the Agency's more definitive analyses of the clinical trial data were 
complete. This would allow us to solicit Advisory Committee input 
before taking further regulatory action.
    While CDER was moving ahead with plans for the February 2, 2004, 
Advisory Committee meeting, Dr. Mosholder was nearing completion of his 
review of the data from the clinical trials provided in response to our 
July 22, 2003, request. Based on his review, he believed that the 
available data were sufficient to reach a conclusion about an 
association between the use of anti-depressants and suicidality in 
children and to recommend additional regulatory action, without the 
need for the more in-depth case classification or analyses that had 
already been initiated by DNDP. Dr. Mosholder shared his conclusions 
with his supervisors and with the DNDP/ODE I review team involved in 
reviewing this issue. The review team and Dr. Mosholder's direct 
supervisors did not agree that the available data were sufficient to 
reach a conclusion and believed that definitive action should await the 
re-analysis by Center staff using the Columbia data. There was a 
discussion within the DNDP/ODE I review team, as well as higher CDER 
management including Drs. Katz, Laughren, and Temple, as to whether
    Dr. Mosholder's scientific and regulatory conclusions on the data 
should be presented in some form at the February meeting, given that 
they did not represent the Agency's (but rather an individual staff 
member-s) determination; it was concluded that they should not be.
    However, at the February 3, 2004, meeting, Dr. Laughren did present 
the data that led Dr. Mosholder to his conclusions, although not in 
detail. These data plainly showed an excess of suicidality in 
individual studies and across the studies as a group.
    Dr. Laughren also explained the Agency's reservations about the 
classification.
    Dr. Katz also acknowledged in his presentation to the Advisory 
Committee that some reviewers had reached a conclusion that the data 
were sufficient to conclude that there was a link between anti-
depressant use and suicidality in children. The Agency did not present 
Dr. Mosholder's conclusion in detail because of concerns that this 
would have given his determination the appearance of an Agency position 
before the Agency had made such a determination. This could have been 
harmful to the public health because it might have led patients who 
were actually benefiting from the use of these drugs to inappropriately 
discontinue therapy with potentially dire consequences, or to avoid 
treatment when it might be the best option.
    Senior CDER staff believed that the best way to serve the public 
health on this very complex and important issue was to: 1) disclose the 
available publicly releasable safety data during the Advisory Committee 
meeting; 2) describe the limitations of those data in supporting a 
definitive conclusion; and, 3) describe the Agency's plans to further 
evaluate the data. The Agency realized its responsibility to the public 
to find the right answer to this question. A premature conclusion that 
these drugs are harmful (when used in the pediatric population) that 
does not hold up during a more careful review would be a disservice to 
the public health given the serious and potentially life-threatening 
nature of severe depression. This is of particular concern since there 
are no acceptable therapeutic alternatives for health care providers 
and their pediatric patients with depression.
            cder's decision-making process on safety issues
    CDER's decision-making process is designed to ensure that 
regulatory actions or policy formulation take into consideration an 
array of perspectives and concerns designed to advance public health. 
The process requires that primary reviewers, team leaders, supervisors, 
and managers work together effectively.
    In the free and open discussion of CDER issues within a scientific 
and regulatory environment, we expect differing professional judgments/
opinions. Individual employees are strongly encouraged to discuss their 
views with co-workers. A number of opportunities are available to 
discuss and resolve scientific differences and enhance decision-making. 
These include meetings among review teams, meetings with the 
supervisory and management chains within the Center and Agency, 
meetings with sponsors, CDER regulatory briefings and Advisory 
Committee meetings.
    It is never the goal of these discussions to pressure or convince 
reviewers to reach any particular conclusion, or to reach a different 
conclusion that they have already reached, but only to provide a forum 
for a free exchange of views by all. After considering all of the 
relevant data and arguments, individual reviewers are expected to write 
reviews that reflect their best judgment. If their supervisor disagrees 
with their conclusions and/or recommendations, the supervisor documents 
the disagreement, and the resolution of the disagreement, in the 
official administrative file on a matter.
      fda's march 2004 advisory: new warning statement in labeling
    At the February 2, 2004, Advisory Committee meeting, experts raised 
concerns about the possible relationship between anti-depressant drug 
products and suicidal behavior and suicidal ideation and supported a 
labeling change to warn of possible suicidality. On March 22, 2004, FDA 
responded to these concerns by issuing a Public Health Advisory and 
asked manufacturers of Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro, 
Wellbutrin, Effexor, Serzone and Remeron to include a warning statement 
in their labeling recommending close observation of adult and pediatric 
patients treated with these drugs for worsening depression or the 
emergence of suicidality.
    In this statement, the Agency informed the public that symptoms 
such as anxiety, agitation, panic attacks, insomnia, irritability, 
hostility, impulsivity, akathisia, hypomania, and mania have been 
reported in adult and pediatric patients who are being treated with 
anti-depressants for MDD. We warned that patients who experience one or 
more of these symptoms might be at an increased risk for worsening 
depression or suicidality. The Agency pointed out that we did not know 
whether the drugs increased suicidality but warned that medications may 
need to be evaluated and perhaps discontinued when symptoms are severe, 
abrupt in onset, or not part of the patient's presenting symptoms. FDA 
urged health care providers to instruct patients, their families, and 
their caregivers to be alert for the emergence of agitation, 
irritability, and the other symptoms described above, as well as the 
emergence of suicidality and worsening depression, and to report such 
symptoms immediately to their health care provider.
                       ``columbia'' study results
    The Columbia group submitted its completed review to FDA in July 
2004. FDA then developed its analysis of the pediatric suicidality data 
based on the case classifications provided by Columbia University. 
While there were findings among these data suggestive of an increased 
risk of suicidality for some of these drugs, inconsistencies remained 
in the results, both across trials for individual drugs and across 
drugs. Thus, an overall interpretation of these findings represented a 
substantial challenge to the Agency. The Agency brought these findings 
to the Psychopharmacologic Drugs and Pediatric Advisory Committees in 
September 2004 for further consideration.
  fda's august 2004 advisory: agency plan to present data to advisory 
                               committees
    As part of its commitment to keep the American public fully 
informed about the status of its review of data concerning the use of 
anti-depressants in pediatric patients, on
    August 20, 2004, FDA informed the public of its detailed plan to 
present new data to the Psychopharmacologic Drugs and the Pediatric 
Advisory Committees. This new data, which FDA posted on its website, 
included the Agency's interpretation and analyses of pediatric 
suicidality data based on information obtained from the Columbia Study. 
In addition, the Agency sought advice on appropriate regulatory 
actions, such as labeling changes to ensure that the labels of anti-
depressants used in pediatric patients reflect the most recent 
information obtained from current studies and analyses.
    As we noted previously, FDA also announced that it posted 
additional summaries on its web site of pediatric efficacy studies for 
drugs that have been studied for depression in pediatric patients. 
These summaries are for Paxil, Celexa, Serzone, Zoloft and Remeron. 
Although specific new labeling language has yet to be developed, FDA 
will work to assure that the labels of the anti-depressants used in 
pediatric patients reflect the most recent information obtained from 
these studies and analyses.
         fda's september 13-14, 2004 advisory committee meeting
    On September 13 and 14, 2004, a joint meeting was held between the 
Psychopharmacologic Drugs and Pediatric Advisory Committees to consider 
the occurrence of suicidality in the course of treatment of pediatric 
patients with various anti-depressants. The primary focus of FDA's 
presentations at the September 2004 meeting was to provide committee 
members with (1) a detailed description of FDA's approach to evaluating 
and analyzing the pediatric suicidality data, and (2) the results of 
this work. The Agency also included presentations on related studies, 
in particular, several pertinent epidemiological studies and TADS 
(Treatment of Adolescents with Depression Study). Committee members 
heard presentations by both FDA staff and experts in pediatric 
suicidality from the academic community outside of FDA.
    The overall consensus of the committee was an endorsement of FDA's 
approach to classifying and analyzing the suicidal events and behaviors 
observed in the controlled clinical trials. Committee members expressed 
their view that the new analyses increased their confidence in the 
results. Further, the committee members concluded that the finding of 
an increased risk of suicidality in pediatric patients applied to all 
the drugs studied (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa 
Wellbutrin, Luvox and Serzone) in controlled clinical trials. In 
addition, the members:

 recommended that the products not be contraindicated in this country 
        because the Committees thought access to these therapies was 
        important for those who could benefit;
 recommended that the results of controlled pediatric trials of 
        depression be included in the labeling for anti-depressant 
        drugs;
 recommended that any warning related to an increased risk of 
        suicidality in pediatric patients should be applied to all 
        anti-depressant drugs, including those that have not been 
        studied in controlled clinical trials in pediatric patients, 
        since the available data are not adequate to exclude any single 
        medication from an increased risk;
 reached a split decision (15-yes, 8-no) regarding recommending a 
        ``black-box'' warning related to an increased risk for 
        suicidality in pediatric patients for all anti-depressant 
        drugs; and
 endorsed a patient information sheet (``Medication Guide'') for this 
        class of drugs to be provided to the patient or their caregiver 
        with every prescription.
            fda's september 17 announcement regarding ssris
    On September 17, FDA announced that the Agency generally supports 
the recommendations made to the Agency by the Psychopharmacologic Drugs 
and Pediatric Advisory Committees regarding reports of an increased 
risk of suicidality (suicidal thoughts and actions) associated with the 
use of certain anti-depressants in pediatric patients. FDA has begun 
working expeditiously to adopt new labeling to enhance the warnings 
associated with the use of anti-depressants and to bolster the 
information provided to patients when these drugs are dispensed.
        effectiveness data for anti-depressants in pediatric mdd
    To date, much of the focus has been on pediatric suicidality and 
the safety of anti-depressant drug products. However, it is also 
important to consider the efficacy data for these drugs because a risk-
benefit assessment is important to clearly understand the benefit side 
of this equation. Of the seven products studied in pediatric MDD 
(Prozac, Zoloft, Paxil, Celexa, Effexor, Serzone and Remeron), FDA's 
reviews of the effectiveness data resulted in only one approval 
(Prozac) for pediatric MDD. (In January 2003, FDA approved Prozac for 
the treatment of children and adolescents ages 7 to 17 for depression 
and obsessive-compulsive disorder.)
    Overall, the efficacy results from 15 studies in pediatric MDD do 
not support the effectiveness of these drugs in pediatric populations. 
It is understandable that people might conclude that these data show 
that the drugs, except for Prozac, have no benefit in pediatric MDD. We 
think that conclusion is premature, however.
    There are many reasons, other than lack of effectiveness, for 
studies to fail to show benefit. This phenomenon is a particular 
problem in depression, and even more so in pediatric depression.
    To begin with, in adult MDD programs for drugs approved for this 
indication, the overall failure rate for studies that appear in every 
respect to be adequate trials is about 50 percent. This indicates that 
showing effectiveness in depression is not easy. In fact, because we 
expected this difficulty, our Written Requests to sponsors asked for 
two studies, not the one that would have been more typical.
    Additionally, the history of pediatric MDD studies with the 
tricyclic anti-depressants (TCAs) is uniformly negative. This finding 
may have several possible explanations, including flaws in study design 
or conduct, or the possibility that TCAs simply do not work in 
pediatric MDD. It is also possible, however, that there is even greater 
heterogeneity among pediatric patients who meet criteria for MDD than 
is true for adults. If true, this would also work against study success 
in pediatric MDD.
    Finally, the context in which sponsors conducted these studies may 
not have been ideal. Sponsors do not need positive results when 
conducting a study in response to a Written Request in order to gain 
exclusivity. The studies simply must be conducted according to the 
terms of the Written Requests, and the results submitted to meet 
deadlines specified in those requests. We are not suggesting that 
sponsors of these studies did not design and conduct them with good 
intent and according to high standards. We merely point out that the 
failure of a drug registration trial to show a drug effect represents a 
more significant loss for the sponsor (i.e., the non-approval of the 
drug) than the failure of a study in response to a Written Request. We 
do not know whether this could have influenced the conduct of the study 
in subtle ways that might have worked against getting a positive 
result, e.g., in recruitment of patients. As an example of how our 
thought process has changed since the time we issued the Written 
Requests, if we were to make a Written Request today for an anti-
depressant, we would ask that the trial include a Prozac arm as well as 
placebo to confirm the ability of the study to demonstrate 
effectiveness. .
    Nevertheless, the failure of most of these programs to show a 
benefit in MDD heightens the concern about the drugs ability to induce 
suicidality. The burden is clearly upon those who believe these drugs 
do have benefits in pediatric MDD to design and conduct studies that 
are capable of demonstrating such benefits. The problem for 
practitioners is what to do in the face of the uncertainty. 
Practitioners must consider the generally negative findings in the 
context of several other facts.
    In all but one of the failed drugs, there were only two studies in 
pediatric MDD. For the remaining failed drug, there were three 
pediatric MDD studies. Among the failed drugs, there was one drug where 
one of the two studies was positive (Celexa), and two others (Zoloft 
and Serzone) where the results, while negative by our usual standards, 
were at least trending toward positive in one of the two studies.
    It has been observed that the published literature gives a somewhat 
different perspective, suggesting more positivity in two of these 
programs. A published paper describes one of the Paxil studies as 
positive on most of the secondary endpoints, while acknowledging that 
it failed on the primary endpoint. Another paper describes the Zoloft 
program as positive, based on a pooling of two similarly designed 
studies that, when looked at individually, failed. As noted, except for 
Prozac, we do not believe effectiveness has been shown for any agent in 
pediatric MDD.
                               conclusion
    FDA was the first to identify a concern about suicidality in 
several of the submitted pediatric studies. We evaluated the data 
closely and raised serious questions about its adequacy. We then took 
the initiative to acquire further relevant data from sponsors and used 
expertise outside the Agency to access the reports of suicidality 
thoroughly. FDA's assessment on this issue is designed to achieve the 
most scientifically rigorous review possible. The Columbia University 
classification project has provided the Agency with a credible basis 
for analyzing the risks of these drug products.
    The results of pediatric depression studies to date raise very 
important problems. First, the poor effectiveness results, except for 
Prozac, make it very difficult for practitioners to know what to do to 
treat a very serious, life-threatening illness. While we believe that 
these drugs may be effective in children, studies have not shown this 
to be true. Second, and of equal importance, the analyses we initiated 
in 2002 appear to show that the drugs in the pediatric controlled 
depression trials can lead to suicidal behaviors or thinking. While no 
suicides occurred in the trials, suicides certainly have been reported 
in treated patients, and the devastating results of these suicides were 
a critical part of the February 2, 2004, Advisory Committee meeting.
    FDA generally supports the recommendations that were recently made 
to the Agency by the Psychopharmacologic Drugs Pediatric Advisory 
Committees regarding reports of an increased risk of suicidality 
associated with the use of certain anti-depressants in pediatric 
patients. FDA has begun working expeditiously to adopt new labeling to 
enhance the warnings associated with the use of anti-depressants and to 
bolster the information provided to patients when these drugs are 
dispensed.
    Thank you for inviting us today to discuss this important subject. 
We would be glad to answer your questions.

    Mr. Walden. Dr. Laughren, do you have an opening statement, 
sir?
    Mr. Laughren. No, I don't.
    Mr. Walden. Okay. Dr. Seligman?
    Mr. Seligman. No, I don't.
    Mr. Walden. Thank you. Well, we appreciate all of you here 
today to share with us this information as we continue to look 
at what happened in this area and maybe what needed to happen, 
and where we are today and where we will be when the FDA makes 
it decision relative to the Advisory Committee's 
recommendations.
    Dr. Knudsen, could you turn in our big binder there to Tab 
71 and 72? While you are looking at that, these are the two 
versions of a letter under your signature sent to Pfizer 
Pharmaceuticals on March 19, 1996, Tab 71 and 72.
    Tab 71 has a FAX cover page filled out in someone's 
handwriting to Martha Brumfield of Pfizer from James Knudsen. 
The top of that page indicates it was sent at 10:18 and shows 
FDA Neuropharm on it as well.
    Does this appear to be your handwriting on the FAX cover 
sheet, sir?
    Mr. Knudsen. It does appear to be.
    Mr. Walden. It does. Okay. The letter attached to this FAX 
has lots of typographical errors in it as well as different 
fonts being used for various words. If you would turn to Tab 
72, it appears to be the same letter in substance as Tab 71. 
However, the typos are removed, and the font is consistent. The 
letters alone have a different FAX time Sent stamp on them, and 
show them coming from a different section of FDA. Yet does the 
signature on both these letters appear to be yours?
    Mr. Knudsen. Tough question, isn't it? They appear to be, 
but then again--yes, they appear to be. Back in 1996 when I 
was--my penmanship may have been a bit better than now. It 
varies somewhat. But I will answer the question as it appears 
to be. I have to equivocate a week bit, just because of the 
duration of time and the instability of my penmanship.
    Mr. Walden. All of our penmanship tends to suffer with age, 
sir.
    Mr. Knudsen. Thank you so much.
    Mr. Walden. Was it your practice to send a draft letter to 
a pharmaceutical company requesting information, then resend a 
cleaned-up version later on, though? Would you have sent it as 
a draft and then send a different version later?
    Mr. Knudsen. No, I don't--I mean, once again I have to 
preface a statement by, regrettably, this was done in 1996. So 
it is somewhat precarious for me to forage around in the 
limited gray matter that is available to answer that 
concretely.
    Mr. Walden. Is it a practice you recall doing throughout 
your career? Do you usually send a draft and then another?
    Mr. Knudsen. I do not--no, I do not usually send a draft 
and another. That's correct.
    Mr. Walden. I mean, this wouldn't be a normal practice, I 
wouldn't think.
    Mr. Knudsen. No. That's correct.
    Mr. Walden. Okay. I don't know. I mean, I'm not the best 
speller in the world, but----
    Mr. Knudsen. Well, quite frankly, I chatted with this--I 
mean, last week I talked with the subcommittee staffers, and I 
was rather appalled at what--with the typographical mistakes. I 
am rather fastidious most of the time. There are periods 
whereby I could deviate from that, but I mean, this is--this 
being Tab 71 is a mess. Draft or otherwise, I wouldn't be 
sending it to Martha, best I can recall anyway.
    Mr. Walden. I understand that. Do you have any explanation 
for the fact that two versions of this letter exist?
    Mr. Knudsen. No, but I suspect others do. I am unable to 
come up with an explanation.
    Mr. Walden. Were you able to find this letter in the files 
at FDA?
    Mr. Knudsen. I checked--no, to answer your question. I did 
check the document room. My own files are in--not trying to 
generate excuses, but they are in boxes which I invite you to 
my office and it is extremely difficult to even find a box. But 
they are all there. We are getting ready to relocate. So maybe 
with another 40 days and 40 nights I could find it.
