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





PUBLICATION AND DISCLOSURE ISSUES IN ANTIDEPRESSANT PEDIATRIC CLINICAL 
                                 TRIALS

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

                                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 9, 2004

                               ----------                              

                           Serial No. 108-121

                               ----------                              

       Printed for the use of the Committee on Energy and Commerce


 Available via the World Wide Web: http://www.access.gpo.gov/congress/
                                 house
PUBLICATION AND DISCLOSURE ISSUES IN ANTIDEPRESSANT PEDIATRIC CLINICAL 
                                 TRIALS




PUBLICATION AND DISCLOSURE ISSUES IN ANTIDEPRESSANT PEDIATRIC CLINICAL 
                                 TRIALS

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

                                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 9, 2004

                               __________

                           Serial No. 108-121

                               __________

       Printed for the use of the Committee on Energy and Commerce


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


                    U.S. GOVERNMENT PRINTING OFFICE
96-094                      WASHINGTON : 2004
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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:
    Camardo, Joseph S., Senior Vice President, Wyeth 
      Pharmaceuticals............................................    60
    Clary, Cathryn M., U.S. Medical, Psychiatry and Neurology, 
      Pfizer, Incorporated.......................................   114
    Davis, Ronald M., Member, ARA, Board of Trustees.............   198
    Gorman, Richard, American Academy of Pediatrics..............   207
    Hayes, John R., Product Team Leader, Eli Lilly Company.......    55
    Loew, Caroline, Vice President, Scientific and Regulatory 
      Affairs, PhRMA.............................................   202
    Marcus, Ronald N., Neuroscience Global Clinical Development, 
      Bristol-Myers Squibb Company...............................    85
    Olanoff, Lawrence, Executive Vice President, Scientific 
      Affairs, Forest Laboratories, Incorporated.................    79
    Osinsky, Patrick, General Counsel, Organon USA...............   112
    Wheadon, David E., Senior Vice President, Regulatory Affairs, 
      GlaxoSmithKline............................................    51
    Woodcock, Hon. Janet, Deputy Commissioner for Operations, 
      Food and Drug Administration...............................    18
Additional material submitted for the record:....................
    Food and Drug Administration, letter to Hon. John D. Dingell, 
      enclosing response for the record..........................   247
    Food and Drug Administration, response for the record........   259

                                 (iii)

  

 
PUBLICATION AND DISCLOSURE ISSUES IN ANTIDEPRESSANT PEDIATRIC CLINICAL 
                                 TRIALS

                              ----------                              


                      THURSDAY, SEPTEMBER 9, 2004

                  House of Representatives,
                  Committee on Energy and Commerce,
              Subcommittee on Oversight and Investigations,
                                                    Washington, DC.
    The subcommittee met, pursuant to notice, at 11 a.m., in 
room 2123, Rayburn House Office Building, Hon. Joe Barton 
(chairman) presiding.
    Members present: Representatives Stearns, Bass, Walden, 
Ferguson, Rogers, Barton (ex officio), Deutsch, DeGette, Allen, 
Schakowsky, Waxman, and Markey.
    Also present: Representatives Stupak and Murphy.
    Staff present: Mark Paoletta, majority counsel; Alan 
Slobodin, majority counsel; Bud Albright, majority staff 
director; Kelly Andrews, majority counsel; Toby Fortson, 
majority counsel; Bill Harvard, majority staff assistant; David 
Nelson, minority senior investigator; Jessica McNiece, minority 
research assistant; Ashely Grossbeck, minority research 
assistant; and Jeff Donofrio, minority research assistant.
    Chairman Barton. The subcommittee will come to order. 
Today's hearing is on the publication and disclosure issues in 
the antidepressant pediatric clinical trials.
    As part of the committee's jurisdiction over public health, 
the subcommittee today will examine the publication and 
disclosure of clinical studies conducted on prescription drugs. 
What has raised public interest in the disclosure of clinical 
trial data has been the controversy over the use of 
antidepressants in children.
    In reviewing this issue, the subcommittee will be focused 
on the 15 placebo-controlled randomized studies submitted to 
the FDA for an indication in children with depression. The FDA 
found that in 12 out of the 15 studies there was no efficacy 
that was shown. I would also note that only 3 out of the 15 
studies have been published as stand-alone articles in peer 
review journals. Therefore, many people want to know what was 
in the other 12 studies? What do those studies show? Why 
haven't those other 12 studies been published in peer review 
journals? Was there sufficient information available to the 
public about these unpublished studies to make informed 
decisions? These are some of the questions the subcommittee 
will attempt to find answers to today.
    Given the highly visible public health question over 
disclosure of clinical studies and the use of antidepressants 
in children, under the leadership of the former subcommittee 
chairman of this subcommittee, the Honorable Jim Greenwood of 
Pennsylvania, the committee launched an investigation 7 months 
ago. As the central repository of the 12 unpublished studies 
and with its own regulatory role in the matter of 
antidepressants, the committee looked to the Food and Drug 
Administration, or FDA, to obtain much of the information for 
this investigation.
    In March of this year, the committee requested records from 
the FDA and also requested interviews with key FDA officials. 
Unfortunately, over the last months, the committee has been met 
mostly with stonewalling, slow rolling, plain incompetency from 
the FDA. That is not acceptable. The FDA's lack of cooperation 
with the committee in obtaining relevant and responsive 
information in a timely fashion on a matter that involves the 
safety of our children leaves me wondering whether this is 
sheer ineptitude or something worse. The examples of the course 
of conduct extend for over 5 months of this committee 
attempting to do its job and oversee an agency on a topic of 
grave concern.
    I am outraged to learn that an FDA employee in the Office 
of Legislation was tasked with handling the Agency's response 
to the committee; in other words, Congressional Affairs at FDA 
is supposed to be there to help the Congress get information 
from the FDA. This individual's response was to defy the 
document request contained in a letter that I signed, and this 
individual unilaterally decided to limit the document request 
to exclude drafts, internal notes or memos to the file. And I 
am reading this from an email from a Mr. Patrick McGarey to 
Anne Henig with re: line 8 is Barton question number 8 
referring to question number 8 in the March 24 letter that we 
sent to the FDA.
    The email states, ``Here is my draft of instructions to the 
CDER employees who have to search for documents for question 
number 8.'' He goes on to say, ``Please do not include draft 
documents, notes or memos to self or file.'' I don't understand 
this, because the question is provide copies of all records 
that raise a concern about the safety or efficacy of 
antidepressants in pediatric or adolescent populations. That 
was the question. And Mr. McGarey's response was, ``Please do 
not include draft documents, notes, memos to self or file or 
incoming communications from non-FDA individuals, i.e. the 
public, business organizations, other HHS operations divisions, 
unless an FDA employee has forwarded such communication to 
others with additional questions or concerns.'' Well, that is 
not going to work, folks. Is Mr. McGarey in the room? Is he 
here? Okay. Let the record show that if he is here, he is not 
standing up and showing his face. We will get that changed. We 
will get that changed.
    If you read this email, it is obvious why FDA's document 
production has been so minimal. The problem is that FDA either 
does not hear the wakeup call we have repeatedly--we, 
committee, on a bipartisan basis--have been trying to send or 
they are choosing to ignore it. We are going to fix that, 
folks. We are going to fix it beginning at this hearing. The 
conduct by the FDA has only reinforced my past sentiments that 
the Food and Drug Administration really stands for Foot 
Dragging and Alibis, and that is not acceptable.
    [The e-mail follows:]

    [GRAPHIC] [TIFF OMITTED] T6094.001
    
    Chairman Barton. Today's witness for the FDA is Dr. Janet 
Woodcock, the acting Deputy Commissioner for Operations. I 
assume that she is here. I have a message for you to take back 
to the acting FDA Commissioner, Dr. Lester Crawford: If you 
folks can't fix it, we will fix it for you. Now, I have 
instructed my staff this morning in preparing for this that if 
we have to, we will send our staff people, if necessary, with 
the Capitol Police to the FDA and we will get enough 
individuals that are familiar with the files and we will go 
through the files ourselves. Do you understand that? Okay. Can 
you instruct Mr. McGarey his job is to cooperate with this 
committee, not to obstruct it? Do you understand that? Let the 
record show that she says she does understand it.
    In addition to the problem of cooperation, this 
subcommittee will also review the FDA's spotty record on 
sharing results from clinical trial data with the public, as 
required under Section 9 of the Best Pharmaceuticals for 
Children Act. Although required by law since 2002, the FDA has 
not published any summaries of the pediatric antidepressants 
until this year, and almost all of them were just 3 weeks ago 
after I made a personal phone call to an individual at the FDA. 
Why did it take so long for the FDA to do its job? While I plan 
to ask the companies about their publication and disclosure 
practices, I am also interested in finding out from the FDA why 
they refused on several occasions to allow the companies to put 
additional labeling on their antidepressants indicating that 
the drug was tested in pediatric clinical trials and did not 
show efficacy. It would seem to me that the first place where 
disclosure of no efficacy in these pediatric clinical trials 
should be shown would be the product label itself. I would like 
to have the FDA explain its reasoning on this point.
    This committee began its investigation for today's hearing 
on the publication of clinical trials based on news reports 
surrounding the possibility that there may be an increased risk 
of suicide related behavior in children and adolescents with 
major depressive disorder, MDD, that take antidepressants. And 
I would point out that on a bipartisan basis we passed--well, 
we had the debate on a bill last night on the House floor, a 
suicide prevention bill, for teenagers and young adults. That 
vote is going to occur sometime today. We have over 4,000 young 
people in our country that committed suicide last year. This 
potential increased risk of suicidal behavior in mostly 
undisclosed studies is what has raised questions regarding the 
safety and efficacy of antidepressants in the pediatric 
population and the release of data to that extent. And that is 
the reason we are having this hearing.
    Late last year the Medical Health Regulatory Agency, the 
British equivalent of the FDA, pulled from public sale all 
antidepressants for people with depression under 18 years of 
age except for Prozac due to the risk/benefit analysis of 
safety concerns coupled with a weak showing of efficacy in all 
of the antidepressant pediatric clinical trials. Likewise, in 
our country, the FDA has approved Prozac made by Eli Lilly to 
treat MDD in children, yet the products of the other six 
companies present today have not been approved as of today.
    Much of the controversy is over whether antidepressants 
really work in children at all. Only one drug, Prozac, has ever 
been judged by the FDA to be effective for depression in 
children and received approval for this use. Nevertheless, I 
note that four different antidepressant drugs not approved for 
children with depression use are prescribed to children at 
higher rates that Prozac, the only drug that has been approved. 
As a father of three and a grandfather of two and stepfather of 
two, I am especially concerned about advances in technology and 
medicine that can help young people better adapt to learning 
and to lie.
    After this committee in the Congress passed the Best 
Pharmaceuticals for Children Act, a number of companies took 
advantage of the 6-month patent extension in the legislation 
granted to companies if they performed pediatric clinical 
trials. The incentives in this law have worked, as companies 
have performed new pediatric clinical trials. I am happy that 
Congress' actions have helped to protect and to promote 
children's health through the performance of such clinical 
trials. The companies here today all have drugs whose primary 
purpose is treating depression in adults. Thus, it was only 
natural to see if these antidepressants also had a pediatric 
use. This strikes at a major public health need: The 
development of more treatment options for teenagers and 
children diagnosed with depression. I am told that one out of 
six of our young people is under prescription for some sort of 
antidepressive drug. That is an amazing statistic--one of our 
every six of our children is under a doctor's prescription for 
some sort of an antidepressant drug.
    Unfortunately, the increase in the number of trials 
undertaken by drug companies to try to find treatment options, 
as I have stated earlier, have so far met with meager results. 
Today, we will review the timeliness and disclosure of these 
companies in regards to the clinical trials that they have 
performed for these drugs. In addition, we will hear from them 
on what practices they have undertaken in regards to the 
publication of all clinical trial results for their company. 
Finally, we are going to hear from leading members of the 
industry discuss their actions and suggestions regarding 
publication of clinical trials. We will also hear from them on 
other issues, such as co-prescribing and how we can better 
inform patients, doctors and the public of possible concerns 
and negative results of clinical trials.
    The bottom line is that we need to ensure that the 
processes we undertake in our trials ensure that the drugs that 
the American people purchase are effective and are safe. I am 
pleased that this committee's investigation may have already 
played a role in the recent actions and policy announcements by 
both the FDA and the private sector. These announcements 
indicate that both will more freely disclose clinical data to 
the medical community, industry and the general public.
    I want to thank our witnesses for attending today, and I 
look forward to hearing their testimony. With that, I would 
yield to the ranking member of the subcommittee, Mr. Deutsch, 
for an opening statement.
    Mr. Deutsch. Thank you, Mr. Chairman. I have a statement by 
the ranking democrat of the full committee, which I would like 
to submit for the record.
    Chairman Barton. Without objection, so ordered.
    [The prepared statement of Hon. John D. Dingell follows:]

    Prepared Statement of Hon. John D. Dingell, a Representative in 
                  Congress from the State of Michigan

    Mr. Chairman, thank you for initiating this investigation and 
holding the first of this Subcommittee's hearings into the safety and 
efficacy of anti-depressants in adolescents and related issues. Today's 
hearing focuses on efficacy. Specifically, whether parents, 
pediatricians, and other physicians who treat children with anti-
depressant drugs should have been notified of the repeated failure of 
clinical trials to show that these medicines, with a single exception, 
are effective in adolescents and how such notice should have been 
provided.
    We are told that the Food and Drug Administration (FDA) does not 
believe that these very potent drugs, which are labeled as a treatment 
for severe depression in adults, need to be labeled as clinical trial 
failures for children. Is withholding this information in the best 
interests of patients? Or is it in the best interest of the drug 
companies that are supposed to be regulated by the FDA? It becomes an 
even more relevant question when we know that those trials were paid 
for by billions of dollars from the pockets of consumers and taxpayers.
    Today we will explore how the drug manufacturers and the FDA 
justify not providing to parents and doctors the evidence of the 
ineffectiveness and dangerous side effects of these powerful drugs on 
children. We will not only ask why the FDA and the manufacturers failed 
to provide this important information on the label, but why the FDA 
ignored the minimal public disclosure requirement in the pediatric 
exclusivity legislation.
    I opposed giving drug companies additional monopoly profits in 
order to induce them to test their drugs on children when the ``Best 
Pharmaceuticals for Children Act'' was passed last Congress. During the 
debate a number of logical amendments were offered that would have 
mitigated the giveaway or at least imposed minimal labeling 
requirements upon the beneficiaries of that Act. The pharmaceutical 
industry opposed every amendment, as did their allies in the 
Administration.
    Since enactment of the law, study after study of dubious design has 
been submitted and apparently approved by those responsible for 
protecting children and other citizens from products that are 
ineffective and cause dangerous side effects. The study designs were 
dubious because they apparently could never satisfy the FDA that drugs 
would not work for children and youth regardless of what the data 
showed. In other words, once the drug had been approved for adults the 
studies could never show ineffectiveness in children.
    This hearing will demonstrate, with the exception of Eli Lilly, 
that the manufacturers and the FDA went to extraordinary lengths to 
keep vital information from the public regarding the ineffectiveness of 
these drugs in children. The hearing scheduled for September 23rd will 
further show how FDA attempted to hide critical information about the 
increase in suicides or suicidal ideation by adolescents who were 
prescribed certain drugs. In both cases, crucial information was 
withheld by an agency responsible for providing public health 
information to the doctors and the parents who care for these troubled 
children.
    We need prompt, accurate labeling of all drugs before any 
exclusivity is granted. I look forward to working with my colleagues on 
legislation to make sure doctors and parents have the information they 
need and expect, and that the FDA and drug manufacturers uphold their 
responsibilities to the public.