    Mr. Walden. Well, should there have been a copy of this 
letter in the NDA files?
    Mr. Knudsen. I would--yes, and I would have kept a copy 
myself in my Certraline file. I keep everything.
    Mr. Walden. Your files are in boxes?
    Mr. Knudsen. I as unable to locate it in the document 
room----
    Mr. Walden. Right.
    Mr. Knudsen. [continuing] when I was there. I checked in a 
cursory way in my office, just trying to find the Certraline 
file that I have. In fact, I did find the Certraline file, 
parts of it, but I could not locate this particular document.
    Mr. Walden. Where did you obtain a copy of your March 19, 
1996, letter, and which version did you see?
    Mr. Knudsen. I obtained two copies, one from the Division.
    Mr. Walden. The Division?
    Mr. Knudsen. HFD, the Division I am in, the day before I 
left to go to Maine. I took it with me, in addition to other 
things, other documents, and then the subcommittee members sent 
via Federal Express another document. I mean the same one.
    Mr. Walden. Another copy of that same document?
    Mr. Knudsen. Yes, sir. Yes, sir.
    Mr. Walden. And where did the agency get the version they 
sent to you?
    Mr. Knudsen. I did not inquire.
    Mr. Walden. Dr. Temple, do you know?
    Mr. Temple. I could be wrong about this. My understanding 
is that Dr. Knudsen got a copy of the letter from the 
committee. Maybe I'm wrong about that.
    Mr. Knudsen. Yes, I just said that.
    Mr. Temple. And that we never were able to find it in our 
files and got it from Pfizer.
    Mr. Walden. There you go. So you had to go to Pfizer to get 
it?
    Mr. Temple. Yes.
    Mr. Walden. That's what you provided to the committee. 
Right?
    Mr. Temple. I'm not sure, but we could not--what I am sure 
of is that we were unable to find a record of this letter 
anywhere in our files. That, I am sure of. I am not sure about 
the rest.
    I should say that it is unusual. Letters don't ordinarily 
go out under a medical officer's signature. They would 
ordinarily go out under Dr. Katz's signature or Dr. Lieber's or 
whoever was in charge at the time, and a copy would be in the 
New Drug Application, in the file. So this was unusual.
    Mr. Walden. All right. Dr. Knudsen, was it your practice as 
a medical review officer in 1996 to directly correspond with a 
pharmaceutical company on a matter you were reviewing, and then 
request information or did you need to apprise any of the 
supervisors of your request for additional information from the 
pharmaceutical company?
    Mr. Knudsen. It was not my practice to do so.
    Mr. Walden. So you would have--was it your practice to tell 
your colleagues or supervisors that you were seeking such 
information from a pharmaceutical company?
    Mr. Knudsen. Correct, 86 to 95 percent of the time. There 
is always a slight opportunity for me to--I mean, once again, I 
mean, I answered the question as best I could that it is not my 
practice to do so. In fact, I received my copy from the 
Division via--of course, I guess the Division received it from 
Pfizer. I wasn't aware of that. I had no need to question that 
anyway. I just wanted to take some materials with me to Maine.
    Mr. Walden. Isn't it a requirement of FDA regulations these 
types of correspondent documents be kept on file by the agency?
    Mr. Knudsen. Yes.
    Mr. Walden. All right. And yet in this case, that doesn't 
appear to be what happened. Right?
    Mr. Knudsen. That is correct.
    Mr. Walden. All right. In these letters, you state ``We 
note that there appears to be an increased frequency of reports 
of suicidality in pediatric adolescent patients exposed to 
Certraline compared to either placebo or Certraline treated 
adult OCD patients. If this is, in fact, the case, what would 
be a plausible explanation?'' That is what is in the letter 
that you signed or you think you signed and sent to Pfizer.
    You asked for summary tables from Pfizer to compare data 
from adult and pediatric patients in their data base. Is it 
fair to say that you wrote this letter to Pfizer because you 
noticed an increase in suicide related behavior in the 
pediatric OCD trials relative to the rates in the adult trials, 
and that that was of concern to you? Is that why you wrote this 
letter to Pfizer?
    Mr. Knudsen. Yes.
    Mr. Walden. All right. And was it of enough concern that 
you wanted answers from the company?
    Mr. Knudsen. Correct.
    Mr. Walden. And approximately 10 days after you sent this 
letter to Pfizer, you complete a safety update to Zoloft. We 
have put selected pages of your safety review at Tab 81, 81, if 
you want to refer to that, sir.
    In your safety update you note on page 15 that, ``In the 
small pediatric adolescent pool population of OCD patients, the 
incidence of suicidality in the Certraline treated patients was 
fivefold greater than the adult OCD Certraline treated 
patients.''
    You go on to note that 4 of 6 Certraline pediatric patients 
had comorbid depression and, ``Depression is an important risk 
factor for suicide.'' You then cite an article published in the 
Journal of American Academy of Child and Adolescent Psychiatry 
that indicated--that also noted the same phenomenon with kids 
being treated with Prozac.
    What did you do other than note these concerns in the 
safety update? Where did you take it from here?
    Mr. Knudsen. I was trying to see whether or not that was 
instrumental in my sending the letter to Pfizer, just to garner 
some additional information. This was March 28, 1996. The 
letter to Pfizer was October, was it?
    Mr. Walden. I think the letter to Pfizer, you will see, is 
dated March 19.
    Mr. Knudsen. March 19, before.
    Mr. Walden. So like 9 days later----
    Mr. Knudsen. Well, in fact, in reviewing the NDA, this was 
a final document that was signed off, the one that--the 
document in Tab 81. So prior to finalizing this document, Tab 
81, I found this information to be--at the time anyway, 
certainly of concern to me to make some further inquiries to 
Pfizer, and realizing, of course, when I finalize this 
document, I believed that Pfizer had not responded yet to this.
    Mr. Walden. That would be correct, based on the timeline I 
have seen. But 9 days before you wrote to Pfizer asking for 
this additional information, why didn't you include in this 
update the fact that you were awaiting additional information 
from the company to explain the fivefold increase? Would that 
have been a prudent thing to do?
    Mr. Knudsen. Yes, it would have been.
    Mr. Walden. Well, my time has expired. I will now recognize 
the ranking member of the subcommittee at this time, the 
gentlelady from Colorado.
    Ms. DeGette. Thank you very much. Dr. Temple and Dr. 
Laughren, I am wondering if you can tell me, knowing what you 
know today, do you believe that Dr. Mosholder's initial 
conclusions about the increased risk of suicidality exists in 
pediatric populations taking anti-depressant medication to 
treat MDD? Dr. Temple?
    Mr. Temple. The reanalysis that Columbia did, did not 
change the overall direction of the results. So----
    Ms. DeGette. So your answer would be yes?
    Mr. Temple. Would be yes. Dr. Hammad's analysis and Dr. 
Mosholder's are slightly different analyses, but in fact the 
relative proportions of suicidality are similar to what Dr. 
Mosholder found.
    Ms. DeGette. What about you, Dr. Laughren?
    Mr. Laughren. Yes, I agree. The relative risk for both 
analyses is roughly twofold. So it is essentially the same. 
There are some differences across drugs. The signal gets a 
little stronger for some drugs, a little weaker for others, but 
overall I agree that it is roughly the same result.
    Ms. DeGette. There was about 8 months between his findings 
and when, I think, the FDA took action. I guess my question to 
both of you: Do you wish that the agency would have taken him 
more seriously and allowed him to present the findings so that 
we could have warned parents and physicians about the increased 
suicidality rates instead of waiting these 8 months?
    Mr. Temple. Let me say a few things. Our concern, as I said 
before, was that the action we take be based on the best 
possible data. Let me describe the kind of data we had here.
    The usual way we expected to evaluate increased suicidal 
risk is by looking at the scales that patients in trials are 
given that ask them how suicidal they are. Dr. Laughren in his 
comments on Dr. Knudsen's review points out that we are going 
to have more data on this question.
    Those analyses revealed nothing in any of these trials. 
There was no increased suicidality by that measure. What we got 
was something unexpected, namely the adverse reaction reports, 
when interpreted, when translated, revealed an excess of these 
suicidal behaviors. What we had very little experience with was 
what those things mean.
    We thought, as we looked at them, that somebody--that 
people expert in interpreting these behaviors needed to look at 
them. Dr. Mosholder specifically in his review says he did not 
try to reevaluate each of these cases, because he was no longer 
blinded. That conclusion----
    Ms. DeGette. But Dr. Mosholder also said that he only 
looked at the most--I'm not a researcher, but he only looked at 
the most serious cases and, in fact, Dr. Temple, you yourself 
in your opening statement said that the comment you had made 
about the face slapping you now regretted that, because he 
didn't take those things into account.
    Mr. Temple. Let me explain. He had--in response to the 
concern that these cases might not be a true bill, might not be 
what they seemed to be, he offered several approaches. One was 
to only look at the serious cases. That is clear, and you can 
see in his review, if you look at the cases that were included 
and not included, that many of the trivial cases were excluded 
by the decision to look only at the serious cases. That is 
perfectly true.
    There were, however, additional cases where you didn't know 
what they meant, and he was in no position to reevaluate them. 
Let me just----
    Ms. DeGette. I apologize, but they only give me 10 minutes. 
So if you can make your answer concise, I would appreciate 
that.
    Mr. Temple. Okay. I wanted to explain one other point about 
it.
    Ms. DeGette. Very briefly.
    Mr. Temple. He also said that, if there is noise in the 
system, if it is inaccurate, that would tend to hide a finding 
rather than to create one, and that is true.
    What is also true, however, is if there was a bias toward 
interpreting certain things that the drugs do, like agitating 
people or making them hostile, as suicidality, that could give 
you the wrong picture. It could cause you to think there were 
suicidal events when, in fact, they were not.
    That is why we thought we needed an independent look at 
these cases in----
    Ms. DeGette. Okay. But at the time that Dr. Mosholder came 
up with his findings, there was already the British study that 
had come out earlier that year.
    Mr. Temple. No, the British were using the same data we 
were.
    Ms. DeGette. Right, but they had concluded this increased 
risk of suicidality.
    Mr. Temple. But we don't know that they----
    Ms. DeGette. But I mean there were two.
    Mr. Temple. Let me make it clear. There was nothing wrong 
with Dr. Mosholder's analysis, the ratios he designed, any of 
those things. That is not----
    Ms. DeGette. Well, right. In fact, it has now turned out he 
was completely right.
    Mr. Temple. No, that is not at issue. What was at issue was 
what the cases were, whether they really showed suicidality, 
and to answer that question you either have to look at them 
closely or decide that they could not have been biased.
    Ms. DeGette. Well, let me ask you this. In the spring or 
summer of 2003, Wyeth came to the FDA, and they wanted on their 
own--we heard this in the last hearing--to strengthen warnings 
on Efexir, and the FDA asked them not to do that. Is that 
right?
    Mr. Temple. Not quite. They were allowed to do that, and 
they did it until we created a new stronger warning or--you can 
call it strong or not--a different warning in march of 2004. 
That warning was in the warning section. It prominently said 
you really need to watch patients, and we thought that was a 
more trenchant warning. That was in response to the Advisory 
Committee.
    Ms. DeGette. Okay. Now do you think that the FDA is going 
to adopt this most recent recommendation about the black box 
warnings?
    Mr. Temple. Our public statement said that we were going to 
do all the things they said. We want to think about the 
conversation they had about the black box. It is true it was 15 
to 8, but there were a lot of people that said a lot of things.
    You know, I don't want to----
    Ms. DeGette. Does that mean no?
    Mr. Temple. No, it absolutely doesn't mean no. It means we 
haven't finished our decision yet. We want----
    Ms. DeGette. Well, what is the FDA's goal with respect to 
labeling of these anti-depressants for off-label use for 
pediatrics? What is the goal at this point, knowing the 
information you know about increased risk of suicidality?
    Mr. Temple. Well, we are unquestionably going to explain 
that the drugs themselves appear to be--are associated with or 
cause an increased risk of suicidality. That is a given. The 
only question is what form it will take.
    The discussion the Advisory Committee had was----
    Ms. DeGette. What kinds of forms do you have that you can 
take with it?
    Mr. Temple. Oh, you could put a warning--I mean, the 
alternative, you could put a warning in dark print, something 
like that, or you can put it in a box. Those are probably the 
two choices.
    Ms. DeGette. So the choice would be to put it on the 
bottle. No?
    Mr. Temple. No, no.
    Ms. DeGette. To put it on the box?
    Mr. Temple. Well, a box warning is the very first thing you 
read in the label.
    Ms. DeGette. Right. Open it up.
    Mr. Temple. A warning comes a little bit later. Those are 
prominent, too, and we sometimes do one and sometimes do the 
other. The particular----
    Ms. DeGette. If there is a black box, that has to be in the 
advertising, too. Right? So if Zoloft has an ad, it has to have 
a warning, may cause suicidality in pediatric use, or something 
like that.
    Mr. Temple. Yes. The contents of the black box would have 
to appear, but----
    Ms. DeGette. It seems to me you would want to do that.
    Mr. Temple. Wait, wait, wait. The content of the warning 
would have to be there, too.
    Ms. DeGette. Well, sure. I understand, but that's the 
effect of a black box versus some of these other warnings. 
Right?
    Mr. Temple. No. The requirement for advertising is you have 
to balance the information. If there was a prominent dark print 
box, that would have to be there, too. I'm not trying to 
discourage a black box. I am just trying to reflect the fact 
that people who spoke to us were concerned that people who were 
at risk of killing themselves would not be treated if we scared 
people too much.
    I'm not saying I agree with that. We put the idea of the 
black box before the committee. You know, we are not shrinking 
from it, but they said multiple things.
    Ms. DeGette. Well, I would imagine you would share my 
concern. My concern is that off-label prescription of these 
nonapproved drugs for pediatrics with, at best, no effect on 
these depressed kids and, at worst, increased risk of 
suicidality will continue unabated. I would assume that is the 
FDA's role to decide that. Right?
    Mr. Temple. One of the problems with off-label use and not 
having enough data is that you don't know what the answer is. 
The Advisory Committee--many, many people said we know how the 
studies came out; they are not impressive; they weren't able to 
show effectiveness. But they clearly were concerned that maybe 
as a second line drug these drugs probably should be available 
and probably worked in people.
    That is not the same as knowing, because we know the 
studies largely failed.
    Ms. DeGette. I think we can probably all agree that it 
would help to have more clinical trials in this area, would it 
not?
    Mr. Temple. Yes, but they--Again, I am talking for them. I 
am not telling you what we decided to do. They were very 
concerned that we would scare people so much that people who 
didn't respond to, say, Prozac wouldn't use it or would be 
afraid to use it, and they were afraid of the consequences. 
They were worried about them.
    You know, these are expert people who treat these 
conditions. They know a lot more about it than I do.
    Ms. DeGette. Can I just ask you a question. Do you think it 
would be a good idea if we had more clinical trials so we could 
get more data on what the effects of these anti-depressants 
are, or should we just rely on faith?
    Mr. Temple. Oh, no, we live by getting more data. We can't 
always manage to get it.
    Ms. DeGette. Can you require more clinical trials as part 
of your ongoing effort?
    Mr. Temple. That is going to be an interesting question. We 
have a number of thoughts about how to do further studies, 
which I would use up your 10 minutes if I told you, but I would 
be glad to.
    Ms. DeGette. It's okay. It's already over.
    Mr. Temple. No, we think there needs to be more data. For 
example, we were very impressed with the TAD study. It was a 
very informative study done by NIMH. We are going to be talking 
with them, see if we can convince them to do some more stuff.
    Ms. DeGette. Great. Now what about the companies? Are you 
going to require--what we learned in the last hearing: 
Pharmaceutical companies are making millions and millions of 
dollars from this off-label prescription of these anti-
depressants.
    Would it be reasonable for the FDA to require further 
studies by the companies?
    Mr. Temple. It is reasonable, and whether we can--well, 
there is a question of our authority. Whether we will be able 
to require further studies when they will perfectly happily say 
we think it is a settled question, we don't want the drug used 
in children--we are perfectly happy to say safety and 
effectiveness in children hasn't been demonstrated, and they 
are perfectly happy to say that, as you pointed out.
    Ms. DeGette. Because they can still sell these drugs.
    Mr. Temple. Whether we will be able to persuade them to do 
more studies is not known to me. We definitely----
    Ms. DeGette. Well, can't you hold the pediatric exclusivity 
stick over their head?
    Mr. Temple. Unfortunately, no. They have done what they 
were supposed to do under the law. They have done the trials we 
asked for, and pediatric exclusivity has been now granted.
    Ms. DeGette. So if you have these recalcitrant drug 
companies who are refusing to do more studies because they can 
just blithely say, well, we don't like this off-label use 
anyway, we don't----
    Mr. Temple. To be fair, they haven't refused yet.
    Ms. DeGette. Okay.
    Mr. Temple. I'm not optimistic. That's all.
    Ms. DeGette. They might agree to do it, but if not, it 
would seem to me it would be in the FDA's interest then, and 
this is within the FDA's authority, to require the strongest 
possible warnings so that doctors and parents understand the 
risk to pediatric patients.
    Mr. Temple. There is no question there is going to be a 
strong warning. The other thing is we suggested to the 
committee that there ought to be patient labeling, a so called 
Med Guide, and they totally agreed with that.
    We also told them that we didn't think a Med Guide works 
unless you create what is called unit of use packaging, so that 
it is always handed out, and I am on lengthy record as saying 
we are going to require that, which we will. But we did all of 
those things. It needs to be a strong warning.
    Ms. DeGette. And staff points out to me, the FDA could 
counterindicate this drug and stop it form being prescribed, 
period.
    Mr. Temple. Well, we couldn't. They could still prescribe 
it. We don't control what people do. The Advisory Committee was 
unequivocal, voted overwhelmingly and uniformly that they did 
not think a contraindication was appropriate, for the reasons 
that I have just given. They think, without data, without 
evidence that these drugs actually work, they think they need 
to be available.
    Ms. DeGette. Excuse me, sir. Let me just say, it seems like 
circular reasoning. We don't have the data to say what we 
should do, but we can't make them get the data. So we are just 
going to go along. I would suggest we work together. Do you 
need statutory changes, whatever you need? We need to get a 
grasp on this, and I think part of it is getting more data.
    My time has long expired. Thanks for your comments.
    Mr. Temple. Can I throw one more thing out? The data were 
not uniformly negative. There was one positive trial with a 
drug called Cetalopram, and there were a couple of trials that 
were close, not entirely negative.
    So it is not out of the question that these drugs can be 
shown to work.
    Mr. Walden. Are you talking about efficacy or suicidality?
    Mr. Temple. Efficacy.