    Mr. Deutsch. Thank you. Thank you, Mr. Chairman. Now, I 
recall the debate and the hearings that we had when we passed 
the legislation regarding pediatric exclusivity, and I wish we 
could play back some of those debates and videos at this time 
because there were many amendments that were offered that in 
fact were defeated at that time, which I think would have 
prevented the situation that we are in at this moment, 
specifically an amendment by Mr. Stupak at the time which would 
have not granted the exclusivity until labeling changes 
regarding pediatric use was approved by the FDA. Had that 
occurred we would not be sitting here with the situation that 
we find ourselves in.
    As you are aware, and I think it is important to point out, 
effectively, consumers paid for this research literally in the 
billions of dollars, literally in the billions of dollars. And 
in terms of the value that was gotten by consumers, if 
anything, we have a negative value in terms of the lack of 
information provided, lack of efficacy provided. Specifically, 
I think in some ways the most disturbing information from this 
hearing and this research by our staffs is that prescriptions 
are being written today, literally today, and I mean hopefully 
we will talk about that and get some testimony about that, but 
as you mentioned in your testimony, the only efficacy that I am 
aware of is in the case of Prozac and yet that is the least 
prescribed of the antidepressants at this moment in time. So I 
look forward to the testimony and compliment our staffs, this 
is a bipartisan effort, and look forward to working with you to 
resolve this issue in a positive outcome for the consumers and 
people of the United States.
    Chairman Barton. We thank the gentleman from Florida. The 
gentleman from Oregon, the vice chairman of the subcommittee, 
Mr. Walden, is recognized for an opening statement.
    Mr. Walden. Thank you, Mr. Chairman. This morning the 
subcommittee holds its first hearing to examine issues related 
to the use of antidepressants in children and adolescents. 
Today, we will focus on the disclosure and transparency of 
pediatric clinical trials of antidepressants.
    Now, I know this is an extremely sensitive topic for many 
parents, caregivers and doctors in this country. Depression, 
especially in teenagers, is sometimes difficult to identify and 
even more difficult to treat. When a loved one is suffering, it 
is only natural to search for any possible solution. What is 
troubling, however, is that millions of antidepressant 
prescriptions are written for depressed kids when the facts 
show that 6 of the 7 antidepressants tested in pediatric trials 
do not show efficacy in kids.
    In 2002 alone, more than 10 million American children were 
prescribed antidepressants, and that number is on the rise. So 
one has to ask, if pediatric clinical trials show that a sugar 
pill is about as effective as an expensive drug, is it 
appropriate for physicians to write millions of off-label 
prescriptions for kids? Does this happen because physicians are 
aware of the studies showing these drugs were effective in 
adults but may not be as aware of the studies showing that with 
one exception they are not effective in children and 
adolescents? Even of more concern is this: In what I am sure 
are good faith efforts to help kids with depression, are 
physicians prescribing drugs that not only show little or no 
efficacy but also may show an increase in suicidal thought and 
action?
    One of the issues that triggered this investigation into 
how the United States through the FDA manages these 
antidepressants was news that the United Kingdom last December 
moved to contraindicate virtually all of the antidepressants 
for children under 18 with major depressive disorder, MDD, due 
to the risk of suicide related behavior in children and 
adolescents. What does our own FDA know about such concerns, 
when did it know it, and what has it done? Well, we know that 
in one review of 22 studies involving more than 4,000 children 
suggested that children taking antidepressants were 1.89 times 
more likely to become suicidal than those given placebos, and a 
recently Columbia University seems to confirm that point. Yet 
every day these drugs are being swallowed by America's youth. 
These issues will be explored in greater detail at our second 
hearing later this month.
    So it is time to ask the tough questions. Are America's 
kids being prescribed drugs for depression that are no better 
than sugar pills yet may nearly double their risk of suicidal 
behavior and thought? Are the companies who sell these drugs 
adequately disclosing the results of their trials in ways that 
allow parents and physicians to get all of the facts? Can and 
should the FDA do more to protect the public health in this 
area? Are adequate steps being taken by the companies and their 
trade association and the FDA to improve disclosure of trials 
and make warnings of risks available to those who prescribe and 
those who take these drugs? It is the responsibility of this 
committee to investigate and provide oversight, and today we 
will focus our bright light on this dark problem. Thank you, 
Mr. Chairman.
    Chairman Barton. Thank the gentleman. We now recognize the 
gentlelady of Colorado, Ms. DeGette. Then the gentlelady yields 
to Mr. Waxman of California.
    Mr. Waxman. Thank you very much, Mr. Chairman, for this 
chance to make an opening statement. We are holding a hearing 
on the question of antidepressants for children, but I think it 
opens up a very much broader perspective for us than just that 
issue, because what we are seeing in fact is that the 
pharmaceutical industry has systematically mislead physicians 
and patients by suppressing important data on their drugs. At 
the same time, the industry has encouraged these physicians to 
use drugs that are ineffective and possibly even dangerous in 
one of the most vulnerable population groups, children, and as 
a result the industry has reaped literally billions of dollars 
in the process.
    Let me give some background because I was the author of the 
legislation to try to encourage the drug companies to do the 
studies on children. Drug companies didn't want to do the 
studies on children; they were making drugs for adults. That 
was the population they expected to buy their drugs, but often 
kids use the same drugs. So in order to get the companies to do 
studies on children, we bribed them by saying we would give 
them a 6-month additional exclusivity over that drug, not just 
for the sales to children but for everyone. That is worth a lot 
of money, hundreds of millions of dollars if it is a big-
selling drug. And antidepressants are pretty big-selling drugs. 
Well, the drug companies did the studies on antidepressants for 
children and it turned out, as a result of their studies, there 
was no conclusive showing that, as someone has said, six out of 
the seven antidepressants were even effective in children. Only 
one study on Prozac showed some effectiveness for children.
    Well, this is not a problem just as it relates to children 
that this information was withheld, it is a problem for all 
users of pharmaceuticals because oftentimes companies will do 
studies and if it is a negative study for the sale of their 
product, they will withhold the information. They will push the 
positive studies that will encourage people to use their drugs 
even though they know that they have negative studies that are 
contrary. But if you don't tell the whole story, people aren't 
getting the whole story, and the people we are talking about 
are physicians and patients.
    So I think what we have to be concerned about is we have 
given this pediatric exclusivity in order to encourage the 
studies for children, but the companies are using that only to 
get a longer patent time or monopoly time over the drug that 
they are selling to adults, and they are not making the results 
of their studies that aren't positive known. They are making it 
known to FDA because they have to, and we want to ask why FDA 
has not done more to get this information out, but there is a 
clear responsibility for the companies, and I am pleased to be 
working with Congressman Ed Markey on legislation that he and I 
will be introducing to require a registry of information about 
all the studies done on pharmaceuticals so that we don't just 
hear about the positive ones but we hear about the negative 
ones and the inconclusive ones so that we can get the full 
picture to the medical professionals.
    In this particular issue of antidepressants, we have, I 
think, learned that we need to go back and look at that 
pediatric exclusivity bill. That law, which we tried to amend, 
Congressman Stupak particularly, to make sure that there was a 
label requirement on the drug, would have then made all this 
information available to the public and we would have known 
whether the drug was going to work or not. The majority on this 
committee refused to go along with that amendment. So I think 
we need to change the pediatric exclusivity law, we need to 
require broad disclosure of the results of clinical trials, and 
I hope we can have legislation to do that.
    We are going to hear from many people in the drug industry 
who are going to tell us we don't need legislation to set up a 
registry; they are going to do it voluntarily. Well, I don't 
accept the idea that voluntary solutions are the only way we 
can approach this problem, because if it is voluntary, it is 
also voluntary not to do it or it is not voluntary to make full 
disclosure. I think we owe the public and the medical 
profession the opportunity to get all the information, the 
negative and inconclusive tests as well as those that the 
companies want us to hear about, which accentuate the positive 
in order to accentuate the profits.
    I appreciate that the leadership of this committee has 
called this hearing. I hope my colleagues will agree on the 
need for data on drugs. It is not a partisan issue. Allowing 
the marketplace of medical information to be significantly 
distorted by those who have a financial interest in the results 
is devastating for good medical care. Access to important data 
is one prescription for health that Congress can and should 
write, and we ought to do it right away. Thank you.
    Chairman Barton. Thank the gentleman for his statement. 
Gentleman from New Jersey, Mr. Ferguson, is recognized for an 
opening statement.
    Mr. Ferguson. Thank you, Mr. Chairman. Thank you for 
holding this important hearing on an issue that is impacting 
children and their families in my district and throughout our 
country. Mr. Chairman, I also want to acknowledge and welcome a 
constituent of mine who is here with us today, who knows 
firsthand what it is like to suffer along with her child. Lisa 
Van Syckel is here in the second row. Lisa, can you raise your 
hand? Hi, Lisa. Lisa is from Raritan Township, New Jersey. She 
is here. She and her daughter, Michelle, have been through some 
harrowing and heartbreaking experiences, and their perseverance 
and hope I believe are an inspiration to parents and families 
who have dealt with the difficulties of childhood depressive 
disorders. I am happy to have Lisa here today to join us at 
this hearing, and I am also happy to report that her daughter, 
Michelle, is a happy and healthy student today at the 
University of Hartford.
    Mr. Chairman, 6 weeks ago, my wife and I welcomed our 
fourth child, and like any parent it breaks my heart to see 
children and their families suffer from the effects of a major 
depressive disorder or any psychological disorder. As a parent, 
it must be torture to see the happy child that you know is 
somewhere deep down within deal with a disease with which they 
might not know how to cope, which them and their families to 
turn to outside help to find a cure. In order to help children 
cope with the effects of these illnesses, parents and doctors 
must have the most complete and accurate research and 
information readily available to them, because the lives of 
these children, quite literally, depend on it.
    In my meetings with Lisa and others, it has become clear 
that there are several problems faced by parents who are 
looking for the right treatment for their child. Sometimes all 
the clinical research for a drug has not been made publicly 
available by the manufacturer. Sometimes doctors prescribe a 
drug for a child when it has not been approved for that 
particular use. And sometimes the FDA has not made enough of an 
effort to inform doctors about potential risks that a drug may 
have when taken by a child.
    It is my hope that this hearing today will examine these 
points and will help all of us to do a better job of protecting 
our children. Pharmaceutical companies, because they do 
incredible work in researching and finding cures to diseases 
and afflictions of all kinds, also bear an enormous 
responsibility to make public any and all clinical research 
data which could potentially impact the decisions of doctors 
and parents when determining the right treatment for a child. 
If that information has not been shared and made public up 
until this point, it damn well better be and soon, because 
children's quite literally depend on it.
    Doctors, too, must examine their role in prescribing 
medicines for their children which might not necessarily have 
been proven safe and effective for them. This, I believe, is a 
weakness in the system, and it needs to be recognized. And the 
FDA must redouble its efforts to gather, analyze and publish 
clinical data on the effects of SSRIs since this will enhance 
their credibility and further their role in protecting children 
and their families from the tragedies like those which we are 
hearing about today.
    In short, there is plenty of responsibility to go around, 
and this hearing will highlight the problems which exist and I 
hope will provide a blueprint for where we go together to 
address this most important issue. Thank you, Mr. Chairman. I 
yield back.
    Chairman Barton. Thank the gentleman from New Jersey. We 
now recognize the gentlelady from Colorado for an opening 
statement.
    Ms. DeGette. Thank you, Mr. Chairman. Today's hearing 
delves into a complex and troubling issue which is well known 
to members of this subcommittee who have worked for many years 
to examine clinical trials and medications for children and 
also those in need of mental health services. For this 
vulnerable population, the ethical considerations are 
substantial and of course the two issues juxtapose here today.
    I have been working for a long time to ensure the safety of 
clinical trials for American patients, and this investigation 
is deeply troubling. Data and results from clinical trials are 
not the most easily understood even by sophisticated observers. 
I remain concerned about the transparency of the data from 
these clinical trials that Mr. Waxman talked about a few 
minutes ago. I am encouraged that some pharmaceutical companies 
have put results of their trial data on the Internet, but I am 
also concerned whether these actions are sufficient, either to 
inform parents and consumers about the risks and the results of 
these clinical trials and even doctors of the same thing.
    Beyond specific cases for specific drugs that I am sure 
will come up in the hearing today, this subcommittee's 
investigation has provided more evidence that our mental health 
system is hindered by inadequate funding and limited labeling 
information. It is simply unconscionable that parents seeking 
easy-to-understand information about mental health 
pharmaceuticals for their children somehow have to try to 
become experts as to what all this data means. NIH and our 
health care system must do more to show parents and patients 
the risks and benefits of the treatment and they also need to 
demonstrate this to physicians.
    We are focusing today on the publication of clinical trial 
results, but I, like many of my colleagues here, are also 
looking forward to the next hearing which will focus on the 
FDA's ability and efforts to ensure that all approved 
pharmaceuticals are safe. The two hearings are truly 
interlocking pieces, because without transparency and improved 
labeling, patients and their physicians will not be assured of 
a drug's efficacy and without comprehensive studies and 
rigorous scientific inquiry, will never be sure if these 
medications are safe for the kids we are giving them to.
    While we must approach this issue with sensitivity because 
it also has a wide-ranging effect on our mental health 
treatment, I don't believe that we can shirk our oversight 
duty. I am alarmed, like the chairman, about reports that the 
FDA has not adequately enforced provisions from the Best 
Pharmaceuticals for Children Act. FDA is supposed to be a 
watchdog agency, and I would like to remind them that this role 
is essential for America's health, especially when we are 
talking about unapproved uses of antidepressants for juvenile 
populations.
    Finally, and most importantly, I think, we need to remember 
that we are here because we are all looking for better health 
for our children. I hope that the researchers here today are 
truly working on developing drugs that will benefit this 
population, and I hope that the physicians and their 
representatives who are here today are carefully prescribing 
and monitoring their pediatric patients, because truly it is 
about the patient and it is about the parents who are trying to 
find the best solution for their children. We cannot allow 
anyone in our system to take advantage of that hope, and we 
also cannot risk snuffing out that hope. We all have to work 
together to make sure our mental health system works and that 
it works not just for adults but for the children who 
increasingly are becoming enmeshed in that system. I yield 
back.
    Chairman Barton. We thank the gentlelady. The gentleman 
from Florida, Mr. Stearns, is recognized for an opening 
statement.
    Mr. Stearns. Thank you, Mr. Chairman, and I appreciate your 
leadership on this. Obviously, this is a question that all 
individuals who have children are concerned about in the 
efficacy of these drugs. You would think something simple like 
this, the data base of clinical trials, should it be voluntary 
or mandated, it would be something we could all agree upon. And 
if you go into the commercial world and you are a consumer, you 
want to buy something, let us say I want to buy a car or I want 
to buy a television or even food, I can always research whether 
I want to buy that car and how much it should cost and whether 
that product is recommended safe or not. The Consumer Report 
will list all the cars that are safe and all those cars that 
are not safe. In this same way, shouldn't American parents be 
able to access some sort of registry to see whether the drugs 
their children are being prescribed are efficacious and safe? I 
mean that seems to be a pretty basic point. I don't think many 
people would disagree on that.
    But there are some things on the other side. For example, 
once you publish this information in a data base and you have 
these clinical trials, then when you get into litigation, you 
are going to have lawyers use that clinical information in a 
way against the drug companies that wasn't intended, and a lot 
of it becomes subject to the jury's interpretation. So from the 
standpoint of the pharmaceutical companies, I can see their 
concern that the litigation that might come about from this 
data base would harm them in such a way that they could not 
speculate. So that is probably one reason that some people are 
worried about publishing negative things about the drugs that 
they are putting on the market because that could come back to 
haunt them, and we don't have tort reform in this country, so I 
think it is a legitimate question.
    Pharmaceutical companies in the United States have been a 
leader, a world leader in drug development and health care. We 
don't want to kill the golden goose here. I commend the 
industry for launching a voluntary clinical trial data base, 
and I commend those companies that go far and beyond what the 
industry requires. I think industry certainly should make every 
effort or Congress will come down with a registry. I think 
improvements need to be made and we can't be complacent with 
the efforts because in the end the American consumer deserves a 