    Mr. Walden. Well, I am going to go to Mr. Ferguson in a 
second. But you could also require that the trials that show no 
efficacy be published. Right? Be printed? Doctors could be 
notified? Couldn't you require that?
    Mr. Temple. That is a difficult question. Published? 
Absolutely not. We have no control over publication.
    Mr. Walden. I'm sorry. I used the wrong term. Couldn't you 
require that on a label it says no efficacy?
    Mr. Temple. I believe we can, yes.
    Chairman Barton. Would the gentleman yield before you go to 
Mr. Ferguson? I just want to follow up on that question very 
briefly.
    Mr. Walden. Certainly, Mr. Chairman.
    Chairman Barton. Dr. Temple, is the FDA now changing its 
criteria for approval to say, if it can be shown that it is not 
out of the realm of question that it might be shown to work, 
that you are going to approve it? I've never heard such a----
    Mr. Temple. We are not approving it. I am trying to reflect 
the views of the experts we had on our Advisory Committee.
    Chairman Barton. I understand that.
    Mr. Temple. They know perfectly well that these drugs have 
not been shown, according to our standards, to work. There is 
no question about it. I totally agree with that conclusion. 
That is not the same as knowing they don't work, and they were 
frightened at the prospect that people would not be able to use 
the drugs in----
    Chairman Barton. I understand that.
    Mr. Temple. That's all.
    Chairman Barton. One reason your agency has such high 
esteem in the public is because, almost without exception, all 
the time drugs or medical devices don't get approved until it 
has been shown without a shadow of a doubt that they do work 
unless it is some cancer therapy or orphan drug where you 
develop some sort of an informed consent that the situation is 
so dire that the patient is going to die unless almost a 
Biblical miracle occurs.
    That statement you just said, to just cavalierly say, well, 
we can't really say that in some cases it might work, just 
boggles my mind.
    Mr. Temple. I'm obviously not communicating. There is no 
question that these drugs have not met the standard for 
approval. I don't want to approve them. I cherish the standard. 
I think the 1962 Act was one of the greatest pieces of 
legislation in all the world's history.
    That is not the same as saying that anyone who uses a drug 
off-label is doing the wrong thing. The requirement for 
approval has to meet--there is a threshold set for approval, 
and I think that is entirely appropriate. I value it 
enormously, and I don't even believe it doesn't apply in orphan 
drug cases, in cancer drugs either.
    But the fact is that data comes in a smear, in a range, and 
what may not be anywhere close to what we would need for 
approval may inform some people or convince them that they 
ought to give something a try. I'm just saying that is a fact. 
I am not saying it is a good thing or a bad thing.
    What I am saying is that our Advisory Committee was 
uniformly concerned that people who hadn't responded 
appropriately to Prozac would have nothing available when they 
were deeply depressed, suicidal, and the like. That seems a 
legitimate concern, too.
    That is not talking about making the drug----
    Chairman Barton. I will do this on my own time.
    Mr. Walden. But don't virtually every single clinical trial 
show there is no efficacy for these drugs in kids and 
adolescents? Isn't Prozac like the only one that shows that for 
kids and adolescents, that there is any efficacy?
    Mr. Temple. The results are certainly discouraging. Prozac 
was three for three.
    Mr. Walden. No, no. How many studies that have been done in 
children and adolescents for this range of drugs showed they 
had efficacy for kids?
    Mr. Temple. Not counting Prozac, I assume.
    Mr. Walden. Count Prozac. I don't care. How many studies 
have been done----
    Mr. Temple. Three Prozacs, one Cetalopram. There is a study 
of Paxil in which all of the endpoints except their primary 
endpoint were successful. Some people would think that shows 
something. We wouldn't. We wouldn't buy it.
    Mr. Walden. So you don't buy it.
    Mr. Temple. I don't buy it.
    Mr. Walden. All right.
    Mr. Temple. Certraline published a report that said we work 
when you throw our two studies together. We don't buy that, but 
it is a trend in the right direction. It is not zero, and----
    Mr. Walden. When it is combined, but not a stand-alone, and 
I thought your own agency rejected that.
    Mr. Temple. That is what I said. We do not believe that 
they have shown effectiveness. Absolutely not. That is the 
wrong analysis. I am just saying that is not proof that it 
doesn't work. I am obviously not making myself clear. I don't 
want to approve these drugs.
    What the Advisory Committee expressed concern about was 
that in a world of uncertainty, they thought that you need to 
be able to think about using them in someone who hadn't 
responded to anything else and who had no other choices. I am 
not here to say that is a stupid thing to do. Those are 
knowledgeable advisors.
    Mr. Walden. Yield to the gentleman from New Jersey.
    Mr. Ferguson. Thank you, Mr. Chairman. Dr. Temple, thank 
you and your colleagues for being here today. We appreciate you 
answering many, many questions that are very important 
questions.
    I may have missed it if someone else asked this question. 
But can you tell me why Dr. Mosholder did not present at the 
February 2 meeting?
    Mr. Temple. Yes. We thought that the--let me just try to 
think what you've heard and what you haven't heard. Our concern 
was that there was uncertainty about what the cases that went 
into his analysis meant. They were collected from adverse 
reaction reports that were not particularly designed to look at 
suicidality, and determining whether a given clinical picture 
represents suicidality is not entirely simple.
    The people at Columbia specialize in trying to sort those 
things out, and we were aware of that. Our concern was not with 
the analysis that Dr. Mosholder did, which was perfectly right, 
but with the very cases that went into the analysis and whether 
they were credible instances of suicidality.
    So we arranged well before that meeting, the Advisory 
Committee meeting, and well before his final report, we 
arranged for Columbia to blindly review each of the cases and 
reclassify them. We didn't want to present what appeared to be 
an FDA conclusion at the February 2004 Advisory Committee.
    Mr. Ferguson. Certainly, he would be capable of explaining 
that himself, though, wouldn't he?
    Mr. Temple. Well, no. He believed the analysis was fine. 
You know, people can probably disagree about this. We didn't 
think he was wrong. We thought it wasn't ripe yet. So for us 
to--you know, for us to go up and say, oh, he's all wet, that 
wouldn't have been appropriate, and it is not that we thought 
it was wrong. We thought the cases needed to be looked at 
before conclusions should be reached.
    Mr. Ferguson. Isn't that the role of the Advisory 
Committee, is to gather information like this and analyze it 
and make a recommendation? Did you think they would be 
confused? Are they an easily confused group?
    Mr. Temple. The Advisory Committee was in no position to 
review each of the cases. We had no capacity to ask them to do 
that. That would have, you know, taken them months. When we 
discussed this matter with them, they clearly sympathized with 
the need to find out what these cases meant. We didn't get a 
vote. So I can't prove what they thought, but they understood 
the problem perfectly well, and expressed no dissatisfaction 
with it.
    In fact, at the most recent Advisory Committee meeting, 
they said the review by Columbia was very impressive, that the 
data looked better than they could have imagined, and expressed 
sort of gratitude that they had something they could readily 
work with.
    Mr. Ferguson. Wouldn't the committee be equipped to analyze 
the arguments? Isn't that what they are supposed to do?
    Mr. Temple. Well, that's sort of what I am saying. It 
wasn't a matter of making arguments. We didn't have a counter-
argument. We didn't think that Dr. Mosholder's review was 
wrong. What we thought was that the basis for doing the review, 
for creating the numbers, was imperfect, because the cases 
hadn't been analyzed----
    Mr. Ferguson. And the Advisory Committee couldn't possibly 
understand that?
    Mr. Temple. Well, I think they did understand it, and they 
nodded in agreement. But they didn't vote on it. We didn't ask 
them to vote.
    Mr. Ferguson. They didn't hear his side. He never got to 
present on February 2.
    Mr. Temple. Well, let me make it clear. What----
    Mr. Ferguson. They had information withheld from them.
    Mr. Temple. What Dr. Laughren showed was the results of 
each of the trials, many of which showed more suicidality in 
the treated group than the other group. Now he didn't show 
exactly Dr. Mosholder's data or the cumulative data, but it was 
easy to see, and we emphasized this in the professional 
advisory that we sent out, that there was more suicidality in 
the treated group in many of the studies.
    So they knew what the issue was perfectly well, and they 
also heard from Dr. Laughren what our reservations about the 
data were.
    Mr. Ferguson. I am not at all satisfied with the reason why 
Dr. Mosholder was somehow blocked from presenting on February 
2, for the record. Let me move on.
    I'd like to go to Tab 40 in the committee's binder. This is 
the minutes from the February 2 meeting. Tab 40 is the minutes. 
I want to go to the top of the last page of Tab 40.
    Mr. Temple. Hang on.
    Mr. Ferguson. Sure.
    Mr. Temple. Top of the last page?
    Mr. Ferguson. The last page of Tab 40, and I am quoting. 
The text states: ``The committee advised the FDA to inform the 
public and health care workers, including pediatricians and 
family practitioners''--it goes on--``of the level of concern 
regarding possible harm to a minority of children on anti-
depressants and the signs associated with the side effect.''
    It is clear that the Advisory Committee wanted you to 
inform the public about the risk to children, not the risk to 
the general population but specifically the risk to children, 
as reflected in these minutes. Is that correct? Do you agree 
with that? That is what the minutes say.
    Mr. Temple. Yes, but I guess we interpreted that as----
    Mr. Ferguson. I am real short on time.
    Mr. Temple. Okay. We put a warning that applied to both 
adults and children.
    Mr. Ferguson. Right. The Advisory Committee seemed to 
indicate--they were specific to children, not the general 
public. That is what it says. That is what the minutes say. 
Right? Why didn't you issue an advisory specific to the side 
effects in the pediatric population?
    Mr Temple. Because the same side effects occur in adults. 
Remember, this--we did not write a conclusion that the drugs 
increased the risk of this, because we thought that was 
premature, and the committee didn't tell us otherwise. But the 
possibility that people being given these drugs get worse when 
they are given them is a phenomenon that has been observed in 
both adults and children. We thought the warning should apply 
to anybody being started on these drugs.
    Mr. Ferguson. But if the committee says in their quotation, 
in the quote from the minutes, from your minutes, the possible 
harm to a minority of children on anti-depressants and the 
signs associated with the side effect, why not issue a warning 
specific to children?
    Mr. Temple. Even though we thought the same warning should 
apply to adults?
    Mr. Ferguson. Why not? What's the harm? Why not?
    Mr. Temple. Well, in the labeling what would we say about 
adults?
    Mr. Ferguson. We consider children and adults different in 
all sorts of ways. You do, too. The side effects in children 
are different from the side effects in adults. Right?
    Mr. Temple. Yes. This was a statement----
    Mr. Ferguson. There is a reason we test on pediatric. There 
is a reason we do tests on kids and different tests on adults. 
We don't extrapolate one to the other necessarily.
    Mr. Temple. Right, but----
    Mr. Ferguson. We do tests on both.
    Mr. Temple. But the potential for getting worse when you 
are starting therapy is a phenomenon of both adults and 
children.
    Mr. Ferguson. Okay. Are the side effects different in 
children and kids--between children and adults?
    Mr. Temple. Well, we now think that they are, because we 
have seen no increase in suicides in adults with a very large 
data base, but we now believe there is an increase in suicidal 
thinking and behavior in children. But that is what we know 
now, and the new labeling will surely say that.
    Mr. Ferguson. Okay. I am going to keep going, because we 
are kind of getting fuzzed over here. To me, it is mystifying 
that, given this information, that you would not have issued--
particularly, because this is what the Advisory Committee 
seemed to be saying, that you wouldn't have issued a warning 
specific to kids. Let me move on.
    The minutes go on to note that the committee is concerned 
that the public does not know that a strong majority of 
randomized controlled trials of SSRIs do not demonstrate 
superiority over placebo in the treatment of major depression 
in children and adolescents.
    Did you address this concern publicly and through a 
labeling change?
    Mr. Temple. We did not introduce a labeling change. All the 
labeling----
    Mr. Ferguson. Why not?
    Mr. Temple. Well, what the labeling all says is that safety 
and effectiveness in children has not been demonstrated, and 
the new warning moves that statement forward to the warning 
language.
    Mr. Ferguson. What warning?
    Mr. Temple. The warning that all of the drugs got in 
March--sorry, after the Advisory Committee meeting.
    Mr. Ferguson. You're talking about the March 22?
    Mr. Temple. We asked for it in March. It was all 
implemented by about August, I think.
    Mr. Ferguson. Okay. Which is Tab 44. So it just seems to me 
that the agency first tries to determine what information that 
the Advisory Committee can handle, for instance pulling Dr. 
Mosholder, not allowing him to present his data and information 
to the committee, and then when they make a recommendation, 
when the Advisory Committee makes a recommendation, you 
disregard the recommendations that they make.
    Mr. Temple. I don't agree that we disregarded it. The third 
paragraph of the thing you just showed me says that anxiety, 
agitation, panic attacks, etcetera, have been reported in adult 
and pediatric patients being treated with anti-depressants. I 
mean, adults are people, too. We thought this is a risk that 
applies to all people who are started on an anti-depressant.
    Mr. Walden. Would the gentleman yield?
    Mr. Ferguson. I will yield. I am mystified that, given what 
is going on with this issue, that you seem to be incapable or 
refuse to decipher the difference between effects on kids and 
effects on adults. I will yield to the gentleman.
    Mr. Walden. Really, I think, what you are asking is: If you 
knew it affected children and adults, but you also knew it 
affected kids more than adults.
    Mr. Temple. We didn't think we knew that at the time.
    Mr. Ferguson. And worse, more and worse.
    Mr. Walden. Dr. Mosholder indicated that in his study. This 
came out--when did this come out, 2004? This came out in 
February 2004. Right? You own agency began flagging this in 
1996 and 1997.
    Mr. Temple. We did not think it had been established--
again, you have heard the debate about that. Obviously, Dr. 
Mosholder thought it was well established. We did not think it 
was established that there was a special risk in children, but 
we knew that both adults and children started on therapy, early 
in therapy, can have all these things, including increased 
suicidality. That is what we wanted to warn about.
    We did not say at this time that there was an increased 
risk in children.
    Mr. Walden. Are you acknowledging that there is an 
increased risk in adults?
    Mr. Temple. Increased risk compared to no treatment?
    Mr. Walden. Right.
    Mr. Temple. No. We don't know that.
    Mr. Walden. So there is no increased risk of suicidality in 
adults who are on anti-depressants in the trials?
    Mr. Temple. We have done analyses of suicides now, and we 
don't see anything like that. Dr. Mosholder presented at the 
last Advisory Committee an analysis of the Paxil adult data 
using exactly the same approach that was used in the children. 
That showed no increase in suicidality in the adults. So at 
this time, that appears to be different, but it remains true 
that, whether there is an increase or not, increased suicidal 
behavior and thinking does occur early in therapy.
    Mr. Ferguson. Mr. Chairman, could I reclaim the time that I 
don't have left for one more question?
    Mr. Walden. Yes, sure.
    Mr. Ferguson. I want to just go to one more, Tab 49, which 
is your statement, the FDA's statement from September 16 on the 
recommendations of the Psychopharmacologic Drugs and Pediatric 
Advisory Committees. These are the recommendations from 
September.
    Mr. Temple. I'm sorry. Which am I looking at now?
    Mr. Ferguson. Tab 49.
    Mr. Temple. Forty-nine? Sorry. Okay.
    Mr. Ferguson. My question is: Given the fact that, in my 
estimation, you seem to have, No. 1, tried to control the 
information that the Advisory Committee was getting; No. 2, 
seemed to disregard the Advisory Committee's recommendations 
that they made back in February.
    What assurance do we have that these recommendations from 
September will be followed or adopted?
    Mr. Temple. Well, you have the statement about what we are 
going to do, and in a couple of weeks you will see the labeling 
change.
    Mr. Ferguson. No, no, no, no. The statement says the FDA 
general supports the recommendations that were recently made. 
That is--I mean, my gosh, this is Washington. That could mean 
anything.
    Mr. Temple. Well, let me make it clear. We had some 
discussion of this before we came in. The only thing we want to 
think further about is the box, for reasons that I explained 
before and would be glad to explain again. All the rest of the 
recommendations are----
    Mr. Ferguson. I heard the conversation about the box.
    Mr. Temple. All the rest of them are clearly going to be 
implemented. We, frankly, suggested half of them.
    Mr. Ferguson. Okay. You said in the New York Times on 
September 14, ``I think we now--I think that we now all believe 
that there is an increase in suicidal thinking and action that 
is consistent across all the drugs.'' And you have the Advisory 
Committee saying 15 to 8 that they think the black box is a 
good idea.
    I mean, that is almost the override of a veto. I mean, 15 
to 8 is substantial. What is left? What is the problem?
    Mr. Temple. Well, you have to have been to a lot of 
Advisory Committees to notice this, but as much as anything 
else, you want to hear the words people use to explain why they 
think what they think and what the reservations are. All I am 
saying is we are going to look at what those are.
    I am not predicting that we won't buy the black box. My 
guess is we probably will, but we owe the people who spoke and 
tried to advise us a look at what they said.
    Mr. Ferguson. If there is a vote on another issue that is 
15 to 8, is it generally adopted or is it something that is not 
adopted or do you kind of think about it for a little while 
longer?
    Mr. Temple. Yes, that is a very hard thing to answer, but 
divided committees recommending approval or not approval--when 
it is reasonably close, we don't necessarily go by the 
majority, you know. You sort of have to read what people say 
and----
    Mr. Ferguson. Is 15 to 8 reasonably close?
    Mr. Temple. Well----
    Mr. Ferguson. That is a whitewash.
    Mr. Temple. There is no question the majority of the people 
thought that it ought to get a box, and they overcame in 
recommending that their concern that use of the drugs would be 
over-discouraged.
    Mr. Ferguson. Recommending a black box is a pretty big 
deal. That is not taken lightly. Right?
    Mr. Temple. We understand it. One of the questions we asked 
them is should we put a black box on it. We put it on their 
table so that we could hear their opinion, and we wanted their 
opinion and their discussion on the pros and cons, and how they 
came to pro, in spite of certain reservations and concerns is 
extremely informative.
    Mr. Ferguson. You have almost a two to one vote on a--you 
don't see a black box on too many drugs.
    Mr. Temple. You see them on a fair number. We are not 
saying that we don't want to do it or don't plan to do it. We 
just owe that one some thought. That's all.
    Mr. Ferguson. I'm done. Thank you. I yield back.
    Mr. Walden. Thank you. I now turn to the gentleman from 
Michigan, Mr. Stupak, for questions.
    Mr. Stupak. Thank you, Mr. Chairman. This black box--where 
is it going to go?
    Mr. Temple. Black boxes are always the first thing in 
labeling.
    Mr. Stupak. Where is the label? Is that for health care 
professionals or do people get a chance to see that?
    Mr. Temple. Sorry. The label refers to the package insert 
that is written for physicians.
    Mr. Walden. Mr. Stupak, I erred. I was committed to the 
chairman to go to him, because he has to go to mark-up.
    Mr. Stupak. That's all right.
    Mr. Walden. Could you----
    Mr. Stupak. Go ahead, Joe.
    Mr. Walden. Mr. Chairman.
    Mr. Stupak. But let me just clarify that. That black box 
only goes to physicians. It doesn't go to the general public?
    Mr. Temple. Right. There will be an equivalent emphasis in 
the patient labeling, what is called a Med Guide, that we were 
also very strongly advised to create. So that will be very 
prominent in that form, too.
    Chairman Barton. I apologize for going out of order, but 
we've got a mark-up on the waste bill upstairs. I thank the 
courtesy of Mr. Stupak.
    Dr. Temple, have you ever run for any political office?
    Mr. Temple. No.
    Chairman Barton. Do you follow Presidential politics?
    Mr. Temple. Oh, yes.
    Chairman Barton. Okay. You are aware there is going to be a 
debate next week between President Bush and Senator Kerry.
    Mr. Temple. So I've heard.
    Chairman Barton. How would you feel if you were really 
looking forward to that and at the last moment the news 
reported that it had been decided that Senator Kerry couldn't 
represent himself in the debate, that Congressman Joe Barton 
had been appointed to represent Senator Kerry's views in the 
debate with President Bush about who is qualified to be the 
next President of the United States?
    Would you think that was a fair thing to do or an unfair 
thing to do?
    Mr. Temple. Unfair thing to do.
    Chairman Barton. Unfair thing to do. So when the decision 
was made that Dr. Mosholder could not present his findings last 
February, nobody was allowed to even hear what his findings 
were, but that when it was finally decided that his findings 
could be presented last week or the week before last, somebody 
else did it, and somebody else did it who probably disagreed 
with his findings. Was that fair or unfair?
    Mr. Temple. He presented his findings. He compared his 
findings with the new findings.
    Chairman Barton. Oh, Dr. Mosholder did present his--I was 
told he did not.
    Mr. Temple. Well, the primary analysis was done by Dr. 
Hammad on the new data, but what Dr. Mosholder did was show how 
the analyses were similar and different.
    Chairman Barton. Well, now I want to be fair. When I'm 
wrong, I'm wrong. I was told that Dr. Mosholder did not get to 
present his own findings. That is apparently not true?
    Mr. Temple. When do you mean now?
    Chairman Barton. Well, there have been two Advisory 
meetings, one last February that I----
    Mr. Temple. Oh, I think I misunderstood you. In the most 
recent Advisory Committee----
    Chairman Barton. There have been Advisory----
    Mr. Temple. A couple of weeks ago.
    Chairman Barton. There was an Advisory at the beginning of 
this year in February. Then there was another Advisory just a 
couple of weeks ago. Isn't that correct?
    Mr. Temple. Yes. At the February meeting, he did not 
present his analysis. If that is what you mean, that is true. 
That is what we talked about.
    Chairman Barton. Well, at that meeting did anybody present 
any of his findings?
    Mr. Temple. I see. I understand. That sort of depends on 
what you mean. The results of the numbers, the number of 
adverse--of suicidality events were shown, study by study, not 
Dr. Mosholder's analysis, by Dr. Laughren. I mean, these are 
the data that we had that were submitted to us. Those were 
presented. They showed an excess in some studies, not an excess 
in other studies, and they did not----
    Chairman Barton. Which meeting are you talking about?
    Mr. Temple. The February 2004 meeting.
    Chairman Barton. But he was not there?
    Mr. Temple. He was there, but he didn't present the 
results.
    Chairman Barton. He was there, but he wasn't allowed to 
speak.
    Mr. Temple. Yes.
    Chairman Barton. Publicly allowed to speak.
    Mr. Temple. He presented other data, but he didn't present 
the--he didn't present the analysis of the controlled trials in 
depression.
    Chairman Barton. Well, I would argue that that was unfair. 
Now let's fast forward to a couple of weeks ago. There was 
another Advisory meeting. Was he allowed to present there?
    Mr. Temple. Yes.
    Chairman Barton. Unencumbered?
    Mr. Temple. Unencumbered.
    Chairman Barton. Okay. So then I was misinformed on that. I 
was told that he was not allowed at the second meeting to 
present, that his data was presented, I believe, by Dr. 
Laughren. That was at the first one? Okay. Well, then I was 
misinformed.
    Mr. Temple. At the first one Dr. Laughren presented 
somewhat different data that were basically derived from the 
same data bases. We didn't try to present Dr. Mosholder's 
views. We just tried to show why we were worried about these 
things in the first place.
    Chairman Barton. Well, my main point, and I think it is 
still valid: If somebody is viewed as credible, which Dr. 
Mosholder was initially when he was appointed, when he was 
still in the Pharmacological Neuropharm Directorate. He was 
picked to do the review, apparently because they felt he was 
the best qualified. Now I understand that he later got 
transferred to a different division or different directorate.
    Mr. Temple. He moved voluntarily. We didn't want him to go.
    Chairman Barton. Okay. He moved voluntarily. Anyway, he was 
no longer in that group.
    Mr. Temple. We consider that a loss for us.
    Chairman Barton. Okay. Well, we agree on that. We agree on 
that. You know, if he was the one who was picked to do the 
initial review, he should be the one that is picked to do the 
presentation of the data. We, I think, all agree up here that 
the impression is that he wasn't allowed to present, because 
higher-ups disagreed with him and wanted to muzzle him.
    Mr. Temple. Well, what higher-ups thought was that the data 
weren't ripe for presentation, because they needed the analysis 
of the cases by the Columbia group, and you know, it is always 
a difficulty when there is disagreement about something like 
that. But the people at the next level have responsibility for 
making that decision.
    We thought it was potentially dangerous for the community 
to present prematurely what appeared to be an FDA conclusion. 
You know, I am positive people can argue that judgment, but 
that is what the judgment was.
    Chairman Barton. Well, we all agree that the best advocate 
for a position is normally the person who is actually most 
responsible for developing the position. You agreed with me 
that Senator Kerry would be a little hacked off if Joe Barton 
got to present his position, because if I was doing the 
presenting and I say, now this is what Senator Kerry said but 
this is really what I think ought to be, you know, and every 
time President Bush said something, I'd say, well, I have to 
oppose that, but you know, really I do agree with you, it 
wouldn't be a very good debate.
    Mr. Temple. This may be more nuance than is safe, but it 
wasn't that we disagreed with him. What we thought was that the 
data weren't ready. So what I didn't want to do----
    Chairman Barton. Why wouldn't you let the Advisory 
Committee--it's not like you are making a presentation to the 
unwashed like Members of Congress. You are making the 
presentation to a technical advisory committee of experts that 
you yourself--not you personally perhaps, but the FDA has 
picked.
    They certainly ought to be able to determine the nuances of 
the data and, if they are really on their toes, they are going 
to ask him a lot of very pointed questions trying to pick out 
any flaws in his presentation.
    Mr. Temple. We could probably have done that and offered 
our own critique and then let them choose. What we were worried 
about, you know, for better or for worse, is that it would 
appear to be an FDA conclusion and that we thought it was 
premature, and we thought that was not the right thing to do 
and was potentially a bad thing for the community.
    I think Dr. Laughren has been trying to--can I let him?
    Mr. Laughren. Can I just try and clarify?
    Chairman Barton. Yes, sir. This is an open hearing. We are 
not going to muzzle anybody.
    Mr. Laughren. Okay. You know, let me just say, first of 
all, that we fully appreciate Dr. Mosholder's role in this. As 
Dr. Temple pointed out, he was the one who discovered the 
signal initially, the potential signal in the Paxil pediatric 
supplement back in 2002, and alerted us to this problem with 
the way the data were coded that led to the report from Glaxo 
in May 2003. And everyone agrees that he was the right person 
to begin looking at those data.
    What he did, he looked at the Paxil summary report, which 
was the first one. In the meantime, he began looking back at 
the pediatric supplements for the other drugs while we were 
waiting for data from the other drugs and made a very important 
contribution at the internal regulatory briefing in September.
    The focus--our focus changed dramatically over the course 
of the fall, as we started looking at the cases and recognized 
that there might be a problem in understanding--in whether or 
not they all represented suicidalities. That was one major 
theme we were pursuing.
    We were also concerned about case finding. We recognized, 
as again we started looking at these documents, that we may not 
have gotten all the cases, and that is why late in the year we 
issued additional requests for more cases from the companies.
    A third theme that we were pursuing was getting what is 
called patient level data so that we could try and understand 
the striking differences between trials.
    So this was our focus, and gradually it became clear that 
we were going to have to do our own analysis of the data, based 
on this more complex dataset. That is why Dr. Mosholder's role 
changed during that period of time. So----
    Chairman Barton. Are you saying he wasn't competent to do 
that?
    Mr. Laughren. No, I'm not--well, I'm not saying that. We 
had the expertise to deal with----
    Chairman Barton. Who is we?
    Mr. Laughren. Well, the Neuropharm Division, in particular 
the safety team, Dr. Hammad.
    Chairman Barton. And Dr. Hammad is not in the direct line. 
He is kind of a staff auxiliary advisory to the main chain of 
command in the Center. Is that not correct? I mean, his job is 
to kind of double check everybody else?
    Mr. Laughren. No, no, no. He did the primary analysis, the 
definitive analysis that we presented to the Advisory Committee 
last week.
    Mr. Temple. There is a group called the Safety Group in 
Neuropharm that specializes in doing safety analyses, and he is 
a member of that group. He, too, is actually moving to the 
Office of Drug Safety.
    Chairman Barton. But Dr. Hammad's--I looked at a flow chart 
to try to figure out who everybody is, and my understanding is, 
of the group that is here, Dr. Temple is the biggest dog and is 
an Associate Director, and Dr. Laughren reports directly to 
you, and Dr.----
    Mr. Temple. Well, Dr. Katz who couldn't be here is the 
Division Director, one of three in the office that I run.
    Chairman Barton. You report to him. Right?
    Mr. Temple. He reports to me, and Dr. Laughren reports to 
Dr. Katz.
    Chairman Barton. And Dr. Hammad is in a staff group that is 
not in the direct chain. Is that correct?
    Mr. Temple. No. Well, there's two Psychopharm groups, one 
of which is headed by Dr. Laughren, and there is a safety group 
that reports the same way as Dr. Laughren does, to Dr. Katz, 
and Dr. Hammad is in that group.
    Chairman Barton. Okay. Well, I have kind of gotten off on a 
rabbit trail here. My time has expired. Let me refocus this 
again to the members of this subcommittee who have really no ax 
to grind except that we want the very best for the American 
people, and in this particular case we don't want children 
taking anti-depressant drugs if there appears to be quite a bit 
of evidence that, not only does it not help them, in some cases 
it actually hurts them, increases the risk of suicidality.
    Time after time in reviewing the documents and reviewing 
the transcripts and the testimony, you know, it really does 
appear to me that the FDA has gone out of its way to short 
circuit the findings of Dr. Mosholder and create this counter-
argument that you epitomized earlier when you said, well, if 
there is some evidence that it might help some people some of 
the time, why should we stop it, which seems to me exactly 
contrary to what the normal FDA standard is, that if you can't 
show that it helps a lot of people all the time, we shouldn't 
allow it.
    Mr. Temple. I was trying to describe what our Advisory 
Committee of people in the field who actually do this were 
worried about.
    Chairman Barton. I am just really puzzled about that.
    My last thing, again back on Dr. Mosholder: Is it true 
that, when ABC contacted him to say that they were considering 
him for man of the week, that higher-ups at FDA tried to stop 
that? Is there any truth to that?
    Mr. Temple. I have no idea. I can't imagine that we would 
try to stop it, but I do imagine that it might have to get 
cleared, something like that. But I have no knowledge of this.
    Chairman Barton. Would Mr. Mosholder--you are still under 
oath. Do you know for a fact if anybody at FDA, when you were 
asked to be man of the week for ABC, either did not clear that 
or tried to prevent that?
    Mr. Mosholder. Actually, I had a conversation about that 
with Dr. Seligman, whose chair I just took, and Dr. Seligman 
had some reservations about it. In my mind, too, was at that 
time I had been asked to be a witness at this hearing, and I 
had some concerns about whether it would be unseemly, because 
being person of the week involves an on-air interview, whether 
that would be unseemly coming just a few days before this 
hearing.
    Chairman Barton. So who withdrew? Did you withdraw?
    Mr. Mosholder. I withdrew. Yes.
    Chairman Barton. You withdrew. You didn't--I am going to 
ask Dr. Seligman as soon as he retakes his seat what is 
concerns were.
    Dr. Seligman, we just heard from Dr. Mosholder that, after 
talking to you, he withdrew from consideration for ABC man of 
the week, which I would think would be something the FDA would 
want, that they would want their employees being men and women 
of the week to show that they are doing good deeds for the 
American people.
    What were the concerns that you expressed to him about 
that?
    Mr. Seligman. I congratulated him for his selection.
    Chairman Barton. That is not expressing a concern.
    Mr. Seligman. No, I know. I am just telling you what the 
nature of our conversation was. I just expressed the same 
concern that I express over any interaction with the media, 
which is to make sure that was careful and thoughtful in his 
presentation and that things he said were, you know, succinct 
so that it potentially could not be taken out of context.
    Chairman Barton. So did you encourage him to go forward or 
did you encourage him to withdraw?
    Mr. Seligman. I did neither. I did neither encourage him 
nor discourage him.
    Chairman Barton. Okay. Well, if ABC is listening, I would 
encourage ABC to nominate Dr. Mosholder for man of the week, 
because I think he is doing the kind of things that we want our 
researchers and evaluators to do. So for what it is worth, the 
chairman of Energy and Commerce Committee that has jurisdiction 
over the FDA thinks that would have been an excellent 
selection.
    Mr. Walden. And Telecommunications.
    Chairman Barton. My time has way expired. So with that, I 
yield back.
    Mr. Walden. Thank you, Mr. Chairman. Now I again appreciate 
the courtesy extended by the gentleman from Michigan, and we 
look forward to your questions. Mr. Stupak.
    Mr. Stupak. Thank you. Dr. Temple, you said the black box 
warnings goes to health care professionals hearing this and not 
to the public. Are you going to do an informed consent on this 
drug?
    Mr. Temple. The Advisory Committee didn't vote on that 
question, but talked about it and did not think that was 
appropriate. The problem here is that----
    Mr. Stupak. So are you going to do an informed consent or 
not?
    Mr. Temple. Well----
    Mr. Stupak. Yes or no?
    Mr. Temple. I don't think that is fully settled, but I 
would say probably not.
    Mr. Stupak. So we don't get the black box warning. There is 
no informed consent. How are people out here going to know what 
is going on with these drugs?
    Mr. Temple. Sorry, I missed the first part of your 
sentence.
    Mr. Stupak. There is no black box warning that people will 
receive. There is no informed consent. How are they going to 
know that these drugs are not effective and increases 
possibility of suicide behavior?
    Mr. Temple. Well, patients will--with unit of use 
packaging, every patient who gets the drug gets the patient 
labeling, so called Med Guide. That will have a very prominent 
statement--whether we box it or not, I think that hasn't been 
determined yet; we don't necessarily----
    Mr. Stupak. You are going to put the Med Guide, which is 
supposed to be in very plain, simple English--you are going to 
put that into every packet?
    Mr. Temple. Yes.
    Mr. Stupak. Every one?
    Mr. Temple. Every one.
    Mr. Stupak. Is the pharmacist going to have to dispense it 
or is it going to be in every one?
    Mr. Temple. No. We despair of success when the pharmacist 
has to dispense it.
    Mr. Stupak. Beg pardon?
    Mr. Temple. We don't think it is successful if the 
pharmacist has to do it. That is why we create--that is why we 
insist, in some cases anyway, on unit of use packaging. Unit of 
use packaging means----
    Mr. Stupak. Right. Familiar with it. You indicated that--we 
have heard testimony the last couple of times that everyone was 
quick to say there were no suicides in clinical trials. Is that 
correct? Yes or no? You can't shake your head.
    Mr. Temple. I'm sorry. Yes.
    Mr. Stupak. Okay. So where did you get the information on 
the suicides then?
    Mr. Walden. Just for our audience, we are being called for 
one vote. We will wait, though, a few minutes, and then we will 
recess while we make that one vote. Then we will come back. Oh, 
is it two votes? Okay. Well, we will do the same drill.
    Mr. Temple. There were no suicides in the 4,000 or so 
patients who were in the controlled trials--in the pediatric 
trials.
    Mr. Stupak. Correct.
    Mr. Temple. In the much larger data bases that have been 
carried out in adults, there were suicides, and we have 
compared the frequency of suicides on-treatment and off-
treatment in those. There, it comes out even. That is our 
suicide data.
    Mr. Stupak. So your suicide data would be coming from 
reports from the drug manufacturers then, right, or unless it 
is voluntarily----
    Mr. Temple. No. These are results of trials. There have 
been a lot of trials altogether. So we have 30-40,000 people. 
Dr. Hammad can tell us how many.
    Mr. Stupak. So the suicides were found in the adult 
population. You extrapolated that to make some kind of 
conclusions as to children?
    Mr. Temple. No. We have reached the conclusion about 
adults. We don't know that adults and children are the same. As 
I said, when Paxil data in adults were examined in exactly the 
same way as they were examined in children, and the children's 
analysis showed a clear excess of suicidal behavior and 
thinking, no similar excess was seen in adults.
    I don't have a good explanation for that. I don't know why 
that should be true, but that is what the result is so far.
    Mr. Stupak. If you have no suicides in the clinical trials, 
do you have suicides in your adverse events file?
    Mr. Temple. Yes.
    Mr. Stupak. With children?
    Mr. Temple. Oh, yes.
    Mr. Stupak. And what percentage are reported?
    Mr. Temple. Well, we have no idea.
    Mr. Stupak. Wasn't it true that with your adverse events 
report, only about at most 10 percent are ever reported?
    Mr. Temple. That is a figure commonly given, but we don't 
know what the right answer is.
    Mr. Stupak. In fact, FDA has used that figure many times, 
somewhere between 1 percent and 10 percent.
    Mr. Temple. We have used that figure to try to make rough 
estimates, but that is not the same.
    Mr. Stupak. What you have is only 10 percent of what may 
actually be out there. We can't say with certainty, but based 
upon, again, extrapolation of the data, it is basically 10 
percent of the known number.
    So when you do your black box warning, are you going to use 
the word rarely, that suicide behavior, suicide thoughts, 
suicide ideation, suicides may rarely occur with the use of 
these anti-depressants in young people?