rate, much like when he buys a car, a piece of food or a 
television or T.V. or toaster. He should be able to find out a 
little bit about how good this product is.
    So I think the hearing we have today, Mr. Chairman, is very 
good, and hopefully we will be able to get more information so 
we can decide whether we should have mandatory prescription for 
the pharmaceutical companies. But I do leave the committee with 
this thought is that once you make this clinical information 
available, you are going to subject these drug companies to 
lawsuits on a very strong, tangible way that they are going to 
have to defend themselves. And in the end, it might be based 
upon specious information. So that with, I return.
    Chairman Barton. We thank the gentleman. And I believe Mr. 
Markey is next.
    Mr. Markey. Thank you, Mr. Chairman. Thank you, Mr. 
Chairman. Let me begin by thanking you, Mr. Chairman, for 
holding this extremely important hearing. Today, we will 
explore the issue of disclosure of clinical trials on pediatric 
antidepressants and hear about several cases in which critical 
data about those drugs were not disclosed. But the problem of 
selective disclosure in publication is not limited to a 
specific type of drug or scenario. The same concern exists 
whether we are talking about drugs to treat depression, heart 
disease or high cholesterol.
    Every day, in hospitals and clinics around the country, 
ordinary people are placing their health and their very lives 
into the hands of researchers who are testing these 
experimental drugs for safety and for effectiveness. In other 
words, the public places great faith in the judgment of the 
researchers and the institutions and companies for which they 
work. Recently, however, the public has had reason to question 
their judgment in certain cases where trials which provided 
important insights regarding a drug never saw the light of day. 
Some of these trials did not become part of the medical 
literature for innocent reasons, but we cannot ignore the 
possibility that some studies were and continue to be 
intentionally buried by companies worried about the impact of a 
negative trial on their bottom line.
    I understand when companies are concerned about how bad 
news might lead their stockholders to suffer a monetary loss, 
but the alternative is that patients' health suffers as doctors 
research and sick people proceed on the basis of false 
assumptions. Regardless of the motivation, the fact remains 
that clinicians, patients, researchers and the general public 
do not have access to all the information currently available 
about the drugs that we use.
    There are two major problems with this situation. The first 
is that in order for doctors to make good medical decisions and 
to provide their patients with the best possible care, they 
need to have access to complete and sound scientific data. 
Every student starting school this fall knows they can't pick 
and choose which tests will count and which won't. Likewise, 
drug companies can't be permitted to decide which trials to 
disclose and which to hide from the public. Doctors should 
never be put in the position of prescribing medications to a 
patient with only partial access to what is known about the 
drug's effects. Doctors should never be put in the position of 
making medical decisions based on misleading or inaccurate 
information.
    In addition, there is a sacred yet unspoken contract that 
binds the participants in clinical trials and the drug 
companies that sponsor them. Participants give up control of 
their medical decisions, willingly take experimental drugs and 
subject themselves to potential harm, because they believe that 
their participation in the studies will add to the advancement 
of medical knowledge and potentially unlock the secrets of 
disease. But if a researcher or a company that sponsors a trial 
does not publicize the results, the knowledge gained from 
putting these participants at risk becomes forever buried in 
some Orwellian memory box locked up in the files of a 
researcher's computer.
    In order to ensure that clinicians have all the information 
they need to make sound medical decisions and uphold the 
ethical responsibility to patients and protect public health, 
Congressman Henry Waxman and I will very soon introduce a bill 
to create a mandatory public Federal registry of all clinical 
trials. Congressman Waxman has already outlined the details of 
the legislation. The data base will expand on 
clinicaltrials.gov and will include both federally funded and 
privately funded clinical trials so that clinicians, patients 
and researchers will be able to know the universe of clinical 
trials on a particular drug and have access to the results of 
those trials.
    Since we believe that companies and researchers have a 
moral and ethical responsibility to share their trials with the 
public, registration in this data base will be a condition of 
institutional review board approval, and failure to report 
results will have consequences, including civil penalties. The 
registry will meet all of the minimal criteria for a trial 
registry set out by the International Committee of Medical 
Journal Editors and will satisfy the American Medical 
Association's call for the results of all clinical trials to be 
publicly available to doctors and patients. The bill will 
require the posting of important results that are not published 
in the peer reviewed medical literature in a timely fashion. 
Although the bill will use the infrastructure put in place by 
clinicaltrials.gov, the bill will reserve patient access to 
enrollment information about clinical trials for serious and 
life-threatening diseases.
    Some companies are now urging that we accept a renewed 
commitment to voluntary disclosure as a substitute for a 
mandatory enforceable system. Well, we tried that approach and 
it didn't work. Since 1997, trials involving serious and life-
threatening diseases have been subject to mandatory 
registration, but since there is no enforcement mechanism, it 
is the equivalent of a voluntary system. As a result, in 2002, 
the FDA found that only 48 percent of trials of cancer drugs 
had been registered. If the idea is to make sure that all the 
clinical trials are available, then it has to be mandatory. If 
it is not mandatory, then the good companies will disclose what 
they want to report, while the bad companies will hide what 
they believe they can get away with.
    This is a very important hearing. Congressman Waxman and I 
are looking forward to working with the committee to pass 
legislation that will ensure the protection of the public. 
Thank you.
    Chairman Barton. We thank the gentleman. We have a series 
of three recorded votes on the floor. The first is 15 and then 
two 5s. If at all possible, I would like to get all the opening 
statements in before we go to the votes. Gentleman from Maine 
is recognized, Mr. Allen, for an opening statement.
    Mr. Allen. Thank you, Mr. Chairman. Let me join others in 
thanking you for calling this hearing on a most troubling 
issue: The systematic withholding of negative clinical trial 
results with a particular focus on antidepressant pediatric 
clinical trials. This is a serious public health issue, and I 
commend your leadership in having the committee conduct an 
investigation into the use and promotion of antidepressants in 
children and the current lack of full disclosure of clinical 
studies, whether the results of positive, negative or in some 
case inconclusive.
    The fact that clinical trials with positive results are 
used for promotional purposes while those with negative 
outcomes may be suppressed is likely to create a bias leading 
to an overprescribing of the newest and more expensive 
treatments regardless of whether they are safe and effective. 
Of course, in this case, illness and even death can be a more 
serious consequence.
    I have a particular interest in the government's role in 
supporting evidence-based research on prescription drugs and 
the public disclosure of clinical trial results. Last June, I 
introduced a bipartisan bill, H.R. 2356, The Prescription Drug 
Comparative Effectiveness Act. This bill would essentially 
provide a consumer report for prescription drugs. It authorizes 
$50 million in funding to NIH and $25 million in funding to the 
Agency for Health Care, Research and Quality. The bill directs 
these agencies to examine existing research and if necessary 
conduct new research, including head-to-head clinical trials in 
order to develop valid scientific evidence regarding the 
comparative effectiveness, the cost effectiveness and 
comparative safety relative to other drugs and treatments for 
the same disease or condition. This legislation is designed to 
provide doctors and their patients with valid, evidence-based 
information on how drugs that treat a particular condition 
compare to one another.
    The FDA deals essentially with the safety and efficacy of 
the drugs that they review, but the larger issue here is 
whether or not we can have a system that is broader than that. 
And what I mean by that, a functioning free market depends on 
good information broadly shared. A vital public health interest 
is at stake in this issue today. I believe we need to have a 
system where the companies producing the most effective drugs 
have a comparative advantage, not the companies which are best 
at manipulating information regarding clinical trials or the 
companies with the largest marketing budget. That ought to be 
the goal that we are striving for here today. I don't see how 
you get there unless all companies are operating on a level 
playing field, all are required to provide the same information 
in the same timely manner, to the same agency. But that has to 
be the goal. We need a system that creates a level playing 
field where the result is the companies with the best drugs 
have the advantage, not the companies with the biggest 
marketing budget or the ones that are best at disclosing some 
studies and hiding others.
    I look forward to the testimony of all of you today, and, 
Mr. Chairman, I yield back.
    Chairman Barton. We thank the gentleman, and the gentlelady 
from Illinois, Ms. Schakowsky, is recognized for an opening 
statement.
    Ms. Schakowsky. Thank you, Mr. Chairman. I thank you for 
holding this hearing to look into the failure of some drug 
manufacturers and the FDA to disclose to pediatricians and the 
public the results of clinical trials aimed at determining the 
efficacy of antidepressants in children.
    I would like to understand why the system that was 
supposedly put in place to protect children from the potential 
side effects of ineffective medications allowed for such a 
breach of trust to occur. And more specifically, I hope we will 
explore whether it makes sense to continue to give drug 
manufacturers 6 months of exclusivity in exchange for their 
conducting clinical trials when the results of those trials are 
not made available to physicians, patients or American 
taxpayers.
    It is important that we all understand why when the FDA was 
informed that clinical trials of several antidepressants 
demonstrated no efficacy in children or worse, far worse, they 
did not make an attempt to inform both pediatricians and 
patients of this critical information. Why were parents not 
given the results of the studies which could very well have 
influenced their decisions to start their children on those 
medications?
    When physicians discuss with parents the possibility of 
starting a child on a drug, an important part of that 
discussion involves the weighing of risks and benefits 
associated with taking that medication. If neither parents nor 
physicians possess information from these trials, they will be 
left in the dark and unable to make informed decisions 
regarding what is best for their children.
    I support Congressmen Waxman's and Markey's effort to 
create a registry that contains the results of all clinical 
trials conducted by all drug manufacturers. I think history 
shows it would be a failure for us, in meeting our obligation 
to protect the public health, to rely on the drug industry to 
create that registry. And I hope that as a result of this 
hearing, we will have a better understanding of how American 
families who subsidize clinical trials through their tax 
dollars can most easily obtain the results which allow them to 
make the right decisions for their children.
    Going further beyond the narrow scope of this particular 
hearing, as one of the perhaps millions of families facing a 
serious medical challenge and interested in the most up-to-date 
information on potential therapies, my family and I find it 
completely unacceptable that data from clinical studies that 
may have a really positive effect on outcomes are unavailable. 
I look forward to dealing with that situation in the near 
future. Thank you.
    Chairman Barton. Before we recognize Mr. Stupak for his 
opening statement, the Chair would ask unanimous consent that 
the hearing binder be put into the record that has all the 
documents that we have received from the FDA. Hearing no 
objections--and others--so ordered.
    [The material appears at the end of the hearing.]
    Chairman Barton. The Chair would recognize the gentleman 
from Michigan for an opening statement.
    Mr. Stupak. Thank you, Mr. Chairman, and thank you for 
allowing me the opportunity to take part in this important 
hearing on the publication and disclosure of antidepressant 
pediatric clinical trials.
    Every day brings new disturbing reports showing a link 
between suicidal behavior and antidepressants used by children. 
Physicians and parents deserve a full accounting of the 
research from both the FDA and drug companies about the risks 
and benefits of these drugs. The integrity of our drug safety 
system is being questioned and I believe rightfully so.
    Right now, drug companies can cherry pick which studies 
they publish and which they don't. We all know that the 
negative ones rarely see the light of day, and the FDA has done 
a truly dismal job of enforcing the two laws on the books today 
that provide for a minimal amount of transparency. Next week, 
the FDA Advisory Committee will meet to address the latest 
analysis that as yet again seems to show a link between 
suicidal behavior and antidepressant use by children. And in 2 
weeks we will hold a second hearing on the FDA's analysis and 
the Advisory Committee's recommendation, including labeling. I 
look forward to that hearing, but as we all know with Accutane, 
the Advisory Committee recommendations will most likely be 
ignored by the FDA.
    There are a lot of concerns about the safety of these 
drugs. What is appalling is until very recently doctors and 
parents had no way of knowing that these concerns existed. 
Drugs companies, aided by FDA's complacency, gave them no 
reason to question the safety or effectiveness of these drugs. 
Congress will not sit back if the drug companies and the FDA 
ignore or are slow to implement those recommendations by the 
Advisory Committee. We cannot allow profits and stock prices to 
trump the safety of our children.
    In 2002, almost 11 million antidepressant prescriptions 
were written for children and adolescents. Two point seven 
million of those prescriptions were for children under 12, to 
kids as young as 7 years old. Prozac has demonstrated some 
effectiveness today, but yet today there are new questions 
about its safety after an NIH study found an increased risk of 
suicidal behavior and thoughts when adolescents are treated 
with Prozac alone or in a combination with talk therapy when 
compared with placebos. This raises concerns about the safety 
of Prozac. We know these concerns and can address them today 
because it was a public study that was actually published. It 
is an example of how the system could work.
    I want to touch on a way the system is not working. Since 
1997, we have given pharmaceutical companies billions of 
dollars worth of patent extensions in exchange for testing the 
safety and efficacy of drugs in children. Those patent 
protections cost taxpayers billions in increased prescription 
drug prices and increased costs to Medicare and Medicaid. Many 
believe this system is justified because of the new information 
we gain in return, but what are we really gaining in return? If 
positive results are shown from pediatric trials, the FDA will 
allow the drug to be marketed to children. However, if the 
efficacy results are inconclusive or negative, the drug 
companies still have their patent extensions, ensuring millions 
in profits and doctors can still prescribe off label.
    I offered an amendment during the Best Pharmaceutical for 
Children Act, BPCA, debate to require results of the trials to 
be clearly outlined on the drug's label before patent 
extensions could be granted. Unfortunately, my amendment was 
defeated. My amendment would have given the pharmaceutical 
companies a powerful incentive to do good studies and to change 
their labels promptly. Remember, each patent extension often 
means hundreds of millions of dollars to the drug companies. 
This systematic flaw that rewards companies for doing a study, 
the results of which are not made public, which may show the 
drug is not effective and actually may harm young people and 
the consumers' notice, the package labeling is not immediately 
changed. We have it backwards. The patent extension should only 
occur if the drug is safe, effective and after the necessary 
label changes are fully implemented. Then, and only then, 
should a patent extension be granted.
    We were successful, however, in including a provision in 
the Best Pharmaceutical Children's Act that the FDA must 
publish the summaries of each of these pediatric trials done in 
exchange for patent extensions. At the very least, the FDA 
could publish the summaries, but this is not being done. The 
committee has found that the FDA had only posted the summaries 
for one of the antidepressants, Effexor, before August 20 of 
this year. There is no room for this kind of incompetence. Now, 
when you go to the FDA web site, you can see the summaries, 
but, interesting, none of the summaries include any mention of 
suicidal thoughts or behavior.
    Mr. Chairman, I have a lot more, and I know we are running 
out of time, but bottom line is let us get to the bottom of 
this, whether it is Accutane or whether it is the 
antidepressants, the FDA and the drug companies have let us 
down, they have not done their job. The complacency has got to 
end, and I look forward to asking questions, and I look forward 
to getting some answers to some of the letters I have written 
over the last couple of months to the FDA, to Ms. Woodcock just 
trying to get some of these studies produced and put out in the 
public.
    Chairman Barton. I thank the gentleman from Michigan. We 
will stand in recess until these series of votes, which will be 
approximately 12:20. All members not present or a member of the 
subcommittee will have the requisite number of days to put 
their opening statements in record. So we stand in recess until 
approximately 12:20.
    [Brief recess.]
    Chairman Barton. The subcommittee will come to order. 
Before we recessed for the votes, we had heard opening 
statements from all members of the subcommittee. Now we want to 
hear our witnesses. The Chair would call forward Dr. Janet 
Woodcock who is the Deputy Commissioner for Operations for the 
Food and Drug Administration.
    Dr. Woodcock, you are aware that the committee is holding 
an investigative hearing and when doing so we have the practice 
of taking testimony under oath. Do you have any objection to 
testifying under oath?
    Ms. Woodcock. No.
    Chairman Barton. Okay. The Chair would also advise you that 
under the rules of the House and the rules of the Energy and 
Commerce Committee, you are entitled to be advised by counsel. 
Do you desire to be advised by counsel during your testimony 
today?
    Ms. Woodcock. No.
    Chairman Barton. Okay. Would you please raise your right 
hand?
    [Witness sworn.]
    Chairman Barton. Be seated.
    Ms. Woodcock. Thank you.
    Chairman Barton. Dr. Woodcock, your written is in the 
record in its entirety. We are going to give you 7 minutes or 
such time as you may consume to advise us of that testimony. 
Welcome to the subcommittee.