    Mr. Temple. No. The results of the trials would not support 
the term rare. Dr. Hammad estimated--well, it is roughly, just 
roughly, 2 percent in people who get placebo and about 3.5 or 4 
percent in people who get the drug. That doesn't meet anybody's 
test for rare.
    The excess risk is in the neighborhood of 2 to 3 percent. I 
think that is the figure Dr. Hammad gets. So that would not be 
called rare.
    Mr. Stupak. When will you end your conversations about the 
black box?
    Mr. Temple. Really, within a few days, we will reach a 
decision.
    Mr. Stupak. Right. You have stated in your testimony, the 
little bit I have been in--we have a mark-up going on upstairs; 
so I am running back and forth between the two. You have stated 
in your testimony that thus far these anti-depressants in 
children, ``doesn't work; do not meet the standards for 
approval; results are discouraging.'' Then why does the FDA 
allow these anti-depressants be given to children under the age 
of 18?
    Mr. Temple. Well, we don't allow it. The labeling all says, 
except for Prozac, that safety and effectiveness----
    Mr. Stupak. Are you telling this committee, if the FDA put 
on the thing that says not to be distributed to children under 
18, you don't have that authority? You can't do that?
    Mr. Temple. Not to be distributed?
    Mr. Stupak. Not to be filled by pharmacists.
    Mr. Temple. We could, for example, contraindicate the use 
in people under 18.
    Mr. Stupak. Yes, you could.
    Mr. Temple. We could. We were advised by our committee in 
the strongest way--this was not 15 to 8----
    Mr. Stupak. This was the Advisory Committee. Right?
    Mr. Temple. Right.
    Mr. Stupak. You don't listen to advisory committees if you 
don't want to anyway. Take Accutane. We have been waiting for 4 
years for certification and registry. Four years, we still 
don't have it. After two advisory committees tell you do it, we 
are still waiting 4 years later.
    The FDA does what it wants. Now the bottom line here----
    Mr. Temple. I have to protest. We take--I can't speak to 
the case you are referring to here. We take----
    Mr. Stupak. The bottom line is you have the authority.
    Mr. Temple. We could seek to contraindicate their use.
    Mr. Stupak. Then if it doesn't work and increases the 
possibility of suicidal behavior in people under the age of 18, 
why don't you do it? Aren't you supposed to protect the safety 
and welfare of the American people?
    Mr. Temple. Yes, and we are not sure that your proposal or 
your suggestion would protect the American public. It might 
harm them.
    Mr. Stupak. Well, let me just read you here. This was an 
article handed out earlier today. This is the San Francisco 
Chronicle, I think it was, the article. It says on paragraph, 
column four, first paragraph: ``But this episode suggests that 
they''--being the FDA--``reject the precautionary principle in 
favor of the idea that no drug is dangerous unless it is proven 
to be so.''
    Mr. Walden. I believe that is the British Journal.
    Mr. Stupak. The British Journal? Okay. So in other words, 
shouldn't you err on the side of caution when you are talking 
about increased possibility of suicidal behavior in young 
people, especially when the drugs thus far has not shown to be 
effective in the treatment of depression?
    Mr. Temple. Well, like the Advisory Committee, I believe we 
have to think about a whole bunch of things. There are--I don't 
want to make more of this than they deserve, but it is very 
clear that the suicide rate in adolescents has been declining 
for the last 10 years, the period in which these drugs were 
started.
    Mr. Stupak. But you can't give the anti-depressants credit 
for that, because you have said that they are not effective in 
that.
    Mr. Temple. No. I have not said that they are not 
effective, and it is very important to recognize the 
distinction.
    Mr. Stupak. Wait a minute. You're saying now they are 
effective in treating depression in young people?
    Mr. Temple. No. What I said is that they have not been 
shown to our satisfaction to be effective. That is, they 
haven't been shown in well controlled studies to do the things 
that you are supposed to do to be considered effective. But we 
know from depression trials in adults that lots of drugs that 
work can't show that they are effective every time.
    In fact, more than 50 percent of all trials in adults fail. 
Why they seem to fail so much in children, we don't know. It 
could be they really don't work.
    Mr. Stupak. You don't know.
    Mr. Temple. We don't know.
    Mr. Stupak. For all indications right now, we know they 
don't work. We know they increase suicide behavior. Then why 
don't you not allow the drugs be prescribed to children under 
18 until you do know--until you do know? Isn't it more harm to 
these people who may be of fragile mind, suffering from 
depression, to give them something like Paxil, which is 
supposed to make them feel better, and it really doesn't? Isn't 
the mind then saying, geez, I had a little hope here; you gave 
me this prescription, and I would be better. It doesn't work. 
In fact, it is not being effective. Aren't you really putting 
that person at risk, at a greater risk with a false hope that 
you are giving them?
    Mr. Temple. Having untreated depression is risky, too, and 
we don't know----
    Mr. Stupak. Absolutely.
    Mr. Temple. We can't know. You can't do mortality studies 
here. No one will let you do them. We don't know whether you 
would be worse off or better off. The Advisory Committee was 
quite convinced, but I am not going to tell you they had data 
to work from. They didn't. They were quite convinced that there 
are many people who are suicidal because of their disease who 
would be made worse off.
    I am not telling you that they know that to be true. I am 
not telling you that is evidence. I am not telling you that 
should lead to a claim in labeling. But I don't dismiss it out 
of hand either.
    Mr. Walden. If I could interrupt just a second, Mr. Stupak. 
Are you able to come back after the votes?
    Mr. Stupak. Sure.
    Mr. Walden. In which case I would extend you another 5 
minutes after the votes. We are probably down to about 7 
minutes or so to go over to vote. What I would like to do is 
recess the committee, return, and then I will return to you for 
further questions, if that is appropriate.
    The committee will stand in recess, and we would request 
our witnesses to stay here as well. Thanks.
    [Brief recess.]
    Mr. Walden. If I could have our witnesses return to the 
table, we will get started here in just a moment. I am going to 
call the Committee on Oversight and Investigations back to 
order.
    When we left for the vote, Congressman Stupak had the 
floor, and we are extending you another 5 minutes for your 
continuing line of questions. So the Chair would recognize the 
gentleman from Michigan.
    Mr. Stupak. Thank you, Mr. Chairman.
    Dr. Temple, in response to one of the questions by someone 
up here, they were asking about the studies, and you said there 
were some studies you could not publish concerning the anti-
depressants.
    Mr. Temple. I said we can't force people to publish things.
    Mr. Stupak. But can you publish them?
    Mr. Temple. Well, let me describe what we can and can't do. 
When we approve a new drug or a supplement to a new drug, our 
reviews and things like that are all made public. They are put 
on our website. If we do not approve----
    Mr. Stupak. Your reviews, but not the studies?
    Mr. Temple. Our reviews, not the studies. But our reviews 
are quite detailed. I would modestly say there are at least as 
informative as a publication in a journal, as a rule.
    Mr. Stupak. Okay. So these are all approved. All these 
anti-depressants are approved drugs. If another study comes 
out, do you get that study? Do you receive that study?
    Mr. Temple. Like if they do another study, they must be 
reported in annual reports, but unless they show something bad, 
they don't have to be--not much has to be done with them. If 
they show something dangerous, then they have to be reported to 
us promptly.
    Mr. Stupak. So they are found in what is called the Annual 
Progress Report or another one they call it is the 
Investigative Drug Brochure. Correct?
    Mr. Temple. Well, that is for a drug that----
    Mr. Stupak. That is for an IND. Right?
    Mr. Temple. Yes.
    Mr. Stupak. Okay. In the Annual Progress Report--that is 
just a summary of what they did. Right? A summary of these 
studies, the drug companies send it to you: Here's what we have 
done in the past year; here is where reference to our pill has 
showed up in a medical journal, or something like that.
    Mr. Temple. They may actually put the reprints, but I 
wouldn't want to boast too much about how useful those 
documents are to us.
    Mr. Stupak. What if the company fails to leave out part of 
the critical point that you are looking for, that something 
would be dangerous, such as causing suicide or affecting the 
central nervous system. They don't put it in their annual 
report.
    Mr. Temple. Well, if we somehow become aware of it, we can 
bring various legal actions against them. You have to tell us 
about things like that. There are examples where delays in 
reporting to us have resulted in criminal penalties of various 
kinds.
    Mr. Stupak. Okay.
    Mr. Temple. Of course, we do have to find out about it.
    Mr. Stupak. Sure. Let me ask you this question. Is it true 
that the FDA published its Public Health Advisory with a 
recommended label change about worsening depression and 
suicidality in patients treated with anti-depressants on March 
22, 2004?
    Mr. Temple. Yes.
    Mr. Stupak. Okay. And who wrote the text of that label 
change?
    Mr. Temple. Wow. Let me ask Dr. Laughren, because he and 
his people would have had a major role in that.
    Mr. Laughren. The initial draft of the label change came 
out of the Division, but there were a number of other groups 
within the agency who had input into that, including people in 
Office of Drug Safety, Office of Pediatrics and 
Counterterrorism.
    Mr. Stupak. Well, let me ask you this then. Who would have 
been the person to sign off? Who gives it final signature? I 
know you have these initial drafts.
    Mr. Temple. I mean, something like that goes through parts 
of the Commissioner's office for final sign-off.
    Mr. Stupak. Okay. So Dr. Crawford would be the guy who 
would sign off on it eventually then?
    Mr. Temple. I can't say that, but someone in the 
Commissioner's office would.
    Mr. Stupak. If you compare the text that the FDA approved 
for the labels of anti-depressants on March 22, 2004, and what 
is on the labels of the anti-depressants today, would they be 
the same?
    Mr. Temple. It depends on how the Public Health Advisory is 
written. Sometimes they are written before----
    Mr. Stupak. I am talking about the March 22, 2004 Public 
Health Advisory. Look at Tab 44. That might help a little bit 
here.
    Mr. Temple. They wouldn't necessarily be the same. You are 
writing in a different way. You are trying to communicate a 
little more in the Public Health Advisory.
    Mr. Stupak. Well, explain this to me. Look at Tab 44.
    Mr. Temple. They shouldn't be in major----
    Mr. Stupak. March 22, 2004, says, and I am quoting: 
``Health care providers should carefully monitor patients 
receiving anti-depressants for possible worsening of depression 
and suicidality, especially at the beginning of therapy or when 
the dose either increases or decreases. Although FDA has not 
yet concluded that these drugs cause worsening depression or 
suicidality, health care providers should be aware that 
worsening of symptoms could be due to the underlying disease or 
might be a result of drug therapy.''
    But now the actual labels say this--that is approved by the 
FDA. It says, ``Patients with major depressive disorder, both 
adult and pediatric, may experience worsening of the depression 
and/or the emergence of suicidal ideation and behavior 
(suicidality), whether or not they are taking anti-depressants 
medications, and this risk may persist until significant 
remission occurs. Although there has been a longstanding 
concern that anti-depressants may have a role in inducing 
worsening of depression and the emergence of suicidality in 
certain patients, a causal role for anti-depressants inducing 
such behaviors has not been established. Nevertheless, patients 
being treated with the anti-depressants should be observed 
closely for clinical worsening and suicidality, especially at 
the beginning of the course of drug therapy or at a time the 
dose changes.''
    This is just one example of how March 22, 2004, labeling 
warning label text is different from the labels we see on the 
drugs today, and there is actually another one. My question is, 
why is the March 22 language published on your website not good 
enough to make it to the labels for the doctors? If you have 
already weakened your March 22 recommendation--I believe you 
have--how can we trust that you won't have strong, clearly 
worded labels on the package that demonstrate the lack of 
efficacy and the increase of risk with these drugs?
    See what I am saying. March 22 you had pretty strong 
warning. That is on your website. Now what we see on the 
package is completely different.
    Mr. Temple. I guess I think the labeling language is of 
similar strength, although the words are somewhat different. 
They both emphasize monitoring. They both emphasize that you 
can get much----
    Mr. Stupak. See, here's our problem. Most of us up here 
aren't doctors. We looked at it. We read it, and we can't--we 
think it is less. We think it is weaker, and then you tell us 
you are going to do this black box warning, which the patients 
and families aren't going to get, and the first notice they are 
going to get about they are not being effective and may 
actually increase suicidal behavior is when they open up their 
package, because in there is going to be a Med Guide.
    Isn't that a little bit too late? They have already had 
their prescription. They already had it filled. They are 
already there. They got it. They've spent the money. Now after 
all this, now you are going to tell them, hey, wait a minute, 
before you do this you ought to know this.
    That is our concern up here. Sounds like we got the horse 
before the cart, the cart before the horse, whatever you want 
to call it. Ain't right.
    Mr. Temple. That's a different question. That is why we 
made sure that the Committee discussed the question of whether 
there ought to be some attempt to give something out 
beforehand. The difficulty with those, and we do do it 
sometimes, mostly in relation to fetal abnormalities where the 
urgency seems maximal, is that how you structure that, how you 
get these into the office, how you get them discussed 
adequately, given the current situation on how long people 
spend, is not so clear.
    Mr. Stupak. Right. When you discuss these, it is between 
the FDA and the drug company. Is anyone there representing the 
people, the patients, a public citizen or anyone like that at 
these discussions that you are having on black box and all 
that?
    Mr. Temple. Well, these discussions aren't being held with 
the drug companies either. We are going to propose labeling. 
Then maybe after that----
    Mr. Stupak. And then you go back and forth?
    Mr. Temple. Maybe, but----
    Mr. Stupak. No, no, you do, every one of them. I have never 
seen a drug company yet accept a first recommendation you made 
on labeling.
    Mr. Temple. Well, we didn't--I mean, Tom would know best, 
but I don't know how much difficulty we had with the one in 
March.
    Mr. Stupak. Let's go back to my original question. See, the 
confusion with your March 22, what you have on the website, 
people get it after they purchase drug. Why don't we just go to 
an informed consent? I would strongly urge you go to informed 
consent before you ever even get this, when you start treating 
with these doctors, that clearly spells out like a Med Guide 
would that here is what we find. And if it changes, we can 
change that informed consent.
    I don't want a voluntary one, because half the doctors 
don't give it. We want a mandatory informed consent, especially 
when dealing with young kids.
    Mr. Temple. To do that, you also have to have a completely 
separate distribution system. It has to be shipped directly to 
the doctor or something like that. It is----
    Mr. Stupak. I know doctors are busy, but if you tell them 
it is a mandatory informed consent and then they are practicing 
improperly, they would do it.
    Mr. Temple. May be. I think what the people on the 
committee thought was that the burdensomeness of it would 
interfere more than they wanted with the appropriate use of the 
drugs. That doesn't mean we can't consider this further, but 
that is what they thought. They did talk about this a fair 
amount.
    Mr. Stupak. I would encourage you to do the informed 
consent, and thank you for the extra time.
    Mr. Walden. You are welcome. Thank you for your 
participation.
    Dr. Knudsen, if you would turn to Tab 73, please, sir. Do 
you recall ever getting this response from Pfizer? I note it 
says a desk copy to you on the bottom of the second page, I 
believe.
    Mr. Knudsen. I did not--I don't recall getting the response 
from Pfizer that addressed that request that I had of them to 
provide additional information. Once again, just because I 
don't recall doesn't--let's see.
    Mr. Walden. Had you gotten an official company response to 
the question about suicidality, what would have been your 
protocol in reviewing that response?
    Mr. Knudsen. Yes. I would have read it and ascertained 
whether or not they answered the questions posed to them, 
whether or not they answered the questions adequately, and 
often indicated what we--well, NAI, no action indicated, signed 
my name.
    I am not saying I did it for this one, because I do not 
recall anything from them.
    Mr. Walden. Right. I understand.
    Mr. Knudsen. But that is how I have done it in the past.
    Mr. Walden. Were you able to find any memo in the Zoloft 
files you looked at, at the agency or in your own files, 
evidencing that you or anyone else within the agency actually 
reviewed Pfizer's response?
    Mr. Knudsen. No.
    Mr. Walden. Had you been satisfied with Pfizer's response, 
would you have most likely written a memo to that effect, had 
you been satisfied with their response?
    Mr. Knudsen. It is conceivable.
    Mr. Walden. I think your mike got turned off there, sir.
    Mr. Knudsen. I may have put a No Action Intended--
indicated, excuse me. But, yes, I----
    Mr. Walden. I mean, you would have written some response.
    Mr. Knudsen. Yes. Yes.
    Mr. Walden. So would you have let your supervisor know that 
you had reviewed and received the company's response to a 
safety question you posed? Is that standard operating 
procedure?
    Mr. Knudsen. I would have put my response in the box, yes.
    Mr. Walden. The box?
    Mr. Knudsen. Well, the mailbox for my supervisor.
    Mr. Walden. Okay. Thank you. Who was your supervisor at the 
time?
    Mr. Knudsen. Dr. Laughren.
    Mr. Walden. Okay. Dr. Laughren, do you recall ever 
reviewing Pfizer's response on this issue of suicidality in 
kids?
    Mr. Laughren. Not at that time. I have looked at it 
subsequently.
    Mr. Walden. And that was because of the hearing coming up 
here?
    Mr. Laughren. I just learned about it as a result of 
document exchanges and what-not. We did not have the letter 
that Dr. Knudsen sent to Pfizer in our files. I believe we had 
to get that from Pfizer.
    Mr. Walden. That is our understanding. But we are talking 
about Pfizer's response to that letter.
    Mr. Laughren. Right, right.
    Mr. Walden. But you didn't have either one, is what you are 
saying. Is that in part because you don't have a record 
retention policy? Dr. Temple, what is your policy for saving 
documents like this?
    Mr. Temple. Materials that are--go ahead.
    Mr. Laughren. We did have the May--was it May 28, the date 
of the receipt?
    Mr. Walden. Yes, May 28, 1996.
    Mr. Laughren. We did have that in our files. What we did 
not have is the letter that Dr. Knudsen sent back in March. We 
didn't have a copy of that letter in our files.
    Mr. Walden. Oh, I see. But you did have Pfizer's response?
    Mr. Laughren. It was in our files. But there was no 
indication that it had been reviewed.
    Mr. Walden. I see. And you hadn't reviewed it prior to the 
committee bringing this to your attention?
    Mr. Laughren. There wouldn't have been any reason for it to 
have come to me, ordinarily.
    Mr. Walden. Unless he had referenced it to you.
    Mr. Laughren. Unless he had given it to me. Right.
    Mr. Walden. All right, and there is no record of that. 
Okay. But I guess the question is: Now you have reviewed it, do 
you think it raises serious safety concerns?
    Mr. Laughren. No. It basically provides additional 
information that supports the view that I expressed in my 
October--I think it was October 25, 1996, memo where I 
commented on the issue that Dr. Knudsen raised in his March 
review. It basically supports that view.
    Mr. Walden. And what he raised at that time was a serious 
safety concern, wasn't it?