   TESTIMONY OF HON. JANET WOODCOCK, DEPUTY COMMISSIONER FOR 
            OPERATIONS, FOOD AND DRUG ADMINISTRATION

    Ms. Woodcock. Thank you. Mr. Chairman and members of the 
subcommittee, I am Janet Woodcock, FDA's acting Deputy 
Commissioner for Operations. The agency appreciates the 
opportunity to participate in this important hearing.
    Today, I will focus on disclosure and publication of 
information regarding clinical trials under the Food and Drug 
Administration Modernization Act and the disclosure and 
dissemination of pediatric information under the Best 
Pharmaceuticals for Children Act.
    Now, it is generally agreed, and we have heard this morning 
already, and it is agreed upon in the biomedical community-at-
large, that results of trials involving human subjects should 
be made available to the public after completion of the trial 
and data analysis. This is especially important for studies of 
marketed products, surgical interventions and other medical 
treatments where a bias toward publication of positive results 
may distort the community's overall understanding of an 
intervention's effectiveness or risk profile. Government, 
academic or industry groups may sponsor human clinical trials, 
and each of these sponsors has a role in making clinical 
results available.
    Now, I would like to say that personally I have always had 
a strong commitment during my career at the FDA toward 
improving transparency of clinical trial results to the extent 
that was legal for the FDA. Starting in my tenure as Director 
of the Center of Drugs, I established web sites where the 
clinical results could be made available when drugs were 
approved. I established templates which are currently being 
used. I wrote those personally to provide summaries of reviews 
and get those results made public. I established procedures for 
redaction under Freedom of Information so that we would have a 
prompt process for making that information available to 
prescribers and to patients once new drugs became available on 
the market. So I have always been involved in this issue, and I 
strongly support the goal of transparency and availability of 
information from human subjects.
    When I took care of patients in clinical trials, I always 
tried to promise my patients I would send them the results or 
the published paper of the studies, because people who enroll 
in clinical trials are altruistic and they want to know that 
their efforts have gone into helping others and improving 
knowledge.
    Now, the FDA Modernization Act required the Department of 
Health and Human Services, acting through NIH, in consultation 
with FDA and CDC, to establish, maintain and operate a data 
bank of information on clinical trials for treatment of serious 
and life-threatening diseases and conditions. The data bank 
must contain information about clinical trials whether 
federally or privately funded that are conducted under an IND 
if the drug under study is to treat a serious or life-
threatening condition and the trial is testing the drug's 
effectiveness.
    Now, the purpose of this data bank primarily was for access 
to clinical trials so that the existence of these trials would 
be posted and patients or families or physicians who had a 
serious and life-threatening illness they were dealing with 
could look at what trials were open.
    NIH implemented Section 113 by establishing the clinical
trials.gov web site in February 2000. The information in the 
data bank must include for each trial a description of the 
purpose of each experimental drug, patient eligibility 
criteria, location of the sites for the trial and a point of 
contact for patients seeking to enroll in the trial. 
Information about other clinical trials such as those for non-
serious diseases or trials that aren't designed to assess 
effectiveness may be included but are not required to be 
submitted. Additionally, the law authorizes but does not 
require that the data bank include information about results of 
clinical trials. That is only voluntarily by the sponsor.
    Currently, clinicaltrials.gov contains information on more 
than 11,000 publicly and privately funded trials of which about 
4,000 are ongoing. Most of the trials are safety and efficacy 
studies for treatment of serious or life-threatening diseases 
or conditions; however, sponsors can and have voluntarily 
listed some early studies and studies for non-serious 
conditions. For some of the completed studies, links are also 
provided to abstracts or publications describing the study's 
outcome.
    Recent public attention on increasing the availability of 
clinical trial information, some of which has been brought 
about by this committee's efforts, have made pharmaceutical 
companies more aware of their responsibility to list these 
clinical trials. Last month, non-Federal sponsors listed 80 new 
trials--2 times the average monthly listing than the year 
before.
    Now, when Congress enacted the Food and Drug Modernization 
Act, it also provided incentives for manufacturers to conduct 
pediatric trials. The FDAMA authorized FDA to grant additional 
marketing exclusivity to pharmaceutical manufacturers that 
conduct studies of their drugs in pediatric populations, and 
that has already been alluded to this morning. To qualify for 
this exclusivity, sponsors must conduct these studies according 
to the terms of a written request from the FDA and then 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. Now, the change in the Best 
Pharmaceuticals for Children Act was it contained new 
disclosure requirements related to these clinical trials.
    Outside of the Best Pharmaceuticals for Children Act, the 
agency generally may not publicly disclose information and 
INDs, unapproved new drug applications or unapproved 
supplemental new drug applications. Only after a new drug 
application or supplemental application is approved can we make 
certain summary information available on the safety and 
effectiveness of the product for the approved indication. And 
these were the efforts I have been talking about that we have 
been working on.
    In contrast, the Best Pharmaceuticals for Children Act 
requires that no later than 180 days after submission of the 
studies in response to a written request the agency must 
publish a summary of FDA's medical and clinical pharmacology 
reviews of those studies. We must publish this information 
regardless of whether our action on the pediatric application 
is approvable or not approve. Since 2002, FDA has posted the 
summaries of 41 products submitted in response to written 
requests on FDA's web site.
    FDA and NIH will continue to work with individual sponsors 
to put required information into the clinicaltrials.gov 
registry. Also, FDA is reviewing sponsor listing in this 
registry to assess whether additional FDA action is warranted, 
and FDA welcomes the continued dialog regarding the kind of 
information from clinical trials that would be most useful to 
providers, patients and families in making meaningful treatment 
decisions. Thank you.
    [The prepared statement of Hon. Janet Woodcock follows:]

 Prepared Statement of Janet Woodcock, Acting Deputy Commissioner for 
Operations, U.S. Food and Drug Administration, Department of Health and 
                             Human Services

                              INTRODUCTION

    Mr. Chairman and Members of the Subcommittee, I am Dr. Janet 
Woodcock, Acting Deputy Commissioner for Operations at the U.S. Food 
and Drug Administration (FDA or the Agency). We appreciate the 
opportunity to participate in this hearing regarding publication and 
disclosure issues in pediatric clinical trials for anti-depressant drug 
products.
    On September 23, 2004, the Committee will hold a hearing regarding 
FDA's process for review of anti-depressants for pediatric use. Today, 
I will focus on the disclosure and publication of information regarding 
clinical trials under the Food and Drug Administration Modernization 
Act (FDAMA) of 1997 and the disclosure and dissemination of pediatric 
information under the Best Pharmaceuticals for Children Act (BPCA) in 
general, and in the context of anti-depressant pediatric clinical 
trials in particular. I will also provide a status report on the 
Agency's review of selective serotonin reuptake inhibitors (SSRIs) for 
pediatric use.
    It is generally agreed upon in the biomedical community that 
results of trials involving human subjects should be made available to 
the public after completion of the trial and data analysis. This is 
especially important for studies of marketed products, surgical 
interventions, and other medical treatments where a bias toward 
publication of positive results may distort the community's overall 
understanding of an intervention's effectiveness or risk profile. 
Government, academic, or industry groups, may sponsor human trials and 
each of these sponsors has a role in making clinical trial results 
available.

                    FDAMA: CLINICAL TRIALS DATA BANK

    Section 113 of FDAMA amended the Public Health Service Act to 
require the Department of Health and Human Services (HHS or the 
Department), acting through the National Institutes of Health (NIH) and 
in consultation with FDA and the Centers for Disease Control and 
Prevention, to establish, maintain and operate a data bank of 
information on clinical trials for treatments for serious or life-
threatening diseases and conditions. The goal of section 113 was to 
improve access to information that would enable the public to learn 
about opportunities to participate in clinical trials of promising new 
treatments. FDAMA specifies that the data bank must contain information 
about clinical trials, whether Federally or privately funded, that are 
conducted under an investigational new drug (IND) application if the 
drug under study is to treat a serious or life-threatening disease or 
condition and the trial is testing the drug's effectiveness.
    Working together with FDA and other sister agencies in the 
Department, NIH implemented section 113 by establishing the 
ClinicalTrials.gov website in February 2000. The information in the 
data bank must include, for each trial, a description of the purpose of 
each experimental drug, patient eligibility criteria, the location of 
the clinical trial sites, and a point of contact for patients seeking 
to enroll in the trial. Information about other clinical trials, such 
as those treating non-serious diseases or for trials that are not 
designed to assess effectiveness, may be included, but sponsors are not 
required to submit this information. Additionally, the law authorizes 
but does not require that the data bank include information about the 
results of clinical trials of such treatments, but only with the 
consent of the sponsor.

                          CLINICAL TRIALS.GOV

    Today, ClinicalTrials.gov contains information on more than 11,000 
publicly and privately funded trials, of which over 4,000 are open for 
recruitment. Most of the trials are safety efficacy studies (Phase II, 
III, and IV) for treatments for serious or life-threatening diseases or 
conditions. However, sponsors can and have voluntarily listed some 
Phase I (safety) studies and studies for conditions not classified as 
serious. In addition, for some of the completed studies in 
ClinicalTrials.gov links are also provided to publications or abstracts 
describing the study's outcome. Information on studies that are no 
longer recruiting patients or that are completed is retained in the 
database and available to the public.
    Recent public attention on increasing the availability of clinical 
trial information has made pharmaceutical companies more aware of their 
responsibility to list clinical trials in ClinicalTrials.gov. In fact, 
non-Federal sponsors listed 80 new trials last month--two times the 
average monthly listing for 2003. Additionally, companies that 
previously listed ``pharmaceutical company'' as the drug sponsor now 
list the specific company name.
    Section 113 of FDAMA does not authorize NIH to require that 
sponsors submit all clinical drug trial information to 
ClinicalTrials.gov. However, NIH does include non-mandatory information 
in the database when the sponsor voluntarily provides this information. 
For example, sponsors can include information about trial design.