    Mr. Laughren. Well, he raised a concern that there might be 
a signal of increased risk of suicidality in pediatric patients 
relative to adults, but if you have seen my October 25 memo, I 
believe I fully addressed that. I mean, there were a couple of 
issues there.
    No. 1, he was comparing risk of suicidality in adult 
patients who had been scrupulously screened out for not having 
depression with a group of children, many of whom had primary 
depression. So it was not, in my view, a reasonable comparison.
    Mr. Walden. all right. If you would turn to Tab 75, we will 
send the book of tabs back your way. This is a memo that you 
authored on October 25, 1996. Subject line is: You note that 
``a concern about the possibility of a signal of emergent 
suicidality, suicide attempts, gestures or ideation association 
with Certraline used in pediatric patients was raised by Dr. 
Knudsen in his 3/28/96 safety review.'' In your memo you did 
not mention the fact that Dr. Knudsen requested and received 
additional information from the company. Why is that? You had 
no idea?
    Mr. Laughren. Because, obviously, I didn't know about it.
    Mr. Walden. Okay. As you know, the company's response was 
May 1996, and so over 4 months before you write this memo. So 
this memo gets written. This is in the file somewhere in 
theory, because it is there today, and nobody reviewed it?
    Mr. Laughren. Well, again I said, now that I became aware 
of it very recently, I have reviewed it; and as I say, it 
supports--sorry?
    Mr. Walden. It doesn't raise serious----
    Mr. Laughren. Well, it answers the questions that Dr. 
Knudsen raised in his letter to the company. It provides 
additional data and, having looked at those data, it supports 
the conclusion that I am reaching in my memo, that there is no 
signal.
    I mean, really, the only data in that final safety update 
that Dr. Knudsen reviewed back in 1996 that is relevant are the 
controlled trials data for that one study in pediatric OCD. 
That was roughly--that was the study that we have subsequently 
reviewed, roughly 100 patients in drug, 100 patients in 
placebo. There is one suicidality event. That occurs in a 
placebo patient.
    That is really the only data there that are directly 
pertinent to the question.
    Mr. Walden. Let me just read the final paragraph of this 
memo. It is Tab 75. This is the one that you wrote to file. It 
says: ``In summary, I don't consider these data to represent a 
signal of risk for suicidality for either adults or children. 
Supplements are planned for both depression and OCD in 
pediatric patients, and when we have more complete data, 
including Ham-D data, we can look more critically at this issue 
using the now standard approach of comparing the proportions of 
drug and placebo exposed patients who show worsening on Item 3, 
suicidality item of the Ham-D during treatment. At the present 
time, current labeling simply notes Zoloft has not been 
adequately evaluated for safety and effectiveness in pediatric 
patients.''
    So you are saying that you are going to look at additional 
studies. Right?
    Mr. Laughren. Well, basically, what I am saying here is 
that we would likely look at the Ham-D item. Every one of these 
depression rating scales that is used in evaluating--they are 
often used in OCD trials as well. They have a standard suicide 
item. In the case of the Ham-D it is the Item 3.
    Dr. Hammad as part of his review of these pediatric 
suicidality data did look at the item scores. He looked at two 
measures of the item scores, both----
    Mr. Walden. But that was when?
    Mr. Laughren. Well, that was recently.
    Mr. Walden. Right. What happened between 1996 and recently? 
Did the agency look more critically at this issue? Did you put 
this in the pediatric trials for anti-depressants for kids, the 
written request?
    Mr. Temple. No. They all do that, though. They all do a 
Ham-D.
    Mr. Walden. Well, that is not my question. My question----
    Mr. Temple. No, no. It did----
    Mr. Walden. Now wait a minute. Dr. Temple, did the FDA 
specifically in your written request ask for exploration of 
this question, suicidality?
    Mr. Temple. The answer is we did not. But again----
    Mr. Walden. Why?
    Mr. Temple. At the time we issued--prepared and issued the 
written request, obviously, it was not an issue that was 
prominent in our thinking. Again, keep in mind, up until this 
point we had never seen a signal for suicidality in the adult 
data.
    Mr. Walden. But doesn't this memo indicate that this is 
something you needed to look at?
    Mr. Laughren. I did consider, and again, as I am saying, 
looking at the data that were available in this safety update, 
there was no signal for suicidality in children. The signal 
that emerged for Zoloft in pediatric patients came later. It 
came in the depression trials.
    There was one study here, only one study,an OCD trial. 
There was no signal in that trial.
    Mr. Walden. All right. But your memo says, when we have 
more complete data, including Ham-D data, we can look more 
critically at this issue. How did you look more critically at 
the issue? How did you go about getting more data?
    Mr. Laughren. We have looked more critically very recently, 
looking----
    Mr. Walden. Very recently?
    Mr. Laughren. Very recently.
    Mr. Walden. See, I am looking at this gap between 1996-97 
when some of these issues began to be raised by various people 
in FDA.
    Mr. Laughren. Well, raised but also addressed. There is no 
signal in these data.
    Mr. Temple. The first real signal came when Dr. Mosholder 
evaluated the Paxil data.
    Mr. Walden. And when was that?
    Mr. Laughren. That supplement came in, in probably the 
spring of 2002, and he finished his review in the fall of 2002, 
and that is when we----
    Mr. Walden. Didn't we already go through this with Mr. 
Mosholder on a 1997 memo where this was also raised as an 
issue?
    Mr. Laughren. Not suicidality. That was agitation and, by 
the way, that information got into labeling. That is included 
in the labeling for Luvox. There was no issue of suicidality 
raised in Dr. Mosholder's review.
    Mr. Walden. So from 1997 to 2002, how did the agency look 
more critically at the data?
    Mr. Laughren. We had no--again, up until the time that Dr. 
Mosholder reviewed the Paxil pediatric supplement in 2002, we 
had no reason to do anything more. There was no signal.
    Mr. Temple. Can I also repeat a distinction I made earlier? 
We thought at the time--and you can see that in Dr. Laughren's 
memo--that looking at the suicide item on a Ham-D or the 
equivalent in a pediatric score would be the way to find 
suicidality. That is plainly not true, because you don't see, 
as Dr. Hammad's review showed--you don't see any increase in 
that item even in the trials that show the increased 
suicidality.
    What turned out to be the place to look, which we didn't 
know, was in the adverse reaction reports, and I would say we 
don't know why that is. Why, if you are not feeling more 
suicidal, do you have more suicidal events? I don't think we 
know the answer to that. But it is very clear now that the way 
to look for suicidal ideation is to, in a more structured and 
better way that we have probably done up to now, look at those 
events that may represent suicidal behavior or thinking, and 
that the----
    Mr. Walden. There is a March 1991 article, a case study 
called Emergence of Self-Destructive Phenomena in Children and 
Adolescents During Fluoxetine Treatment.
    Mr. Laughren. Is that the King article?
    Mr. Walden. I am sorry?
    Mr. Laughren. I am sorry. Is that the King article?
    Mr. Walden. I believe it is, yes, sir.
    Mr. Laughren. Right, and that is reporting on individual 
cases. Those are not controlled trials data.
    Mr. Walden. Is this a peer reviewed study? Is this in 
Journal of American Academy of Child and Adolescent Psychiatry?
    Mr. Laughren. It very likely is. It came out around the 
same time as the Teicher article reporting on a series of, I 
believe, six adults being treated with fluoxetine. Again, it is 
a suggestion that there might be something, but it is far from, 
in any sense, definitive.
    Again, we had been systematically looking at the adult data 
for almost that entire decade, you know, looking at both 
suicide item scores, looking at event data, and more recently 
had begun to accumulate the completed suicides in adults, had 
not seen a signal. So there was no particular reason why that 
issue should have been on our radar screen.
    Mr. Walden. Okay. So, basically, you had no reason in these 
trials to even look for it, is what you are telling us? When 
you put out the written request----
    Mr. Laughren. They were looked at in the routine ways. 
Adverse events were reported, and the item data were collected. 
Again, a signal did emerge in the Zoloft data later on with the 
two pediatric trials in depression, but even that wasn't 
recognized until--actually, Dr. Mosholder was the medical 
officer who reviewed that supplement initially. He did not 
observe a signal for suicidality. it is only when he went back 
during the summer of 2003 and looked at--relooked at the same 
data that a weak signal emerged.
    Mr. Walden. Dr. Temple, did you have the authority to ask 
the companies to look at this, to keep better data so you 
could, in your written request to them?
    Mr. Temple. Let me be clear. You always measure the 
standard suicide scores, and we have the capacity to look at 
those. That is what you do in all these studies. It is how you 
measure improvement.
    So every time you do these studies, you get a suicidality 
score, and we look at it. There isn't anything the company has 
to do except give us the data. What we could have thought--what 
we conceivably could have asked but didn't know to ask was a 
better, more structured, more careful look at events that might 
or might not represented suicidality, but we didn't know to do 
that.
    Mr. Walden. But didn't Dr. Laughren say that in the 
depression trials you should look more critically?
    Mr. Temple. We were looking at the items in the Ham-D 
score, and nobody saw anything. It shouldn't surprise us that 
we didn't see it, because in the very data that have created 
the signal we are worried about now, you don't see any increase 
in the pediatric version of a Ham-D. That is not where it shows 
up, for some reason.
    Mr. Walden. I guess, as I have listened to this, and I have 
sat through these hearings a long time, the picture that begins 
to emerge in my mind isn't a pretty one, because it is one that 
says you are worried less about suicidality than in continuing 
to allow physicians to prescribe a drug that most studies show 
at best has no effect in treating depression in kids and 
adults.
    Mr. Temple. I don't agree that that is our conclusion. We 
spent tremendous resources and devoted tremendous effort to 
evaluate the suicidality question.
    Mr. Walden. Well, when Dr. Mosholder does the review and 
says I am spotting something here that is very troubling, when 
you are dealing with drugs in kids that virtually every trial 
shows have no effect and Dr. Mosholder is finding some link to 
suicide, you--well, it seems to me, my opinion is you ended up 
on the side of let them prescribe it, because they might be 
okay; we don't necessarily agree Mosholder has got this right; 
we are going to go run it out somewhere else and see, and take 
that risk.
    Mr. Temple. We didn't think we were letting them prescribe 
it or not letting them prescribe it. The question we were 
trying to face was do we have enough information to say there 
is increased suicidality in children given these drugs. That is 
what we were grappling with.
    Mr. Walden. You have said earlier today that you didn't 
want to discourage the prescribing of these off-label, because 
they may work in some people.
    Mr. Temple. That is a different question. We thought that 
it was very important to get the right answer on this question. 
That is correct.
    Mr. Walden. Well, I will tell you, I guess that is where we 
are just going to agree to disagree maybe, but if I had to err 
and I saw a sign from one of my top scientists that I 
handpicked to take a look at this and who I have a great 
respect for, and he came back and said I have looked at the 
data and I am seeing a link to suicide in kids, I'd say we 
better err on the side of caution here. And maybe you got to go 
peer review it, but meanwhile since most of these drugs don't 
show any efficacy in kids, let's err on the side of against 
suicide.
    Mr. Temple. But we put out several public announcements 
saying that you should be careful and that we are worried about 
this. We didn't change the label, though. That is correct.
    Mr. Walden. I have way overrun my time. Thanks for your 
patience. I yield to the ranking member, Mr. Deutsch.
    Mr. Deutsch. Dr. Temple, in an earlier point there was a 
discussion regarding this issue of different sort of 
contraindications for children versus adults, and you are 
saying that it applies to both--you know, no separation of 
warning. At what point is a recommendation that there be a 
separate warning? Are there separate warnings--I mean, how 
atypical is this? Is this the process? Is this the procedure? 
Are there cases where you do have separate warnings?
    Mr. Temple. Well, the warning language that will describe 
the now documented increased--now we believe it is documented. 
Maybe someone else thought it was documented before. What we 
now believe is the documented increase in suicidality in 
children. That will be a separate statement, because we don't 
think such a----
    Mr. Deutsch. What tips it to make that difference, the 
separation?
    Mr. Temple. Well, it isn't so much the separation, but we 
now----
    Mr. Deutsch. Well, the dual warning.
    Mr. Temple. Well, we now believe--we have not seen such a 
thing in adults. As I mentioned before, Dr. Mosholder presented 
an analysis on Paxil that quite clearly does not show that 
finding in an adult population, using the same methods that 
showed it in pediatrics.
    So you need a special warning on that subject for children, 
because they are the ones who get that reaction. The warning in 
March was about pay attention to people when you are starting 
therapy. That is still a good warning for everybody. That still 
applies to everybody.
    Mr. Deutsch. I guess the question I am trying to get at is 
at what point do you tip the balance and then say a separation 
for children?
    Mr. Temple. I don't think it is a balance. I think, as soon 
as you have information that says children are different, you 
do it.
    Mr. Deutsch. And are you looking for that information or is 
it just----
    Mr. Temple. Well, one of the points of doing studies in 
children is that very point, to see if they respond 
differently.
    Mr. Deutsch. Right, but is that only done in terms of, you 
know, the incentives that we have put on in terms of increased 
exclusivity based upon that issue?
    Mr. Temple. The usual request for data, written request for 
data, includes a request for studies of effectiveness, 
pharmacokinetic studies because that can be something, and a 
safety study . That is what they usually consist of.
    Mr. Deutsch. Right, but generally those safety studies 
don't break out children. So that----
    Mr. Temple. Sorry. This is for a written request on gaining 
pediatric exclusivity.
    Mr. Deutsch. Right.
    Mr. Temple. So that is only children.
    Mr. Deutsch. Right. Right, but if it is a pediatric 
exclusivity, then you would have that. But outside of that, a 
pediatric exclusivity, then you would have no information.
    Mr. Temple. Outside of that, it is extremely hard to get 
any studies in children. That is why we have the Best 
Pharmaceuticals for Children Act, because children--well, it is 
extremely unusual, and most people would say it is not 
appropriate, to start studies of children before you have the 
drug properly worked up in adults. There's a lot of nervousness 
about, you know, children can't give consent and so on.
    So it has always been true, whether we have the Best 
Pharmaceuticals for Children Act or before, that we expected 
the pediatric studies to be done afterward.
    Mr. Deutsch. If I can switch to Dr. Seligman, I have a 
series of questions, but I want at least to open it up and give 
you an opportunity, because my understanding, this has not been 
brought up at this point, which is the investigation 
regarding--I guess in response to the San Francisco Chronicle 
article detailing the FDA's decision to remove Dr. Mosholder's 
presentation.
    If you can at least give us your perspective of why that 
investigation began and the appropriateness of that 
investigation.
    Mr. Seligman. Certainly. Both prior to and subsequent to 
the publication of two articles in the San Francisco Chronicle, 
a number of staff in the Office of Drug Safety approached me 
raising a concern of the possibility that there may have been 
an inappropriate disclosure of confidential information to the 
reporter at the San Francisco Chronicle.
    Upon receipt of that information, as you have in your book, 
I forwarded those concerns on to the Office of Internal Affairs 
at the FDA.
    Mr. Deutsch. Did you result in finding who had leaked the 
information?
    Mr. Seligman. I'm sorry?
    Mr. Deutsch. Did you find out who leaked the information?
    Mr. Seligman. No, I did not.
    Mr. Deutsch. If you can turn to Tab 65, an e-mail dated 
February 20, 2004, from yourself to Horace Coleman and Thomas 
Doyle at the Office of Internal Affairs in which you outline 
your reasons for initiating this investigation. You attached an 
article, the San Francisco Chronicle article.
    I assume you are familiar with the article. Is that 
correct?
    Mr. Seligman. Yes, I am.
    Mr. Deutsch. Your e-mail states that a member or members of 
the staff of the Office of Drug Safety may have inappropriately 
disclosed information of a sensitive matter.
    Were staff members of the Office of Drug Safety the only 
people with access to the information contained within the 
newspaper article?
    Mr. Seligman. No, they were not.
    Mr. Deutsch. But you were only concerned with the 
activities of your staff?
    Mr. Seligman. No, I was not.
    Mr. Deutsch. Then why is the memo only talking about the 
staff of the Office of Drug Safety?
    Mr. Seligman. Only members of the Office of Drug Safety 
raised the concern to me that such information had been 
improperly disclosed.
    Mr. Deutsch. Why would that be?
    Mr. Seligman. Because I am their direct supervisor.
    Mr. Deutsch. Right, but if you are asking Internal Affairs 
to be looking for a leak in your office--I mean, the leak would 
only be within that particular group of people?
    Mr. Seligman. I don't believe I stated that I thought the--
that is correct. I did say that I am concerned that a member or 
members of the staff of the Office of Drug Safety may have 
inappropriately disclosed information. I did state that, 
although in my interview with the Office of Internal Affairs, I 
did point out that there were clearly others who had access to 
such information as well.
    Mr. Deutsch. If you turn back to Tab 66, the report of the 
investigation, on page of that report it notes that you named 
five employees of the ODS who had been called at home by 
Waters. How did you know that these five individuals had been 
called at home?
    Mr. Seligman. They either came to me or they reported such 
to my deputy, Dr. Anne Trontell, who informed me of that 
information.
    Mr. Deutsch. And apparently another ODS employee, David 
Bram, merely because he had been very vocal in the past 
regarding the scientists' findings being suppressed--did you 
call--again, is that--we are trying to understand why--I mean, 
were you suspicious of people within your own group for any 
particular reason because of actions like that?
    Mr. Seligman. As I indicated in the interview, the 
investigator asked me whether there were people of whom I had 
particular concern in the office, and I indicated as such, that 
there were such individuals.
    Mr. Deutsch. If you turn to the conclusions on page 6, you 
will note the initial conclusion was that no evidence was found 
that classified or proprietary information from the FDA was 
released. In fact, the release of the classified or proprietary 
information is the only basis to initiate an investigation into 
a leak. Is that correct?
    Mr. Seligman. That is correct.
    Mr. Deutsch. So let me just again follow up on Tab 69. The 
fourth page of that exhibit is headed by the date 5/7/04. This 
is a document which Horace Coleman of the Office of 
Investigation noticed that he is closing the case, and further 
noticed that he had to ask you to contact Dr. Mosholder to 
assure him that he was not a specific target of this 
investigation, that OIA found no evidence to indicate that 
classified or proprietary information had been released and 
that OIA was closing the investigation.
    Why did Mr. Coleman need to have you assure Dr. Mosholder 
that he had not been the target of this investigation?
    Mr. Seligman. I don't know the answer to that question, but 
I did reassure Dr. Mosholder of that fact.
    Mr. Deutsch. On that same page, Dr. Coleman notes that he 
had advised you that he would also contact the CDR Director 
Galson to advise him of the above information. Since Galson had 
left the office to attend an awards ceremony, he would be 
requesting his director, Terry Vermelion, to reach out and 
debrief Director Galson.