                 FDA DISCLOSURE OBLIGATIONS UNDER BPCA

    When Congress enacted FDAMA in 1997, it also 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 BPCA Act.
    BPCA contains important, new disclosure requirements. Outside of 
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 our action 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 is publicly available 
irrespective of the action taken on the application. Since 2002, FDA 
has posted the summaries of these reviews of 41 products submitted in 
response to a Written Request on FDA's website at: http://www.fda.gov/
cder/pediatric/Summaryreview.htm.

  DISCLOSURE OF INFORMATIUON RELATED TO PEDIATRIC SSRI CLINICAL TRIALS

    Prior to the enactment of BPCA, using 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 and Zoloft, received pediatric exclusivity 
for doing those studies. The third sponsor, the manufacturer of 
Remeron, did not receive pediatric exclusivity. Under FDA's general 
disclosure provisions regarding the availability of information in 
approved applications, pediatric anti-depressant data on Prozac are 
publicly available at: http://www.fda.gov/cder/foi/nda/2003/1893
6s064_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 also 
considered those Written Requests to be reissued under the BPCA. In its 
July 2002 letter, FDA further advised manufacturers that any studies 
submitted in response to the Written Requests would be subject to the 
terms of 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 and 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 BPCA.

      STATUS OF SSRIS AND SUICIDALITY IN THE PEDIATRIC POPULATION

    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. Later reports on studies of other drugs supported 
the possibility of an increased risk of suicidal thoughts and actions 
in children taking these drugs. There were no suicides in any of the 
trials.
    FDA has closely examined the studies of the anti-depressants 
because of the potential public health impact of a link between the 
drugs and suicidality and the importance of these drugs in treating 
depression and other serious mental health conditions. After examining 
the initial reports of suicidality, it was unclear whether some of the 
identified suicidal behaviors reported in these studies represented 
actual suicide attempts or self-injurious behavior that was not 
suicide-related. FDA therefore arranged with Columbia University 
suicidality experts to review these reports.
    Meanwhile, FDA brought available information on this issue to its 
Psychopharmacologic Drugs Advisory Committee and Pediatric Subcommittee 
of the Anti-Infective Drugs Advisory Committees on February 2, 2004. 
The advisory committee members advised FDA that even before the 
Columbia analysis was complete, the labeling should draw more attention 
to the need to monitor patients closely when anti-depressant therapy is 
initiated. Based on this recommendation, FDA asked manufacturers to 
change the labels of ten drugs to include stronger cautions and 
warnings about the need to monitor patients for worsening of depression 
and the emergence of suicidality, whether such worsening represents an 
adverse effect of the drug or failure of the drug to prevent such 
worsening. The new warning language has now been added to the labels 
for seven of these products. Sponsors for the other three drugs have 
also agreed to adopt the language. The ``Columbia'' Study
    Because of concerns about whether the varied events identified by 
sponsors under the broad category of ``possibly suicide-related'' could 
all reasonably be considered to represent suicidality, FDA asked 
Columbia University to assemble an international panel of pediatric 
suicidality experts to undertake a blinded review of the reported 
behaviors using a rigorous classification system. The Columbia group 
submitted its completed review to FDA in June 2004.
    FDA has analyzed the pediatric suicidality data, based on the case 
classifications provided by Columbia University, and has posted the 
analysis on its website at http://www.fda.gov/ohrms/dockets/ac/04/
briefing/2004-4065b1-09-TAB07-Iyasu-Audit_report.pdf. While there are 
findings among these data suggestive of an increased risk of 
suicidality for some of these drugs, there remain inconsistencies in 
the results, both across trials for individual drugs and across drugs. 
Thus, an overall interpretation of these findings remains a substantial 
challenge.

The September 2004 FDA Advisory Committee Meeting
    As a public health agency, FDA must weigh the possibility of an 
increased risk of suicidality in young patients taking these drugs 
against the known risk of suicide in patients whose depression goes 
untreated. FDA's next step, as we announced in March 2004, will be to 
update the Psychopharmacologic Drugs and the Pediatric Advisory 
Committees about the results of these reviews and to seek assistance 
from the committees in interpreting the data and in considering what 
additional regulatory actions may be needed to promote the safe use of 
these drugs. This meeting will be held in Bethesda, Maryland on 
September 13 and 14, 2004.

                               CONCLUSION

    FDA and NIH will continue to work with individual sponsors to put 
required information into the registry. Also, FDA is reviewing sponsor 
listings in ClinicalTrials.gov to assess whether additional FDA action 
is warranted. FDA will continue to actively provide summaries of 
pediatric trials in a timely manner. FDA welcomes a continued dialogue 
regarding the kind of information from clinical trials that would be 
useful to providers, patients, and families so they can make more 
meaningful treatment decisions. Finally, FDA will carefully consider 
what further action may be required for the safe use of anti-depressant 
drugs in children.