    This raises several questions. What was the urgency to get 
this information to Galson?
    Mr. Seligman. I have no--I don't know the answer to that 
question.
    Mr. Deutsch. And what about the propriety to initiating an 
investigation? Whom did you talk to in CDER and what were their 
opinions about your proposed actions?
    Mr. Seligman. I took these actions independently. I 
informed Dr. Galson, who is indeed my supervisor, that I was 
considering such action, but received no direction from him, 
one way or the other, as to whether I should take it. He was 
the only person with whom I discussed these matters.
    Mr. Deutsch. Who did you keep informed regarding the 
progress of the investigation?
    Mr. Seligman. The only time I received any information 
about the progress of the investigation was at the conclusion 
of the investigation on May 10 when I met with Agent Coleman 
and Kurisky who provided me the report and debriefed me on the 
investigation.
    Mr. Deutsch. One final question. This summary report, also 
Dr. Hammad's reanalysis and its comparison to Dr. Mosholder's 
original work was widely reported in the press before FDA 
released any of the information publicly.
    My understanding is you did not initiate an investigation 
into these leaks and, if not, why not?
    Mr. Seligman. I did not report those allegations to the--I 
did not--that is correct. I didn't mention that to the Office 
of Internal Affairs.
    Mr. Deutsch. Why was that different than the earlier 
release?
    Mr. Seligman. Probably no different than the earlier 
release.
    Mr. Deutsch. I mean, there is no basis for the difference? 
The original investigation is technically considered a criminal 
investigation. I mean, is it just by whim that we start 
criminal investigations? I mean, is there some basis of 
differentiating?
    Mr. Seligman. This is not treated as a whim. I take, and I 
imagine everyone at the agency takes the protection of 
proprietary information and trade secret information very 
seriously. When allegations of such are brought to my 
attention, I----
    Mr. Deutsch. Let's be very specific, though. The Mosholder 
thing didn't involve proprietary information.
    Mr. Seligman. As it turned out, that is correct.
    Mr. Deutsch. Right, but even the allegation, even the 
report wasn't proprietary.
    Mr. Seligman. The allegation had to do with inappropriate 
disclosure of----
    Mr. Deutsch. Yes, but not proprietary.
    Mr. Seligman. That is correct. Inappropriate disclosure of 
confidential information. That is correct.
    Mr. Deutsch. I mean, I am just going to ask one more time 
and give you a chance to maybe try to be clearer or think 
again. But why were these two leaks treated differently?
    Mr. Seligman. I can't explain why they were treated 
differently.
    Mr. Deutsch. And it was your decision to treat them 
differently.
    Mr. Seligman. It was probably my oversight in the latter 
circumstance to treat it differently, yes.
    Mr. Deutsch. Thank you.
    Mr. Walden. Dr. Seligman, can we go to this affidavit 
again.
    Mr. Seligman. Certainly. What tab was that?
    Mr. Walden. This is troubling just in--this is the one that 
I think is Tab 57, I believe, sir. Now walk me through again. 
What was the reason for, and who would have suggested that Mr. 
Mosholder modify this?
    Mr. Seligman. I wasn't involved in that at all.
    Mr. Walden. Who was?
    Mr. Seligman. I would have to turn to Dr. Mosholder for 
that. I wasn't involved in the discussion or consideration of 
this affidavit.
    Mr. Walden. Okay, but this is an affidavit that was 
provided to you. Right? The original affidavit?
    Mr. Seligman. The affidavit did appear in the May 10 
report. That is the first time that I saw it.
    Mr. Walden. All right. So it was an official affidavit. It 
comes to your--it is part of your investigation. Right?
    Mr. Seligman. It was part of the Office of Internal Affairs 
investigation Mr. Walden. I'm sorry. All right, part of the 
Office of Internal Affairs.
    Mr. Seligman. I did not conduct any such investigation.
    Mr. Walden. All right. So I guess what I am trying to 
figure out with this affidavit is what was the need to--who can 
answer why this affidavit would need to be altered to be 
presented to somebody else?
    Mr. Temple. I don't think anyone at the table can. It was 
my understanding that a letter or something like that has been 
sent to the committee explaining all that. Am I mistaken?
    Mr. Walden. All right. If there is nobody here that can 
address that, I believe we do have a letter. I just remain 
concerned about it is all. I was hoping to dive in a little 
deeper on it, because it is sort of----
    Mr. Temple. I am sure, if after looking at our response the 
committee has more questions, we will be glad to answer them.
    Mr. Walden. I appreciate that, Dr. Temple. Dr. Hammad, 
would you agree that, with only 400 or so person years of 
exposure that FDA cannot rule out that there is a risk of 
suicidal behavior of one out of 100? I'll make you a deal. You 
turn your mike on, and I will repeat the question. There we go.
    Would you agree that, with only 400 or so--we are talking 
about the pediatric clinical trials. Would you agree with only 
400 or so person years of exposure that FDA cannot rule out the 
possibility there is a risk of suicidal behavior of one out of 
100?
    Mr. Hammad. Actually, I did not deal with the person years. 
I used the individuals as the unit of analysis. So I can't 
answer the question, because I did not analyze it.
    Mr. Walden. Dr. Mosholder, would you mind returning, and 
perhaps you could help us on this question. I appreciate your 
long day here, sir.
    Here's the deal. You have 10 million prescriptions for 
anti-depressants written on an annual basis for children in the 
United States, and so how many person years of exposure would 
you estimate this prescription volume represents?
    Mr. Mosholder. Well, 10 million prescriptions, just a very 
rough rule of thumb, one would figure a month per prescription 
is usual practice. So that would be 10 million months divided 
by 12. So I guess that is something like 800,000 person years, 
if my arithmetic is correct.
    I think you may be referring to a calculation that was in 
my March consult report, if I may. If that is in this binder, 
perhaps I can refer to it.
    Mr. Walden. Yes, sure. I think it was in your presentation, 
too, the PowerPoint presentation that is dated September 13, 
2004. It is one of the slides there. Reference is 406.9 patient 
years.
    Mr. Mosholder. Oh, yes, that is correct. Having observed no 
actual suicides in that amount of person time, there is a way 
to calculate sort of the upper limit of what a true number of 
suicides might be expected, which I did in my March consult. If 
it is in the binder, I can probably find that.
    Mr. Walden. We are going to see if we can't find it in the 
binder. It looks like there are 74 sponsored defined suicide 
related events, 54 serious, it says on your slide. But again we 
are trying to find the right tab in our binder of documents. 
Tab 53, I am told.
    Mr. Mosholder. Oh, yes. These are my slides from last week. 
The calculation I was referring to, I think I can find in the 
March consult document, which I think may address your 
question.
    Mr. Walden. Well, I'll tell you. Why don't we go to this 
question, the one that is more recent, dealing with the 400. I 
guess the question is: Would you agree that with only 400 or so 
person years of exposure that FDA cannot rule out there is a 
risk of suicidal behavior of 1 out of 100?
    Mr. Mosholder. I am not sure I----
    Mr. Temple. You don't mean suicidal behavior. You mean 
suicide.
    Mr. Mosholder. Do you mean--yes, that was my question.
    Mr. Temple. Suicidal behavior, we know, occurs at 2 percent 
in the control group and about 4 percent in the treated group. 
So as Dr. Hammad showed, there is a 2 to 3 percent frequency of 
that. I think you must be referring to how sure can you be that 
there are no suicides, and the answer is, with that exposure, 
you don't have much information on that.
    Mr. Mosholder. Yes. If I can refer to my March consult, 
which is Tab 29, page 20 at the top paragraph, this is a 
calculation I did based on some statistical assumptions. The 
upper one-sided 95 percent confidence limit for the actual rate 
given in observation----
    Mr. Walden. Dr. Mosholder, can I interrupt you a second, 
sir. What page in that document are you referring to?
    Mr. Mosholder. Page 20.
    Mr. Walden. Page 20. Thank you. Okay, and where are you on 
that page?
    Mr. Mosholder. The top paragraph on that page, I think, is 
maybe pertinent to your question.
    Mr. Walden. Okay. Go ahead and read that for us, would you.
    Mr. Mosholder. Yes. What it says is that the upper 95 
percent confidence limit, as we say, for an actual rate in the 
population given an observation of zero suicides out of 407 
patient years of exposure is 1 in approximately 136 patient 
years, the point being not the numbers so much, but just to 
illustrate that 407 patient years, as we reckon these things, 
doesn't--it only goes so far in reassuring about whether or not 
there is a risk of actual suicide as opposed to suicidal 
behavior, which we have already established is increased.
    Mr. Walden. So, basically, 400 patient years is not a very 
long time for the kind of research you need or the data you 
need?
    Mr. Mosholder. Well, the real question here, one of the 
limitations of all this is that the real issue is whether there 
is an impact on suicide, not just suicidal behaviors, and we 
don't have enough information to really address that as 
adequately as one would like.
    Mr. Walden. But there could be a risk of death?
    Mr. Mosholder. There could be----
    Mr. Walden. You can't rule that out either.
    Mr. Mosholder. There could be. The clinical trials aren't 
long enough in exposure to give us a precise risk estimate.
    Mr. Walden. But you do know from the data we have that 
there is a higher risk of suicidality. Correct?
    Mr. Mosholder. That is true.
    Mr. Walden. Okay. All right. Dr. Temple, on page 4 of your 
testimony you state, the pediatric suicide rate, ``has fallen 
about 25 percent over the last decade, the period in which the 
use of anti-depressants has grown steadily. This association 
does not prove that the increasing use of anti-depressants is 
the cause of the decline in suicide, but it at least is 
suggestive.'' However, according to the slide presentation by 
Dr. Diane Wiskausky of FDA's Office of Drug Safety before the 
September 2004 Advisory Committee meeting, the increasing use 
of anti-depressants and decreasing suicide may simply co-exist 
and may not relate at all to each other. Her slide states that 
correlation does necessarily imply causality, and that numerous 
factors may be coincidental, not causal.
    Dr. Temple, did you ever have a discussion on ecological 
association with Dr. Wiskausky?
    Mr. Temple. Well, we talked a little at meetings about 
this. I don't think I had a particular discussion, and I don't 
disagree with the assertion that these kind of data are hard to 
interpret. There could be other factors. But these were 
presented to us at an Advisory Committee by people who thought 
that there weren't any obvious other explanations, and it is 
something to be considered.
    I would never allege that that is proof. It is not a 
controlled trial. You can't do controlled trials of that, but 
it is what you got. And it also doesn't seem to be going up, 
which is not a trivial matter either, because the drug use has 
been going through the roof, as people have pointed out.
    Mr. Walden. If that is all the case then, why would the 
Europeans suddenly find there are problems?
    Mr. Temple. Well, I don't think the Europeans found 
anything that we didn't find also. In fact, they used our data. 
The question is what to do about it. What they decided to do 
about it was tell everybody to start with Prozac and, if that 
doesn't work, only experts should use the other drugs.
    You know, it depends on the arrangements you have, whether 
experts are available, and a lot of other things. That 
determines what you do.
    One of the major concerns of our advisors was that people 
who aren't really knowledgeable about these drugs are using 
them, and that is one of the reasons, you know, all these 
warnings go in there. One of the hopes--there is sort of pro 
and con here. One of the hopes is that it will scare people who 
aren't very qualified into sending people to doctors who are.
    Nonetheless, the same figures, I understand, are seen in 
Europe, too, that the rate is declining.
    Mr. Walden. But they prescribe a far lower percentage, do 
they not, among this class?
    Mr. Temple. Yes, they do. That is correct.
    Mr. Walden. Do you know the difference?
    Mr. Temple. No, I wouldn't have those figures.
    Mr. Walden. I thought I had heard it was like 1/6 of what 
we do in young people.
    Mr. Temple. That could certainly be.
    Mr. Walden. That would tend to lend some credence to Dr. 
Wiskausky, her comment that it may not be causal.
    Mr. Temple. Well, or it could mean they are better at 
picking the people who really can benefit.
    Mr. Walden. I see.
    Mr. Temple. One of the concerns that was expressed. There 
isn't any doubt that people--almost everybody thinks the drugs 
are used casually for people who really probably don't need it, 
and if there is a risk of making people worse, there may be no 
compensating benefit in those people. So that is a legitimate 
worry.
    Mr. Walden. Just seems like, when these concerns have been 
raised, again it seems like effort by the FDA hasn't been to 
put that word out. You've really erred on the side of caution 
in terms of putting any word out there that there may increased 
rates of suicidality, and yet when the studies are there that 
show these may be no more effective than sugar pills, that 
doesn't seem to be something that gets put out there much. I 
just--I don't get it.
    The Chair recognizes the gentleman from Michigan, Mr. 
Stupak.
    Mr. Stupak. Thank you, Mr. Chairman. On the last document 
you just showed from Diane Wiskausky--this was shown at last 
week's Advisory Committee hearing--underneath there it mentions 
a patient level controlled observation study, the Jick, et al., 
study. Is that Dr. Jick from Saskatchewan, Canada? Do you know?
    Mr. Temple. No. I think he operates out of Seattle.
    Mr. Stupak. Okay. I was interested in your conversation 
when you were going back and forth with the Chair on, you call 
it, suicidality scores or signals, and you were saying, not 
that Dr. Mosholder was wrong, but you were looking at different 
signals, and there's different signals to look at, and you 
mentioned the Hamilton-D scale, Hamilton depression scale, Ham-
D you called it. Okay? Remember that?
    Mr. Temple. Yes.
    Mr. Stupak. Earlier today when Dr. Mosholder was 
testifying, I had a couple of exhibits there. One was 
pharmacology/toxicology consultation from September 2001, and 
that was on Accutane, but they related to an SSRI. Remember 
that discussion?
    Mr. Temple. Yes.
    Mr. Stupak. Then I had the PET scan which, again with 
Accutane at 4 months, showed a decrease in the brain in the 
frontal orbital lobe. You remember that?
    Mr. Temple. I remember that. Not that I know how to read 
those.
    Mr. Stupak. I'm not asking you to read it. But that study 
showed that the 17-year-old was noted by her family and 
clinician to have behavioral disturbances and dropped out of 
school. She did not, however, have a clinically significant 
increase in depression as measured by the Hamilton depression 
scale. Even though we can see a physical change in the brain, 
the Hamilton-D scale did not pick it up, but the PET scan 
picked up.
    Are we maybe looking at the signals?
    Mr. Temple. Maybe Tom knows the answer to this. I don't 
know how well any particular brain lesion or finding has been 
correlated with depression. The world is full of people who are 
trying to do that, to try to pick out who is going to be a 
responder and things like that. But I don't know that 
literature. So I don't know whether there is a credible PET 
scan that indicates depression or anything like that.
    Mr. Laughren. I am not an expert in that area, but from 
what I know, most experts agree that we don't understand--we 
really don't understand the pathophysiology of depression or 
any other psychiatric illness. But what I wanted to come back 
to is this issue of whether or not the Ham-D, as it is 
currently used, or any other depression rating scale, is an 
adequate instrument for assessing suicidality.
    I think that is one of the things that we have learned 
here, and one future direction in which we are moving and 
trying to greatly improve our ability to do ascertain it for 
suicidality. This is one of the things that we hope to come out 
of this collaboration with Columbia University.
    The one thing that they have done is help us in classifying 
more appropriately and rationally events, but the other thing 
that was apparent in these trials is that it appeared patients 
were not asked all the right questions.
    Mr. Stupak. Well, isn't the questions on the Hamilton-D 
scale the same?
    Mr. Laughren. No, no. Again, there is no clear instruction 
on these instruments as to what sort of follow-up questions 
should be asked if a patient responds positively. That is 
something that Columbia is working on, developing an instrument 
that gives clinicians very clear instructions about how to 
follow up if there----
    Mr. Stupak. Sure, but the point here is the patient, 
whether you want to believe the PET scan or not, had social 
behavior, like dropping out of school and behavioral 
disturbances, but one of the scales you used, the Hamilton-D 
scale, to judge depression didn't pick it up, which would 
indicate--which would indicate either the person didn't tell 
the truth when they did the testing on the Hamilton-D scale and 
is good enough to fool the clinician and everything, or does it 
really beg to another question that maybe there really is 
something going on here in the brain with these SSRIs that we 
are not picking up and we never thought of before.
    That's the only question. I am putting forth another 
possibility here, because the jury is still out, as you keep 
saying, and if the jury is still out, I think you ought to 
start looking at other factors, because obviously you guys are 
missing something.
    I think Dr. Mosholder, more or less, said that. You didn't 
want to believe his stuff. So you went to a different set of 
signals, and those set of signals, at least according to the 
little bit I have seen from this one study, can be fooled.
    Have you ever thought about bringing in outside experts 
other than just the FDA, like a workshop to bring in other 
experts and see what is happening with the orbital frontal 
cortex, which is an area we know mediates depression, or the 
hippocampus with retinoids and all these other things, and the 
SSRIs. Have you thought about bringing in outside experts, 
outside the FDA, to take a look at this data and ask them their 
suggestions on how do we get to this problem, which we don't 
seem to have a good answer for?
    Mr. Laughren. It is undoubtedly true that our understanding 
of depression and other psychiatric illnesses is in its 
infancy. We really do not understand them at a biological 
level. There is a lot of work going on. You know, it is 
something that we would hope in the future to have a better 
understanding of.
    There is a lot of work going on, trying to identify various 
genetic markers and other things that might help us make 
distinctions among people who clinically all look the same.
    I mean, that is one of the problems, is that you have a 
number of people who all have the same--roughly the same 
clinical state, but they may have different underlying 
pathophysiologies, and that may explain why some respond to 
drugs differently than others, both in a positive sense and in 
a negative sense. We just don't understand this.
    Mr. Stupak. Absolutely. So that is why I am asking, have 
you brought in different people for a workshop or a study to 
look at this anti-depressant, this SSRI, to see what are we 
missing here? Do we have different ideas on how best to explore 
it, to measure it, test it, to do some studies?
    Mr. Temple. Tom is going to know this better. There are 
just constant workshops on these very questions, some of them 
devoted to----
    Mr. Stupak. Okay. But I am asking about SSRIs. Have you 
done that, like you have done for Accutane and some of these 
others? Have you done that? That's what I am asking.
    Mr. Temple. You mean to see if there is something about the 
effects on the brain of SSRIs that would tell you something? Is 
that the specific question?
    Mr. Stupak. No. The question was: On SSRIs have you brought 
in to do a workshop to try to figure out maybe what else--are 
we just missing something, just kick it around with the 
experts, whether it is the talk about SSRIs, the effect on 
hippocampus where we know there is depression, the frontal 
orbital cortex where we know it mediates depression, different 
ideas other than--you know, we all, even Members of Congress, 
believe it or not, get rigid in our thinking, and sometimes we 
don't think outside the area and bring i n other experts to 
help us out.