    Chairman Barton. Thank you. Thank you, Dr. Woodcock. The 
Chair would recognize himself for 10 minutes of the first round 
of questions.
    The purpose of our hearing today, the title of our hearing 
is, ``Oversight Hearing on Publication and Disclosure Issues in 
Antidepressant Pediatric Clinical Trials.'' And as I said in my 
opening statement, for us to have a hearing, we need to have 
documents in which to base our questions and give our members 
of the subcommittee a chance to see what the facts are. We 
could have had a hearing on the disclosure of FDA to document 
requests by this subcommittee, and we have got seven or eight 
members here that are going to ask a lot of very specific 
questions on the policy issues. I am going to primarily limit 
my questions to a procedure issue.
    I was subcommittee chairman of this subcommittee from 1995 
through 1999, and one of my primary emphasis was the FDA under 
Dr. Kessler, and the FDA Reform Act that you referred to in 
your testimony was a bipartisan effort between myself, Mr. 
Bliley, Mr. Bilirakis, Mr. Dingell, Ms. Eshoo and Mr. Burr on 
this committee. So I have been away from doing active oversight 
and investigations for approximately 6 years. Now with Mr. 
Greenwood's resignation as subcommittee chairman, I have an 
excellent vice chairman in Mr. Walden, but for the remainder of 
this Congress I am serving kind of de facto as the acting 
subcommittee chairman of Oversight and Investigations. And I 
want to tell you straight up, as a senior representative from 
FDA, your agency's cooperation with this subcommittee and this 
investigation is as poor as it could possibly be and still be 
called cooperation.
    Mr. Greenwood and I sent a letter on March 24 to Dr. 
McClellan when he was still Commissioner of the FDA, it is 
about a 6 or 7 page letter, but we had a number of questions 
that we asked that we get a timely response to. Question number 
8, and I am going to read the question, ``All records relating 
to communications by FDA employees that raise questions or 
concerns about the safety or efficacy of antidepressants in the 
pediatric adolescent population, we are asking for those 
records.''
    Now, as an addendum to the letter, we sent our standard 
attachment where we define the term, ``records.'' ``The term, 
`records,' is to be construed in the broadest sense and shall 
mean any written or graphic material, however produced or 
reproduced, of any kind or description consisting of the 
original and any non-identical copy, whether different from the 
original because of notes made on or attached to such copy or 
otherwise, and drafts and both sides thereof, whether printed 
or recorded electronically or magnetically or stored in any 
type of data bank, included but not limited to the following: 
correspondence, memoranda, records, summaries of personal 
conversations or interviews, minutes or records of meetings or 
conferences, opinions or reports of consultants' projections, 
statistical statements, draft contracts, agreements, purchase 
orders, invoices, confirmations, telegraphs, telexes, agendas, 
books, notes, pamphlets, periodicals, reports, studies, 
evaluations, opinion logs, diaries, desk calendars, appointment 
books, tape recordings, video recordings, emails, voicemails, 
computer tapes or other computer stored material, magnetic 
tapes, microfilm, microfiche, punch cards, all other records 
kept by electronic, photographic, mechanical means, charts, 
photographs, notes, drawings, plans, interoffice 
communications, interoffice or interdepartmental 
communications, transcripts, checks, canceled checks, bank 
statements, ledgers, books, records or statements of accounts 
and papers and things similar to any of the foregoing, however 
denominated.'' You got that. Not you, personally; Dr. 
McClellan.
    Here is the answer. This is from Mr. Patrick McGarey who is 
in the Office of Legislation for the FDA. It was sent on 
Monday, May 3 to Anne Henig who is a CDER employee who is 
responsible for coordinating the response to this letter. And 
there were blind copies sent to Karen Meister who is also in 
Legislative Affairs at FDA, Donna Katz and Kim Dettelbach who 
are in the Legal Counsel's Office at FDA. And I am quoting 
verbatim from this email. ``Here is my draft of instructions to 
the CDER employees who have to search for documents for 
question 8: Provide copies of all records that, one, raise a 
question or concern about the safety or efficacy of 
antidepressants in the pediatric or adolescent populations. Be 
sure to forward only records that raise safety or efficacy in 
the body of the record. Please do not--please do not--include 
draft documents, notes, memos to self or file or incoming 
communications from non-FDA individuals, i.e., the public, 
business organizations, other HHS ops divisions unless an FDA 
employee has forwarded such communications to others with 
additional questions or concerns. Finally, Anne, there are 
different timeframes for the two employees. For Dr. Avagan, we 
need to search back to January 1, 2002; For Dr. Knudsen, they 
do not place a timeframe on the documents, so we need to search 
back as far as possible. Patrick McGarey, FDA Office of 
Legislation.''
    Now, I take this as a direct contradiction to what we were 
asking for. How do you take it?
    Ms. Woodcock. I was not directly involved in this document 
search.
    Chairman Barton. I am not saying that you were.
    Ms. Woodcock. My understanding is that, No. 1, that the 
subcommittee has the documents, all the documents, that have 
been requested.
    Chairman Barton. That is not a true statement.
    Ms. Woodcock. And my other understanding is that there is a 
prioritization of what would be provided to the committee, 
because this was a very massive document request, and therefore 
those sets of documents that were mentioned in the email were 
the first types of documents that were produced.
    Chairman Barton. Well, I appreciate that answer, but it is 
non-responsive. Now, I want this subcommittee to be able to 
conduct a full and fair investigation. That is not possible if 
we don't get the documents and we don't get true cooperation. 
Now I know that you are not the acting Commissioner. You are a 
Deputy Commissioner in charge of Operations, and you are here 
primarily to testify about the subject of disclosure of these 
clinical trials, but you are the senior ranking FDA person 
here. What can you tell me that gives me comfort that we are 
going to get cooperation? I do not want to have to subpoena 
records of the FDA. That is not the way this committee is 
operated under Chairman Dingell, it is not the way it operated 
under Chairman Bliley nor Chairman Tauzin, but we have got--
this is a very important issue, and we have simply got to get 
the documents that we need to have so that members on both 
sides of the aisle have access to the proper information. We 
have never had a problem on either side of the aisle with 
proprietary information, with disclosure, leaks, things of this 
sort when we had an agreement with the agency that we are 
getting the documents from about how to handle those documents. 
So what do you think we can do to solve this problem?
    Ms. Woodcock. The FDA will make every effort to cooperate 
with the committee. We recognize this is a very important 
investigation. My understanding is we have invited the 
investigators to come to the FDA and evaluate the records in 
situ but they have declined. However, that offer is still open. 
But we also will cooperate fully in production of documents.
    Chairman Barton. Well, I could give you two or three more 
instances of information that we have requested that has not 
been received, and there has been some technical reason why it 
wasn't received. We didn't ask for it in just the right way or 
whatever. So I am going to ask--I have got a meeting at 2:30 
with former Chairman Dingell. I am going to seek his counsel on 
this, but we are almost certainly going to ask for a senior 
principals meeting in the very near future, in my office, and 
we are going to come up with a protocol that not only is FDA 
comfortable with but the committee is comfortable with. Would 
you please take that message back?
    Ms. Woodcock. Certainly.
    Chairman Barton. On the policy--my time is almost expired, 
but on the policy issue, do you feel there is any reluctance on 
behalf of the FDA to disclose negative clinical information--
clinical trial information?
    Ms. Woodcock. No. I believe that we have legal restraints 
on the amount of information we can disclose and when we can 
disclose that information. And we must follow the law as far as 
it pertains to information disclosure. As I said in my 
testimony, prior to approval of a drug, it is not possible for 
FDA to disclose information on clinical trials, clinical trial 
results and so forth until the drug would be approved for that 
particular indication.
    Chairman Barton. Well, what do you do when you have a 
situation, as apparently is the case with some of the clinical 
trials under discussion today, where the trials all appear to 
be fairly negative, if there is no showing of efficacy and yet 
some of those drugs are being prescribed off label even though 
the clinical trial data shows that they are not helpful? What 
do you do in that situation?
    Ms. Woodcock. Well, as you probably know, the FDA has been 
criticized many times for not approving drugs, and in many 
cases that is because we have access to information about the 
drugs that would provide an explanation that we are not 
currently able to disclose. Now, as was said earlier, this has 
been remedied for pediatric clinical trials that are done under 
the Best Pharmaceuticals for Children Act provisions, because 
after submission of the information to the FDA, reviews are 
automatically disclosable after 180 days. So that gives FDA the 
permission to make those data available in summary form, and we 
have been doing that. We have done that with 41 products so 
far.
    Chairman Barton. My time has expired. I recognize the 
distinguished ranking member, Mr. Deutsch of Florida for 10 
minutes.
    Mr. Deutsch. Thank you, Mr. Chairman. Dr. Woodcock, I am 
trying to get to the timeline of reviews and analysis. Is it 
correct that an initial study completed last year by Dr. Andrew 
Mosholder at the FDA concluded that the pediatric use of 
certain antidepressants increased the risk of suicide?
    Ms. Woodcock. Correct. Not suicide--excuse me for 
interrupting you--but suicidality; in other words, thoughts 
about suicide.
    Mr. Deutsch. And if we explore the safety issue at length 
at the next hearing, if I wanted to be aware of the facts 
involved, is it further correct that the FDA wasn't prepared to 
allow Dr. Mosholder to present his findings to the Advisory 
Committee?
    Ms. Woodcock. We presented Dr. Mosholder's analysis to the 
Advisory Committee. He did not present a recommendation to the 
Advisory Committee because we were seeking their advice on what 
to do.
    Mr. Deutsch. Is it true that after Columbia University 
finished their study, which was analyzed outside of the Office 
of Drug Safety, that the results agreed with Dr. Mosholder's 
finding about the increased risk of suicidal thought in 
pediatric patients taking antidepressants?
    Ms. Woodcock. Yes. The analyses were generally in 
agreement.
    Mr. Deutsch. Is this going to be followed up on as well as 
the Advisory Committee meeting?
    Ms. Woodcock. This will be discussed at an open public 
Advisory Committee meeting next week where the full analyses 
will be presented before an extensive panel of experts in 
pediatrics and depression, and we will seek advice of that 
committee on further steps.
    Mr. Deutsch. So just to be clear, FDA aided and abetted the 
industry in helping to keep the findings of ineffectiveness 
from the public and in keeping information showing evidence of 
increased suicide risk hidden from the public through this 
Advisory Committee process. And if you can, again, I mean try 
to explain to us these drugs that make the agency believe that 
keeping the information at this point non-public, what were the 
policy reasons for that to be?
    Ms. Woodcock. FDA made all information available that we 
were legally able to do, and although Dr. Mosholder's 
particular conclusions about those analyses were not presented 
to the committee, the full data were presented publicly at that 
committee meeting, so no information was withheld.
    Mr. Deutsch. Could you cite a specific statute or 
regulation that would have prevented you from providing that 
information to the public?
    Ms. Woodcock. Well, I am not counsel for the FDA, but this 
is--we have had numerous discussions of this within the FDA and 
provisions of freedom of information and provisions of statutes 
governing confidential commercial information.
    Mr. Deutsch. Is counsel with you today who can present to 
us any specific----
    Ms. Woodcock. We can get back to you on that.
    Mr. Deutsch. Your testimony touches upon the subject of 
pediatric exclusivity. On average, how many proposed pediatric 
study requests has the FDA received?
    Ms. Woodcock. We send them out. We send out written 
requests, and, I am sorry, I don't have that. We can provide--
it has been hundreds, and we can provide the exact numbers to 
you.
    Mr. Deutsch. So there is a difference between the proposed 
request and written request; is that accurate?
    Ms. Woodcock. Under the Best Pharmaceuticals for Children's 
Act, FDA has a responsibility to request of a company that they 
perform these studies, whether or not they have sent a proposal 
in or not. And it is that request that governs the process.
    Mr. Deutsch. And, specifically, how many labeling changes 
have occurred? Would you----
    Ms. Woodcock. I don't know how many labeling changes.
    Mr. Deutsch. Could you give us a relative sense between the 
number of requests, the number of studies and the labeling 
changes?
    Ms. Woodcock. I don't have that information at my 
fingertips, I am sorry.
    Mr. Deutsch. Okay. Our staff actually has some numbers that 
actually points out that, at least according to our staff, the 
numbers are 71 labeling changes based upon 678 requests, and I 
think that really highlights the statement that I made in my 
opening statement. There have been 678 requests for pediatric 
studies. I am not aware of exactly how many studies have been 
made, but, as you have said, in the hundreds, but only 71 
actual labeling changes, which would clearly indicate that in 
many cases the studies are made without any operational 
changes, at least on the label. Is there any request that the 
FDA get the companies to change the labels on more of the drugs 
after the pediatric studies have been made?
    Ms. Woodcock. We certainly make every attempt to get any 
relevant information that has been obtained from those studies 
into the label. Some of the studies that you referred to are 
still ongoing and therefore the information will not be 
available to go into the label or to be submitted to FDA. In 
other cases, and the pediatric depression example is a good 
one, where the studies are negative or inconclusive, there is 
currently no provision that that information would be in the 
label.
    Mr. Deutsch. Now, it seems--again, it goes back to maybe 
the whole point of the pediatric exclusivity statute that if 
the point is--and, again, I raise it again because we are not 
talking about a small amount of money. On the antidepressant 
side, the amount that effectively taxpayers in this country 
have paid is close to $4 billion on the six drugs that are the 
topics of this hearing, yet in terms of actual benefit to 
consumers, without the information, where is that benefit 
shown? I guess, really, I pose that as a question. I mean this 
whole issue, which we raised previously, about without putting 
it on the labels, without making it a use, either negative or 
positive, saying that it has efficacy or doesn't have efficacy, 
where is the value? Where is the ultimate value?
    And then could you respond to the amendment that was 
offered in committee by Mr. Stupak that I referred to earlier? 
Would you support that type of change that the exclusivity 
provision not be granted until--I mean that would be one way--
you mentioned how you try to, I guess, jawbone the companies to 
change the labeling. Well, I can tell you that if that was a 
requirement for the increased exclusivity, you wouldn't have to 
jawbone. So maybe that is something that we should be looking 
at at this point in time. I mean could you respond specifically 
to that proposal?
    Ms. Woodcock. Yes. Well, to step back, you asked what value 
for the BPCA in this situation. I think we need to take the big 
picture into account and remember without the provisions of 
this act, none of these studies would have been done probably, 
and we may not have had this information about side effects 
that the committee is now investigating. So more information, 
more studies about use of drugs in children, because they are 
being used already now, this is very desirable and we will 
eventually buildup a knowledge base that will help us decide 
what drugs should be used in pediatric diseases. And this is a 
very positive step.
    On the other hand, this issue of disclosure is something 
that has been identified, I think, as this program has 
unfolded, as we have done written requests, as studies have 
been done and we have gotten new information that we are 
discussing here today.
    As far as amendments, I think we have to balance the issue 
of timeliness of information. I believe that the summary, the 
180-day release of information by the FDA of review summaries 
is timely, and so many of these drugs that we are discussing 
today did not have the written requests done under the Best 
Pharmaceuticals for Children Act. They were done under the 
FDAMA provisions, which did not have a disclosure piece to it. 
So for further pediatric studies that are done under written 
request, we will have prompt disclosure at 180 days. But it is 
true, that is not the same as having information in the label.
    Mr. Deutsch. All right. Thank you. My time has expired.
    Mr. Walden [presiding]. Okay. Doctor, could you please turn 
to tab 41? This is a ``Dear Health Care'' letter dated August 
22, 2003. It is tab 41, that Wyeth decided to send out the 
positions along with a labeling change that included a strong 
warning about hostility and suicide related events occurring in 
pediatric patients and recommending the product not be used in 
kids under the age of 18. The language was included in the 
section of the label called, ``precautions-usage in children.'' 
FDA did not require that Wyeth put this stronger labeling on 
Effexor back in 2003, correct? The FDA didn't require them to 
do that?
    Ms. Woodcock. Correct.
    Mr. Walden. On March 19 of this year, the FDA issued 
letters to the antidepressant companies requesting a labeling 
change. It is my understanding this labeling change was not 
directed just at the pediatric population but was to, ``kids 
and adults,'' correct?
    Ms. Woodcock. That is correct.
    Mr. Walden. So the FDA's warning would not appear under the 
pediatric use section, correct?
    Ms. Woodcock. Right.
    Mr. Walden. Now, if you would turn to tab 40. This is a 
letter sent from Russell Katz, the Director of the Neuropharm 
division to Wyeth, and it states, and I quote, ``We note your 
agreement to our request,'' emphasis added, ``to remove your 
proposed addition of hostility and suicide related adverse 
events from the precautions usage in children section.'' And 
then the letter goes on to say, ``We continue to feel that it 
would not be helpful to include the language regarding reports 
of hostility and suicidality that you have proposed for the 
pediatric use sections.'' Why would FDA request that a company 
remove stronger labeling, that is labeling that would be more 
informative to parents and doctors about the risks that may be 
associated with children taking this drug?
    Ms. Woodcock. The FDA attempts to make the language in the 
label factual and based on the scientific data that is 
available, and that includes not going beyond the data that are 
available scientifically on which those statements may be 
based. The FDA had developed a statement to be put in all drugs 
of this class, a very prominent statement, a warning about 
development of some of these psychiatric side effects and 
potential association with these agents and was requesting that 
that be put in labels of all the drugs, and that has been done.
    Mr. Walden. Is it FDA's position that if a company's own 
internal analysis of, for example, suicide-related events turns 
up a signal the company thinks practitioners and the public 
should be aware of, that they are prohibited from doing so 
because the FDA has found no causal connection?
    Ms. Woodcock. I don't believe that we require causal 
connection. The FDA tries to make sure that labels are factual 
and based on the scientific data.
    Mr. Walden. Well, under tab 40 in the letter from Dr. Katz, 
in part, down toward the bottom, it says, ``As currently 
written, the language is uninterpretable since it notes there 
were increased reports but without noting with reference to 
what data. If a reference to placebo data were added, this 
would suggest a causal association. However, this suggestion 
would be contradicted by the new language that follows.'' I 
guess the question is it seems to me as a parent that if a 
company, Wyeth, sends out a letter to 400,000 or so health care 
professionals saying, ``We think you need to be aware, alert to 
signs of suicidal ideation in children and adolescent patients 
prescribed Effexor or Effexor XR. You may need to reassess 
risk/benefit balance when treating individual patients with 
Effexor or Effexor XR.'' FDA would want to encourage a company 
to do this sort of thing, and you would want that sort of added 
to the label, especially is a company wanted it added. I mean 
we have heard a lot about companies maybe going the other 
direction. Here you have got one saying, ``Warning, there may 
be suicidal and hostility increases.'' Wouldn't you want that 
on the label?
    Ms. Woodcock. We want balanced information that really 
reflects what is known scientifically about the drug.
    Mr. Walden. So you think what Wyeth found isn't based on 
science?
    Ms. Woodcock. That is what we are talking about over the 
next week at our Advisory Committee. We will be discussing how 
much we know about the science right now of psychiatric adverse 
events in patients treated with SSRIs.
    Mr. Walden. Their letter, I would just suggest, came out 
August 22, 2003. In fact, 12 of the 15 clinical trials for 
depressed kids showed no efficacy, according to the FDA, 
correct?
    Ms. Woodcock. The other trials did not meet FDA standards 
for showing effectiveness. Some of them were completely 
negative; others did not reach statistical significance.
    Mr. Walden. Is that a yes then?
    Ms. Woodcock. That means they didn't meet FDA standards 
for----
    Mr. Walden. Efficacy.
    Ms. Woodcock. [continuing] approval, for efficacy, that is 
correct.
    Mr. Walden. For approval for efficacy, correct? Why doesn't 
FDA mandate that the labeling for pediatric use state that 
clinical trials were done in depressed children and adolescents 
and they did not show efficacy?
    Ms. Woodcock. Again, we are discussing how to relay this 
information. In general, the labels are only able right now to 
discuss approved indications, and this is not an approved 
indication.
    Mr. Walden. So if a drug were going to do something really 
bad to somebody or do nothing at all, you don't think that 
needs to be defined in the label?
    Ms. Woodcock. I am not saying what I think; I am saying the 
way the law is structured. We can add side effects even if they 
are seen for off-label uses, but we are not able to compel 
companies to put extensive information on negative trials 
within the labels.
    Mr. Walden. Can you cite the legal barrier to that?
    Ms. Woodcock. The law and the regulations. We can provide 
you that information.
    Mr. Walden. Provide me that.
    Ms. Woodcock. We would be glad to do that.
    Mr. Walden. I just find that amazing. We are talking, what 
is it, 10 million kids taking these drugs, being prescribed off 
label, and you have got companies, some of them saying, ``We 
think, by the way, Mr. and Mrs. Physician, look for hostility 
and suicidal.'' You have got internal studies that say suicide 
is maybe up 1.89 percent on Mosholder and Columbia says, I 
think, 1.78 times, right?
    Ms. Woodcock. Suicidality, yes.
    Mr. Walden. Okay. We have been told by various 
pharmaceutical companies that conducted these antidepressant 
pediatric trials they proposed labeling changes stating that 
their clinical trials did not show efficacy in depressed kids 
and that FDA told them they did not want that, the fact of the 
failed trials to be mentioned in the labeling. Can you explain 
why that is? Is this again the law in the rules?
    Ms. Woodcock. I am sorry, I don't have knowledge of that 
exchange.
    Mr. Walden. Why would FDA prevent a company from disclosing 
the fact that clinical trials performed failed to show 
efficacy?
    Ms. Woodcock. As I said, I can't explain that particular 
statement by the companies. I am not familiar with that.
    Mr. Walden. Has FDA ever told a company not to disclose the 
fact that clinical trials were performed and failed to show 
efficacy?
    Ms. Woodcock. I don't know that.
    Mr. Walden. Who is in charge that would know that?
    Ms. Woodcock. We can also get back to you on that question.
    Mr. Walden. Aren't you head of this division?
    Ms. Woodcock. I am normally head of the Center for Drugs at 
the FDA, which regulates drugs.
    Mr. Walden. And you do labeling.
    Ms. Woodcock. That is correct.
    Mr. Walden. And you can't tell me why the center that you 
head would prevent a company from putting on the label the fact 
that trials show no efficacy?
    Ms. Woodcock. You asked me if it has ever happened, and I 
do not know. I don't have factual knowledge of that. Certainly, 
I wouldn't feel that companies should be prevented from 
disclosing information, as I said at the beginning of my 
testimony, but I can't assure you that it never happened.
    Mr. Walden. But does that include disclosing clinical 
trials that show no efficacy?
    Ms. Woodcock. Correct.
    Mr. Walden. They should not be precluded from disclosing 
that on a label. I mean shouldn't--I mean I don't know, I am 
not a doctor, but it seems to me that if you have got companies 
doing trials and 12 of the 15 trials show no efficacy in kids 
and you have got data that show that potential higher suicide 
rates and hostility, you would want that information out there.
    Ms. Woodcock. Well, there is a distinction here. We cannot 
compel companies. That is the law and the regulations I was 
talking about. We can't compel companies to reveal this 
information.
    Mr. Walden. But some of them have asked you for the ability 
to release that information and you have said no.
    Ms. Woodcock. I don't have information on that.
    Mr. Walden. Well, this is the hearing on disclosure and we 
had sort of hoped you would be prepared to address that. Who 
can answer this?
    Ms. Woodcock. We have to go ask all the divisions, and we 
can do that and get back to you on that, that specific 
question.
    Mr. Walden. Yes. We are going to have a hearing on the 
23rd.
    Ms. Woodcock. Right.
    Mr. Walden. Fill the room with the people that can answer 
our questions.
    Ms. Woodcock. Certainly.
    Mr. Walden. My time has expired. I now turn to Mr. Waxman 
for his opportunity for questions.
    Mr. Waxman. Thank you, Mr. Chairman. I find it hard to 
believe a company would like to put on the label some statement 
that they have a study that shows their drug may not be 
effective for children. Now, you are going to try to give us an 
answer to whether the company asked you to do that and was 
turned down. I suppose we could find out from the companies if 
they have made that request and turned down. We could find out 
from them what their thinking was.
    Let me review the situation because it gets to be 
complicated. Manufacturer produces a drug, they do all the 
studies, they go into the FDA with their data and they have to 
show that they are safe and effective and they establish this 
through clinical trials. You review it, FDA, the data, and 
decide whether in fact the drug is safe and effective for a 
clinical purpose; is that right?
    Ms. Woodcock. Correct, for an intended use or uses.
    Mr. Waxman. For intended use. Now, once that drug is 
approved for that intended use, it can be prescribed for 
anything.
    Ms. Woodcock. That is correct.
    Mr. Waxman. That is what we refer to when we say off-label 
use. They don't have to go to FDA to prove that they are 
effective for that other use; they just have to have a doctor 
willing to prescribe the drug for that different use; is that 
correct?
    Ms. Woodcock. Yes. And as you know, manufacturers are not 
permitted to promote any off-label use to physicians or others.
    Mr. Waxman. But others can promote it on their behalf.
    Ms. Woodcock. That is correct.
    Mr. Waxman. And many drugs are prescribed by physicians 
without FDA having reviewed whether there is an effective for 
that other additional use; is that correct?
    Ms. Woodcock. Yes. And that was one of the impetuses for 
the Best Pharmaceuticals for Children Act, as you know, because 
much therapy in children was off-label because drugs had not 
been studied in the pediatric populations.
    Mr. Waxman. So we wanted--we meaning you and the medical 
world and the Congress--to give an incentive for the companies 
to do the studies for pediatric use of some of the drugs that 
are already being used for adults. If they came in and wanted 
to get an approval on the label for use with their drug for 
children, they would have to establish the validity of their 
statement, wouldn't they?
    Ms. Woodcock. Yes.
    Mr. Waxman. That would mean they would have to prove the 
effectiveness.
    Ms. Woodcock. That is correct.
    Mr. Waxman. But they still can sell it to kids even without 
getting your approval.
    Ms. Woodcock. Right. As I said, they cannot promote it or 
cause others to promote it, but often these uses are taken up 
in the medical community because there are many diseases that 
lack adequate treatment. For example, pediatricians were not 
able to simply ignore children and not treat them when no good 
data were available on what drugs they should use.
    Mr. Waxman. So the solution to this problem was, in effect, 
to bribe the pharmaceutical companies by saying, ``Look, if at 
least you do the studies, we are going to give you 6 months 
more of a monopoly over your drug for everybody you sell it 
to.'' And for the most part, their drug could be sold to 
adults. It could be a very high-selling drug for adults; is 
that right?
    Ms. Woodcock. Yes.
    Mr. Waxman. Okay. But once we give them the additional 
monopoly time, we don't require them to come in and ask for a 
change in their label as it relates to the use of the drug for 
children.
    Ms. Woodcock. What is required under the statute, the Best 
Pharmaceuticals for Children Act, is that the company submits 
studies that are responsive to the written request.
    Mr. Waxman. Right. And the studies could show that the drug 
is positive and effective, it could show that it is not 
effective, the studies can show that they are inconclusive.
    Ms. Woodcock. Correct.
    Mr. Waxman. And unless it is a study that shows it is 
effective, they are not going to come in and ask for a label 
change, presumably.
    Ms. Woodcock. Right.
    Mr. Waxman. Now, I have been told that in some of these 
antidepressant trials that were not made public were 
inconclusive and that the FDA believed that those trials 
produced no useful information to be added to the label; is 
that correct?
    Ms. Woodcock. That is correct. I can expand on that if you 
would like.
    Mr. Waxman. Well, maybe we will come back to it, but I 
wanted to follow through on this. It is hard for me to see why 
a company would work hard to get conclusive results if they are 
rewarded for inconclusive results. They are going to get that 
6-month monopoly. Why do all the extra tests to show some 
conclusive result when all they have to do is do a study even 
if it is inconclusive and they automatically get this 6-month 
monopoly?
    Now, FDA may decide that one or two studies submitted in 
exchange for exclusivity are too inconclusive to put in the 
drug's label from the FDA's perspective. We just don't know if 
the drug works or not. Let me go back on this point. Under this 
law that gives them this reward for doing the studies, as it 
was revised, now called the Best Pharmaceuticals for Children's 
Act, you have the right to put out the studies that were 
inconclusive or even showed that it was not effective after 180 
days; is that right?
    Ms. Woodcock. That is correct, and we do that.
    Mr. Waxman. And you do that. But that has only been recent.
    Ms. Woodcock. Since 2002.
    Mr. Waxman. And the antidepressant trials the information 
was not put out about the children's use of a lot of these 
antidepressants. I think that there were two studies that were 
made public, and then when there has been a lot of press 
attention, congressional concern, then you put out five more 3 
weeks ago. Why weren't they all put out at the same time?
    Ms. Woodcock. The original approval for an SSRI for 
pediatrics was of Prozac, and the data were made available at 
the time of approval. As I said earlier, that is our standard 
practice. One of the drugs, Effexor, I believe, was actually 
under the Best Pharmaceuticals for Children Act provisions, and 
therefore the 180-day posting kicked in and we were able to 
make those data available, the summaries available under the 
Best Pharmaceuticals for Children Act provisions.
    Mr. Waxman. By the way, you only put out the summaries of 
the clinical trials; is that correct?
    Ms. Woodcock. What we actually post is FDA's reviews, which 
are fairly detailed summary reviews of the safety and efficacy 
data. So that would go over the different studies that were 
done and discuss their results, but it wouldn't go into 
excruciating detail.
    Mr. Waxman. Okay. Now, a doctor wants to find out more 
information about this drug, and they want to find out whether 
it is really a good idea to use it for the children but as the 
antidepressant cases illustrated all too well, physicians may 
be given a very different picture of the drug's effectiveness 
by the drug companies. In the case of both Paxil and Zoloft, 
the manufacturers had actually taken studies that FDA viewed as 
negative and published them as if they showed that these two 
drugs were effective in kids. Now, that raises a very serious 
problem. Do you think that the medical community is well served 
by allowing drug companies to cherry pick and even distort 
which data are made public and which are not?
    Ms. Woodcock. As I said in my oral testimony, I believe 
that results of clinical trials should be made available to the 
medical community and to patients.
    Mr. Waxman. When manufacturers choose to publish only the 
positive studies and to withhold the negative studies or, 
worse, to portray negative studies as if they were positive and 
FDA knows about the missing or distorted data, does FDA have 
any responsibility to the medical community?
    Ms. Woodcock. We have long tried to deal with this issue. 
The differing interpretation of clinical trial results is by no 
means confined to the pediatric depression area, and this is a 
conundrum for the agency because it is often difficult for us 
to explain our actions to the public when we are constrained 
from revealing the data upon which our opinion is based.
    Mr. Waxman. Well, that is really a very important point 
because when we talk about pediatric uses of drugs, you have 
the ability to release some of the data, at least a summary of 
it, but when we are talking about off-label uses for anybody 
other than a pediatric study, that information may never even 
get out to the public because you are restrained because of the 
proprietary nature of this. Shouldn't there be some mechanism 
for making the totality of the data on drugs available to the 
medical community, if only so that the expert groups making 
recommendations to physicians about how to use drugs have 
access to the full picture rather than only to the data the 
drug companies want them to have?
    Ms. Woodcock. We recognize that there have been a number of 
good ideas circulating about this, and we look forward to 
participating in any thought process there would be about this 
issue.
    Mr. Waxman. I know it is complicated and it is difficult, 
but don't you think there ought to be some way for the medical 
community to get this information? I know we have to work it 
out in detail, but the concept of withholding the information 
from them, having them set up to be in a position where the 
drug companies can misrepresent the situation to them and they 
have no other recourse to further information, that just seems 
to me absolutely wrong. So don't you think we need some 
mechanism to get the whole story out, all the tests out?
    Ms. Woodcock. I think, as I said, the entire biomedical 
research community believes that information is needed, 
especially around effectiveness and safety trials so that 
physicians and patients can reach conclusions. I don't think 
there is a lot of disagreement about that.
    Mr. Waxman. Well, we don't have the ability to do it yet, 
and so we have go to work together to establish that mechanism.
    Mr. Walden. Thank you. The Chair now recognizes the 
gentleman from New Hampshire.
    Mr. Bass. Thank you, Mr. Chairman. If I could continue the 
line of questioning of my friend from California. Could you 
repeat again for me, Dr. Woodcock, why isn't it a good idea for 
the FDA to compel or to have in place full disclosure of the 
entire clinical trials for these drugs before doctors have to 
make decisions with respect to whether they are going to 
prescribe them for children?
    Ms. Woodcock. Under the Best Pharmaceuticals for Children 
Act, there is disclosure of this information.
    Mr. Bass. But it is just a summary, right? How about the 
whole thing?
    Ms. Woodcock. That isn't how the statute was set up.
    Mr. Bass. But can't you ask the drug companies to do it?
    Ms. Woodcock. My understanding is that under some of the 
announcements that have been made, a more expansive disclosure 
is going to be made voluntarily by some of the firms.
    Mr. Bass. But can't you ask them to do it? They don't have 
to volunteer; you can ask them to do it, can you not?
    Ms. Woodcock. Certainly.
    Mr. Bass. Under law. Have you done that?
    Ms. Woodcock. Oh, under law, no.
    Mr. Bass. You haven't done it.
    Ms. Woodcock. We can't compel----
    Mr. Bass. Can you ask their permission to disclose the full 
clinical trial?
    Ms. Woodcock. We ask their permission to disclose the 
summary information that would be the same as under BPCA.
    Mr. Bass. But those are the results. What about the full 
trial?
    Ms. Woodcock. No, we haven't disclosed that.
    Mr. Bass. You haven't asked their permission to disclose 
it.
    Ms. Woodcock. Right. That would be usually the obligation 
of the sponsor of the trial themselves.
    Mr. Bass. Why is it the obligation of the sponsor of the 
trial and not--why can't you ask them?
    Ms. Woodcock. We can ask them but we can't disclose their 
data.
    Mr. Bass. No, but why haven't you asked them to disclose 
all that data? You don't think it matters?
    Ms. Woodcock. I have personally talked to the members of 
the pharmaceutical industry and they are planning, as you know, 
to set up disclosure results of all clinical trials, but----
    Mr. Bass. Just the results but not the clinical trials 
themselves. Just the seven-page results?
    Ms. Woodcock. Yes. This would be extensive----
    Mr. Bass. Do you think that the whole trial ought to be 
disclosed?
    Ms. Woodcock. It is often very useful to see the protocol 
for somebody who is experienced in analysis of clinical trials 
to make sure that the analytic piece was done the same way it 
was prospectively laid out in the protocol; in other words, to 
make sure that there wasn't a post hoc modification of 
interpretation of the results. So I think a lot of experts in 
this area feel that looking at the clinical protocol is also 
are very important piece. However, you must recognize that what 
is submitted to the FDA in a new drug application is often 