    Have you done that in this problem which has confronted you 
on these anti-depressants? That's all the question is. No 
trick, just a simple question.
    Mr. Temple. I'm sure Tom would know better. There are 
constant workshops on every neurologic disease and every 
psychiatric disease you can name on these very subjects. They 
must, by definition, deal with the question of whether the 
drugs work differently and things like that.
    I mean, I don't go to those workshops, but the people in 
the Division regularly would. The interest in those things is 
partly because people, as Tom said, hope to find out who is a 
responder and who is not, who gets toxic and who doesn't, and 
it is partly because people hope to be able to choose drugs to 
develop better on the basis of the effects on some of these 
markers.
    So there is a tremendous amount of interest in it. But I 
can't speak to SSRIs particularly.
    Mr. Stupak. Okay. Let me ask you this, Dr. Temple, just a 
couple of quick questions here. My time is almost up. I want to 
ask a couple of series of questions on the pediatric 
exclusivity.
    As I understand it, there's 293 written requests that have 
been written by the FDA for products to be studied in children. 
Of these 393, studies have been submitted on over 110 products. 
How many of these studies were efficacy studies?
    Mr. Temple. I am just not going to know the answer to that. 
In neurology----
    Mr. Stupak. Do you require efficacy studies on all drugs? 
Do you require efficacy study? No?
    Mr. Temple. Not necessarily.
    Mr. Stupak. Why not?
    Mr. Temple. There are some kinds of drugs where the 
pediatric request is based on what you call a pharmacologic 
effect. For example, if you wanted to see whether a beta 
blocker works in children, you might look at heart rate, if 
that was thought to be relevant, for example, for protection 
against arrhythmias. That is a judgment call.
    In psychiatric disease, there is no marker like that. So I 
am quite positive that everyone of them called for efficacy 
studies.
    It is worth noting that the written requests in depression 
always called for at least two studies, because we know it is 
so hard to do. The written request in other things, like 
obsessive compulsive disease, sometimes have only called for a 
single study.
    Mr. Stupak. So you don't know how many efficacy studies 
were done of these 293 studies. Right?
    Mr. Temple. I don't. I may have some notes on it. I will 
keep looking.
    Mr. Stupak. We will put it in writing to you, because we 
would really like to know that.
    Mr. Temple. Okay, that's fine.
    Mr. Stupak. Of those for which efficacy studies were done, 
how many showed they were not effective, that there was no 
efficacy?
    Mr. Temple. Yes. I'm not going to know that either, but we 
can get you the answer.
    Mr. Stupak. It would be interesting, because we are working 
on some legislation on pediatric exclusivity.
    If efficacy is shown, is this then added to the label of 
the drug in pediatrics?
    Mr. Temple. At least usually, and we can get you numbers on 
how many have had----
    Mr. Stupak. And if efficacy is not shown in a pediatric 
study, is that added to the label?
    Mr. Temple. Well, we are in the process of changing our 
view on that. Historically----
    Mr. Stupak. Up until today, before you change you mind, was 
efficacy--if efficacy was not established, was that put on the 
label?
    Mr. Temple. Usually not.
    Mr. Stupak. So we give them the good news but not the bad 
news.
    Mr. Temple. Well, the reason, which you have heard me say 
before, is that failing to show something in a trial doesn't 
mean that it doesn't work. This is not related to the pediatric 
setting particularly.
    Mr. Stupak. Sure.
    Mr. Temple. However, in reconsidering this, what we have 
come to think is that, really, the whole point of the Best 
Pharmaceuticals for Children Act is to find out if what you 
know--mostly--mostly--is to find out if what you think you know 
about--what you know about adults is applicable to children, 
and it is more relevant than usual to say, hmm, I didn't see 
anything in children. We are intending to put----
    Mr. Stupak. When you are talking about adults and children, 
dosage has a lot to do with that, too, does it not?
    Have you done any dosage studies on the SSRIs ?
    Mr. Temple. No. The substitute for dosage studies--and it 
is not an adequate substitute--is to look at the 
pharmacokinetics and at least try to get close on the blood 
levels. Dose response information in a disease that is hard to 
study at all is murderously difficult to get.
    Mr. Laughren. Actually, I have one comment on the question 
of SSRIs and dose and exposure. Actually, the written request 
for the Luvox application was specifically focused on looking 
at pharmacokinetics, because what we found--the company had 
already done the efficacy trial even in advance of the written 
request. They had done the one study that we actually talked 
about earlier.
    What they had shown is that the drug appeared to work in 
children, but there were also adolescents in that trial. It did 
not work. So we asked them as part of the written request to go 
back and look at exposure, and that helped us to understand 
possibly why that trial had failed to show efficacy in 
adolescents.
    Mr. Stupak. Well, our concern is, being the policymakers 
and writing the Best Pharmaceuticals--I didn't write it, thank 
God. But in 1997 when we did it, and again in 2001, the Best 
Pharmaceutical Act, we were told efficacy would be labeled. Now 
you are telling us, up until today, it has not been labeled.
    That was one of the big contentions on this committee. If 
you are going to give people the good news, you also have to 
give them the bad news.
    Mr. Temple. Just let me be sure I understand. You were told 
that, if the studies were negative, that would go in?
    Mr. Stupak. That would go in?
    Mr. Temple. That would go into the labeling.
    Mr. Stupak. Of course, you shouldn't label before you give 
the patent extension, so people know what the heck is going on. 
But we don't do that either.
    Mr. Temple. We have pretty much decided to do that. So it 
is a little late, but we are going to do that.
    Mr. Stupak. We are not a little late. FDA is a little late, 
since 1997.
    Mr. Temple. That is what I said. We are a little late.
    Mr. Stupak. Okay. I thought you said it is a little late 
now. All right. Probably got time to vote.
    Chairman Barton. Is the gentleman through? Okay. The Chair 
would recognize himself for what he hopes to be the last 10 
minutes. I'm sure you all are glad to hear that.
    We want to thank you all for being here this afternoon. It 
has been a long day, and I appreciate your patience. I have 
just 2 or 3 questions, and then a wrap-up.
    I am going to direct some of these questions to Dr. 
Knudsen--Is it Knudsen or K-nudsen? Knudsen? Sure. Okay. You've 
got to push that little button there.
    Now I know that some of this ground has been plowed before, 
but I wasn't here when it was plowed. So I apologize if we have 
gone over this.
    You are aware that your letter of March 19, 1996, was not 
in the FDA file. I think you are also aware now that there are 
two versions of the letter that wasn't in the file, one 
apparently a typographically incorrect that was sent at 10:18 
on March 19, 1996. The other was sent at 12:10.
    I believe you told the staff that you have no recollection 
of these letters. Is that correct or incorrect?
    Mr. Knudsen. That is correct.
    Chairman Barton. So once you saw the letters, did that 
revive any memories of them?
    Mr. Knudsen. No.
    Chairman Barton. What were you involved in, in March 1996, 
that would have caused you send these letters to the Pfizer 
Corporation?
    Mr. Knudsen. I was involved in the review of the OCD NDA 
Supplement for Certraline.
    Chairman Barton. Which is an anti-depressant?
    Mr. Knudsen. That is correct.
    Chairman Barton. And they were attempting to have it 
approved for use in adults or in adolescents?
    Mr. Knudsen. Treatment of OCD in adults, I believe.
    Chairman Barton. And you--were you the reviewer of that 
application or were just asked to comment on it by somebody 
that was reviewing the application?
    Mr. Knudsen. I was the reviewer of the supplement or the 
OCD supplement submitted by Pfizer--for Certraline by Pfizer.
    Chairman Barton. Taking aside the point that the letter 
wasn't in the file, and apparently you didn't have a copy in 
your personal files, the substance of the letter is that it 
appears--and I will read the last paragraph: ``We note''--These 
are your words: ``We note that there appears to be an increased 
frequency of reports of suicidality in the pediatric/adolescent 
patients exposed to Certraline compared to either placebo or 
Certraline treated with adult OCD patients. If this in fact the 
case, what would be a plausible explanation?''
    So even though you have no recollection, you apparently 
were looking at some data that caused you to think that, if 
this particular drug was used, it would increase suicidality in 
the pediatric population, which is a serious concern. Would you 
agree with that?
    Mr. Knudsen. Yes.
    Chairman Barton. Now once you sent the letter, apparently 
you and everybody at FDA forgot about it. Is that true or not 
true?
    Mr. Knudsen. I want to back up a second. I commented upon 
the fact that I did not recall at the time--since it was 1996 
this letter was generated, I personally do not recall 
information back that length of time. Even with looking at the 
letter, you asked if I generated the letter or if I recall 
generating the letter. In fact, as I said, I do not recall 
writing the letter.
    It does not mean that I did not. I simply do not recall. I 
understand. But 1996, for me--even yesterday is a little 
difficult to remember sometimes. But 1996, quite frankly, as I 
told the subcommittee folks who called me in Maine, much to my 
chagrin, I simply do not recall writing that letter. I may 
have.
    Chairman Barton. You do recall that you were involved in 
the review of an application for the drug.
    Mr. Knudsen. That is correct, although that is a bit 
different than generating and writing a letter and not--I 
just----
    Chairman Barton. Well, but this isn't a run of the mill 
application. Your last paragraph is pretty important. ``There 
appears to be an increased frequency of reports of suicidality 
in the pediatric/adolescent patient exposed to Certraline 
compared to either the placebo or the Certraline treated with 
adult OCD patients.''
    That is a pretty important finding or pretty important 
question. Yet once you sent the letter off, which nobody at the 
FDA kept any copies of, everybody forgets about it until 8 
years later or 6 years later.
    Mr. Knudsen. Well, in fact----
    Chairman Barton. You can't even remember writing the 
letter.
    Mr. Knudsen. Well, I mean, how many people in this room, I 
would like to ask, can remember writing letters in 1986? This 
is purely speculative, and I am not going to speculate. I 
cannot recall writing the letter.
    The point of fact is it is a very important issue. I may 
have written it. For simplicity, I will say I did write it, and 
because I was very much concerned about this issue when I 
reviewed the OCD----
    Chairman Barton. You are missing my point. Nobody is 
challenging whether you wrote the letter or not. Now if you 
want to--you know, you said it looked like your signature, so 
you probably did or you did. You will stipulate. I could care 
less.
    What I am concerned about, that we have a drug that is 
being used in adolescents to treat depression and, according to 
whoever wrote this letter, there appears to be an increase in 
suicidality. Now that is an important thing, and nobody at the 
FDA did anything on it for 6 years. That is pretty important.
    Mr. Temple. That is not entirely correct. Dr. Laughren 
reviewed----
    Chairman Barton. It is more correct than incorrect.
    Mr. Temple. Dr. Laughren reviewed the data that was the 
basis for that letter, wrote a memo.
    Chairman Barton. Well, you all didn't even find a copy, and 
now we got two different copies from the drug manufacturer, and 
we get--when we asked about document retention policy--you 
don't have access to this, because it didn't come in until 
today.
    It is an e-mail that was sent today to the young lady to my 
right, and it says, ``FDA does not have a specific regulation 
that governs the record retention of NDA files and drug master 
files.''
    It is pure serendipity that the manufacturer kept a copy.
    Mr. Temple. I think the problem was that the letter never 
went into appropriate channels. That is why it was never seen.
    Chairman Barton. Well, it is not stamped. There is no stamp 
that it was.
    Mr. Temple. It didn't go to Dr. Laughren. It didn't get 
into the file. That is why nobody knows it was there.
    Chairman Barton. Do you think you should have a document 
retention policy? Do you think that something like this should 
have gone through channels, that somebody at your level or some 
level should have checked into it and done something before 6 
years later?
    Mr. Temple. Of course.
    Chairman Barton. Yes or no?
    Mr. Temple. Of course, it should have gone through 
channels.
    Chairman Barton. And you think something should have been 
followed up on this?
    Mr. Temple. Had anybody known about it and seen the result, 
yes, of course. But I do want to point out that the basis for 
that letter was reviewed by Dr. Laughren a couple of months 
later, and his conclusion was that there was no signal there.
    Chairman Barton. Beg your pardon?
    Mr. Temple. His conclusion was that there was no signal 
there, that the analysis was invalid. I believe the letter 
never should have been sent. It doesn't make any sense.
    Chairman Barton. In spite of all the studies that have been 
done since then--and correct me if I am wrong. We have looked 
at 15 studies. Twelve of the 15 have shown no effect, no 
efficacy. Some of those have shown an increase in suicidality, 
and in spite of that, you say this letter shouldn't have been 
sent?
    Mr. Temple. This letter reported that there was an 
increased risk of suicidality in children compared to adults.
    Chairman Barton. Let's be fair. It says there appears to 
be.
    Mr. Temple. Okay.
    Chairman Barton. He is just questioning. Even though he has 
developed amnesia, at the time he was doing his job, and he was 
saying that somebody needs to check--well, he didn't say that. 
He just says what are your comments on it. Now once he wrote 
it, he forgot he wrote it. He didn't keep a record of it, and 
it was forgotten about.
    Mr. Temple. Right. The----
    Chairman Barton. Now this gentleman to your right, Dr. 
Laughren, says that he reviewed this letter?
    Mr. Temple. No, not the letter, the review that led to the 
letter.
    Mr. Laughren. I would like to clarify.
    Chairman Barton. All right. So you reviewed the same data.
    Mr. Laughren. No, no. Let me explain. Dr. Knudsen wrote a 
review of March 1996 around the same time that he sent the 
letter. He raised the concern in his review, and I responded to 
that concern in a memo that I wrote to the file later that 
year.
    It is true--I mean, there is no question. This is a failure 
in our document flow. However, the response that Pfizer sent in 
response to his letter in May of that same year----
    Chairman Barton. The response is in the file. Isn't that 
correct?
    Mr. Laughren. That response apparently is in our file. I 
have since--I agree that it is years later, but I have recently 
looked at it. It is completely consistent with the conclusion 
that I reached in the memo that I wrote in October of the same 
year, in October 1996.
    So it is true, you know, this is a document failure. No 
question about it.
    Chairman Barton. Well, it is more than document failure.
    Mr. Laughren. No, no. There is no signal there. There is 
just no signal there. There is no signal in those data.
    Mr. Temple. The analysis included three uncontrolled trials 
and one controlled trial in excessive compulsive disease. In 
the OCD trial there was one suicidality case in the placebo 
group and none in the treated group.
    The comparisons are entirely invalid. The letter should not 
have been sent.
    Mr. Laughren. Yesterday I spoke to someone completely 
independent, an epidemiologist in our Division, the head of the 
safety team, about these data just to get another view on this, 
and she completely agreed with me, that looking at those data 
that Dr. Knudsen looked at back in 1996, there is no signal for 
pediatric suicidality. None.
    Chairman Barton. But nobody did that. You all didn't even 
look at the data.
    Mr. Temple. No, he did.
    Mr. Laughren. I did.
    Mr. Temple. He looked at the data that Dr. Knudsen had 
placed in his review, not the letter. We didn't know about the 
letter.
    Chairman Barton. Well, let me ask another, because I don't 
follow the--I am not a medically trained person.
    This particular drug--in 1996 was it being prescribed off-
label for adolescents?
    Mr. Laughren. I can't answer that. It probably was.
    Chairman Barton. It probably was?
    Mr. Laughren. The point of this----
    Mr. Temple. But it is not for depression.
    Mr. Laughren. Right. This study was for--sorry.
    Mr. Temple. This was for a different condition.
    Mr. Laughren. This study was for obsessive compulsive 
disorder in kids.
    Chairman Barton. But it leads to an increase in--it could--
it appears that there could be, ``that there appears to be an 
increased frequency of reports of suicidality.''
    Mr. Temple. Yes, that is what it says, but----
    Chairman Barton. That was in 1996. This is 2004. It is 8 
years ago. If it was prescribed to 10,000 children and 100 of 
them committed suicide because they took it, I think something 
should have been done.
    Mr. Temple. That would be a bad thing. This provides no 
signal that that is a risk. There is no signal in those data. 
In the controlled trial there were more suicidality----
    Chairman Barton. What did--apparently, what the FDA--I've 
got some other questions, but apparently what the FDA did about 
this, this gentleman or others looked at this data and said we 
don't see a problem there. And so you did nothing. You did 
absolutely nothing.
    Mr. Temple. I don't understand. There was no signal.
    Chairman Barton. Well, you know what I would have done?
    Mr. Temple. What would you have done?
    Chairman Barton. I would have gone in and done some more 
trials. I might have even told the drug manufacturers not to 
let it be--strongly encourage them not to prescribe it off-
label. I might have erred on the side of safety and prudence 
and said let's don't take a chance. That's what I would have 
done.
    Mr. Temple. So in response to a study that showed more 
suicidality in the placebo group than in the treatment group, 
you would have done more studies? I don't think I understand.
    I understand why the words--this looks like it might be a 
signal--would be distressing, but that was a wrong 
interpretation of the data.
    Chairman Barton. Well, even Dr. Laughren said--and again 
this is a memorandum. It is Tab 75 dated October 25. This is 
apparently after he had reviewed the data. He says, ``I don't 
consider these data to represent a signal of risk for 
suicidality for either adults or children. Supplements are 
planned for both depression and OCD in pediatric patients, and 
when we have more complete data, including Ham-D data, we can 
look more critically at this issue using the now standard 
approach of comparing the proportions of drug in placebo 
exposed patients to show worsening on Item 3, which is the 
suicidality item, to the Ham-D during the treatment.'' So even 
he said that there should be something done.
    Mr. Temple. Well, those things were done, but we now have 
exquisite evidence that looking at the Ham-D doesn't work.
    Chairman Barton. Well, I am going to, unfortunately, have 
to run and vote.
    Should FDA develop a document retention policy for NDAs and 
drug master files? Yes or no? You have none now.
    Mr. Temple. Well, I believe we have one, but we will----
    Chairman Barton. Well, your e-mail says you don't.
    Mr. Temple. We don't have a rule.
    Chairman Barton. If you don't, should you?
    Mr. Temple. Yes.
    Chairman Barton. What did the British see when they pulled 
these things off the market that you didn't see, that FDA 
didn't see?
    Mr. Temple. You mean when they wrote their thing 
contraindicating it?
    Chairman Barton. Yes, sir.
    Mr. Temple. It is a different interpretation of the same 
data. I don't know why they reached that conclusion. One reason 
might be that they are less inclined to use these drugs in the 
first place. Why that is, I can't say.
    Chairman Barton. All right. I am going to thank you 
gentlemen. There will be further questions for the record, and 
we are going to adjourn this hearing.
    [Whereupon, at 5:46 p.m., the subcommittee was adjourned.]
    [Additional material submitted for the record follows:]
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