1,000 volumes long of raw data and there are very few 
individuals who are capable of going through all that at that 
level. So if you are talking about patients and physicians, we 
are talking about summary data.
    Mr. Bass. Dr. Woodcock, in the third paragraph of your 
written testimony you state that public availability of the 
results, ``is especially important for studies of marketed 
products, surgical inventions and other medical treatments 
where a bias toward publication or positive results may distort 
the community's overall understanding of an intervention's 
effectiveness or risk profile.'' In other words, are you saying 
that there may be a bias problem because medical journals tend 
to publish the positive results, the drug works, but rarely the 
negative results that the drug doesn't work, and therefore the 
public may get a distorted understanding on the effectiveness 
of a medical product because the positive results are out there 
but very little of the negative?
    Ms. Woodcock. You are absolutely right, and this has been 
well recognized in the medical community as a problem. It is 
not only pharmaceutical research, it is all sorts of research, 
and it is also that the journals are biased toward publishing 
good news.
    Mr. Bass. So you get all the information for the positive 
trials and all you get is the summaries for the negative 
trials. Is that right or not?
    Ms. Woodcock. No. What FDA publishes as summary data is an 
analysis of the trial. So you get FDA--who has reviewed all of 
the data--you get FDA's review opinion on what those trials 
showed in the summaries that FDA publishes. A report in a 
clinical journal may be subject to bias, all right, and that is 
what Mr. Waxman was alluding to earlier. And it is also a 
summary of the information. It doesn't include all----
    Mr. Bass. All right. In your opinion, how do we get 
comparable disclosure then of negative and positive 
information? We are the policymakers here. We are trying to 
correct a problem----
    Ms. Woodcock. Yes.
    Mr. Bass. [continuing] and we are asking you to help us 
with this. Now, what would you do?
    Ms. Woodcock. Well, I think you have already make great 
progress because there is a tremendous ground swell now of 
availability of information based on what the committee has 
accomplished already. But it is clear that the results of 
trials should be made available to the public in some form.
    Mr. Bass. Just the results, though. We are back where we 
were before, but not the actual clinical trial.
    Ms. Woodcock. Well, you have to decide what you are talking 
about. As I said, the raw data from a clinical trial, if you 
print it out, can run to hundreds or thousands of volumes.
    Mr. Bass. Okay. Assuming that you agree with me that there 
may be on occasion a bias in publications information, what is 
the FDA's role in combating this bias?
    Ms. Woodcock. The FDA's role has traditionally been the 
gatekeeper for approval, and so we get all the data and we are 
able to look at all the data. Although we cannot disclose this 
information, we look at it, and so we see all the negative 
trials and we see the positive trials. We don't approve drugs 
unless we think they are shown to be effective, that meets our 
effectiveness standards and that their benefit outweighs the 
risk because there is always going to be risk from drugs. That 
is the role we play.
    Mr. Bass. Dr. Woodcock, do you believe such a problem 
existed in the area of antidepressant use in children? Is that 
the reason the FDA sought to publish the summaries of clinical 
trials even for studies not covered under the requirement that 
FDA publish the summaries of the results?
    Ms. Woodcock. Clearly, yes. This is, as other members have 
said, is vital information in determining benefit and risk 
analysis.
    Mr. Bass. So it is more than just evaluating the 
information in this case. You had reason to believe that you 
needed to get more information out.
    Ms. Woodcock. As you know, these drugs are widely used in 
the pediatric population.
    Mr. Bass. I am going to talk for a minute about the 
Columbia study. FDA asked Columbia University to conduct a 
blinded interview of reported behaviors associated with the 
pediatric use of antidepressants using a rigorous 
classification system. Was Columbia University given a sole 
source contract, and if so, why?
    Ms. Woodcock. I read over that material. I believe they 
were, and, if so, it would be--I can't tell why that would be. 
Probably because they had experts in suicidality, specific 
expertise.
    Mr. Bass. Has the FDA ever before used a sole source 
contract for an outside use of drug data?
    Ms. Woodcock. I believe so.
    Mr. Bass. Can you give us some citations for that?
    Ms. Woodcock. I could get back to you with that. That is 
kind of specific information going back many years. I know we 
have previously contracted for reviews by outside parties. We 
have done that.
    Mr. Bass. Sole source?
    Ms. Woodcock. I don't know how we did it.
    Mr. Bass. Okay. Well, if you could answer that question, 
that would be helpful.
    Ms. Woodcock. I certainly will.
    Mr. Bass. Was this contract reviewed by any government 
oversight board to assure that this contract was a good deal 
for the government? You wouldn't know because--I guess the 
answer is you wouldn't know, right?
    Ms. Woodcock. Well, I know that it went through standard 
procedures if it was an FDA contract.
    Mr. Bass. What are the procedures?
    Ms. Woodcock. There is a separate contracts office that 
makes sure the applicable regulations----
    Mr. Bass. Do they check for conflicts of interest?
    Ms. Woodcock. I can get back to you on exactly what was 
done.
    Mr. Bass. Does the FDA concede that some members of the 
Columbia University have financial relationships with some of 
the drug companies that manufacture antidepressants?
    Ms. Woodcock. I can't specifically answer that. We can 
certainly look at that.
    Mr. Bass. Okay. If there were, it would be a pretty serious 
issue, wouldn't it?
    Ms. Woodcock. I think it depends on the magnitude of that 
relationship. Most experts in the field, in every field, be it 
HIV, cancer, depression, suicidality, have been consulted by 
members of the pharmaceutical industry or other medical product 
industries.
    Mr. Bass. Is there, in your opinion, any process for 
evaluating whether or not a conflict of interest is serious or 
not?
    Ms. Woodcock. We have an extensive process for our Advisory 
Committee members. They must undergo this vetting at every 
Advisory Committee meeting on the specific topics that are 
being aired at that meeting, and we also have disclosure 
procedures.
    Mr. Walden. I want to thank the gentleman from New 
Hampshire, his time has expired, and the Chair would recognize 
the gentlewoman from Colorado.
    Ms. DeGette. Thank you, Mr. Chairman. Dr. Woodcock, as I 
understand it, there is one drug that is specifically approved 
by the FDA for use in pediatric depression and that is Prozac, 
correct?
    Ms. Woodcock. That is correct.
    Ms. DeGette. And I understand that there are some--I am a 
little confused about the number but somewhere up to 10 million 
people who are being prescribed some kind of antidepressant 
off-label. Do you have any idea how many of the 10 million are 
being prescribed off-label?
    Ms. Woodcock. No.
    Ms. DeGette. It is a substantial number, would you agree 
with that?
    Ms. Woodcock. I would agree that much of the pediatric use 
of antidepressants is currently off-label.
    Ms. DeGette. Right. That is millions of people, right?
    Ms. Woodcock. Yes.
    Ms. DeGette. Does that concern the FDA that there is all 
this off-label use?
    Ms. Woodcock. It has always concerned the FDA, and that is 
why FDA passed the pediatric regulation back in the nineties 
that led to the provision in the Modernization Act, which led 
to the Best Pharmaceuticals Act.
    Ms. DeGette. I was just going to say that is one of the 
reasons why Congress passed the Best Pharmaceuticals for 
Children Act, right?
    Ms. Woodcock. Yes.
    Ms. DeGette. But that was 2 years ago, and it seems like 
the practices we are all concerned about have not changed, at 
least with respect to prescriptions for depressions for 
pediatric patients, right?
    Ms. Woodcock. What happened is those trials were done under 
either the pediatric regulations or the FDAMA that didn't have 
disclosure requirements. That has been remedied to some extent 
under the Best Pharmaceuticals for Children Act.
    Ms. DeGette. Well, is there a provision of BPCA that says 
that you can't disclose the results of trials that were done 
before the bill was passed?
    Ms. Woodcock. We were following the law to----
    Ms. DeGette. Well, what law was it that said that?
    Ms. Woodcock. The Best Pharmaceuticals for Children Act had 
provisions for disclosure for studies, written requests done 
under the Best Pharmaceuticals for Children Act.
    Ms. DeGette. So your interpretation is then that you had no 
authority to even request disclosure of studies done before 
that?
    Ms. Woodcock. I am not an FDA lawyer; however, we evaluated 
this issue and we attempted to follow the provisions of the 
law.
    Ms. DeGette. Well, so what is that answer?
    Ms. Woodcock. We think that is what the law said.
    Ms. DeGette. So you think the law says you cannot require 
the results of these clinical trials that occurred before 2002?
    Ms. Woodcock. That is right.
    Ms. DeGette. Did you ever talk to the pharmaceutical 
companies about whether they would voluntarily disclose this?
    Ms. Woodcock. Recently, we certainly did when they 
disclosed----
    Ms. DeGette. After we started these investigations----
    Ms. Woodcock. Correct.
    Ms. DeGette. [continuing] of this committee. Did it occur 
to anybody to do that before?
    Ms. Woodcock. I do not know.
    Ms. DeGette. Because most of these drugs have been approved 
for a long time for adult usage, right?
    Ms. Woodcock. Correct.
    Ms. DeGette. So the clinical trials wouldn't have happened 
before 2002 because they are not new drugs, right?
    Ms. Woodcock. The clinical trials were maybe started under 
the pediatric rule that FDA passed or under the Food and Drug 
Modernization Act.
    Ms. DeGette. Well, I understand that, but given the fact 
that there is so much off-label prescribing going on, there is 
absolutely no incentive for the pharmaceutical companies to now 
start conducting new studies, right? I mean there is absolutely 
no reason why someone would do a clinical trial right now on an 
established drug that is being prescribed with abandon off-
label.
    Ms. Woodcock. Well, there are the exclusivity provisions.
    Ms. DeGette. Good point. Now, I would like to know why the 
FDA waited 6 months to send the letter to the drug sponsors, 
the written requests that were sent in July 2002? Why did it 
take so long to send that letter out after the BPCA was passed?
    Ms. Woodcock. There were many technical issues on 
implementation of the BPCA that the FDA addressed, and we got 
that out as soon as we could.
    Ms. DeGette. Now, I wonder if you can tell me how the FDA 
considered the studies for Paxil, Celexa and Serzone to have 
been submitted under FDAMA and did not consider their written 
requests to be reissued and did not apply the public disclosure 
provisions of the Best Pharmaceuticals for Children Act to 
those studies, but the only reason the FDA made such a 
determination is because of the 6 months that the agency let 
pass before issuing their letter to the drug sponsors; is that 
right?
    Ms. Woodcock. That is the legal interpretation that was 
made, correct.
    Ms. DeGette. Okay. Now, you said that after having examined 
the initial reports of suicidality, the FDA found it unclear 
whether some of the identified suicidal behaviors reported in 
those studies represented actual suicide attempts or self-
injurious behavior that was not suicide behavior, right?
    Ms. Woodcock. Yes.
    Ms. DeGette. Now, was not Dr. Andrew Mosholder the person 
chosen by both the Office of Drug Safety and Neuropharm to do 
the FDA analysis?
    Ms. Woodcock. Correct.
    Ms. DeGette. Now, was it unclear to Dr. Mosholder what a 
suicide attempt or self-injurious behavior was, do you know?
    Ms. Woodcock. Well, I think you need talk to Dr. Mosholder 
about that specifically.
    Ms. DeGette. Okay. Now, was it unclear, do you know--did 
you look at the conclusion of the British reviewers who came to 
the conclusion that antidepressants should not be prescribed to 
pediatric patients?
    Ms. Woodcock. Yes.
    Ms. DeGette. And what was the view of the agency on that?
    Ms. Woodcock. The agency's view is that the jury is still 
out on these drugs. Depression, as you know, is--suicide is a 
very serious problem for adolescents in the United States. It 
is third leading cause of death and only ranked above by 
accidents and homicides in this country. Much of the underlying 
cause of suicide in adolescents is depression, and, as you 
said, there is only one current drug approved for the treatment 
of depression in this age group in this country.
    Ms. DeGette. Right. But this is why--I completely agree 
with you, so I would think that rather than waiting till the 
attorney general of New York undertook an investigation and 
Congress undertook an investigation to act on this, there are 
millions of parents out there, as I said in my opening 
statement, these parents are frantic. Their children are 
depressed, and they are under the illusion that these drugs 
will work.
    Ms. Woodcock. Right.
    Ms. DeGette. And not only do the drugs have no known 
efficacy under the clinical trials that have been undertaken, 
but what is worse there is some evidence that they may increase 
suicidal tendencies, right?
    Ms. Woodcock. Correct.
    Ms. DeGette. I mean this may be the biggest problem we have 
right now with respect to adolescent health vis-a-vis 
pharmaceuticals, right?
    Ms. Woodcock. Possibly.
    Ms. DeGette. What do you think we can do to clarify what 
you believe to be the deficiencies in the law that would allow 
you to require full disclosure of all of these trials?
    Ms. Woodcock. We would be glad, as I said, to work with the 
Congress on this issue.
    Ms. DeGette. Do you have any specific ideas?
    Ms. Woodcock. Well, I think we need to balance a number of 
things, and I do believe it is a complex issue, but I think we 
would be very willing to work with you on it.
    Ms. DeGette. So you don't have any--do you have any 
specific--I mean would you like to supplement your testimony 
with any specific ideas?
    Ms. Woodcock. We would be happy to work with you on our 
thoughts.
    Ms. DeGette. Well, we may have some thoughts of our own 
based on these hearings. I just have one more question. I am 
sure you are aware of the settlement between the New York 
Attorney General Spitzer and GlaxoSmithKline as it relates to 
Paxil, correct?
    Ms. Woodcock. Yes.
    Ms. DeGette. And that was August 30, right, of this year. 
Now, as a part of that settlement, GlaxoSmithKline agreed to 
put all of the clinical trial results online, right?
    Ms. Woodcock. That is my understanding.
    Ms. DeGette. And in fact they did it. Now, have you looked 
at both the summary and the--have you looked at the posting 
online?
    Ms. Woodcock. I have not, personally.
    Ms. DeGette. Okay. Well, I mean the good news, from my 
perspective, and I might disagree with some of my colleagues, I 
actually thought the summary was pretty clear. For example, it 
says, ``GlaxoSmithKline has conducted several trials in 
pediatric patients,'' and then it says, ``In the GS case 
studies for treatment of major depressive disorder in pediatric 
patients, treatment with Paxil was not statistically superior 
to placebo with respect to efficacy.'' That is pretty clear, 
right?
    Ms. Woodcock. Yes.
    Ms. DeGette. Certainly, it would be clear to a physician.
    Ms. Woodcock. Right.
    Ms. DeGette. Why is it that the FDA can't either require or 
work with voluntarily the pharmaceutical companies to make sure 
things like this are posted online?
    Ms. Woodcock. Well, as I said, we have talked to the 
pharmaceutical companies. They have announced a plan that, had 
it been in effect at this time, these studies would have been 
posted according to their plan and made available.
    Ms. DeGette. But what? I don't understand, they would have.
    Ms. Woodcock. Had the proposal that the pharmaceutical 
industry has now made for revealing trial results such studies 
as these pediatric depression trials would be made public.
    Ms. DeGette. And would that all be made public?
    Ms. Woodcock. Pardon me?
    Ms. DeGette. Under the proposal by PhRMA, would all of 
those be made public? I know they will be testifying in a 
minute.
    Ms. Woodcock. Yes, because those are drugs that are 
marketed drugs, and the trials were testing outcomes.
    Ms. DeGette. And do you think that is sufficient to ensure 
that Congress and most importantly the parents and physicians 
of this country know the results of these trials? Is this a 
voluntary program?
    Ms. Woodcock. If it is followed through on, those trials 
would be available.
    Ms. DeGette. Okay. Thank you.
    Mr. Walden. Before I go to Mr. Ferguson who has stepped out 
of the room for a moment, I am going to go Mr. Stupak. Before I 
do that, I just have to reiterate what the full committee said 
about cooperation from the FDA and again say I appreciate your 
statements about your willingness to cooperate, but it is 
pretty hard to swallow when we have these emails from Mr. 
McGarey basically outlining to other employees in your agency 
how not to cooperate with this committee and so things are 
going to change. Mr. Stupak.
    Mr. Stupak. Thank you. Dr. Woodcock, did the FDA receive 
notice from the manufacturers that the British had said they 
should not be using these antidepressants in adolescents?
    Ms. Woodcock. I believe so, yes. Our reviewers had 
originally detected the signal in our own review of the 
clinical trials and had requested additional information, and 
that was then submitted to the British authorities, and that 
led to their decision.
    Mr. Stupak. You submitted your information to the British 
authorities, but you didn't submit it to the American people?
    Ms. Woodcock. It was submitted then to FDA as well.
    Mr. Stupak. Okay. But my question was did the 
manufacturers, as required under the Food and Drug and Cosmetic 
Act, notify you of the action of the British government in 
pulling these drugs for adolescent use in December of last 
year?
    Ms. Woodcock. I can't answer specifically for each 
manufacturer. We can get back to you on that question.
    Mr. Stupak. Okay.
    We have talked a lot about summaries and publishing 
summaries, not the trials, the clinical trials. Who prepares 
the summaries?
    Ms. Woodcock. The FDA medical officers and clinical 
pharmacologists.
    Mr. Stupak. Okay. So it is something internal then.
    Ms. Woodcock. That is correct.
    Mr. Stupak. Where does the information gleaned from?
    Ms. Woodcock. As you know quite well, we receive reports. 
We are required by law to receive reports of all clinical 
investigations and all literature at the time a submission is 
made to FDA for an application, and so we receive that all from 
the company. We have extensive audit system where we try to 
verify the validity of all the information that is submitted to 
the FDA.
    Mr. Stupak. If you go through this audit and try to verify 
the validity of this information, studies and trials submitted 
by a manufacturer, then in hindsight now wouldn't it be best to 
grant a pediatric exclusivity extension after you had a chance 
to do that, after there are--shouldn't a pediatric exclusivity 
patent extension only be granted if the drug is proven to be 
safe, effective and all necessary changes are made on the 
packaging label? Isn't that what it should be?
    Ms. Woodcock. Well, I am not one to presume to tell 
Congress where it should be. There are obviously considerations 
on either side.
    Mr. Stupak. I am not asking you to tell Congress; I am 
asking for your opinion.
    Ms. Woodcock. My opinion is that it is desirable to have 
information available to the physicians and the public about 
the results of clinical trials so they can make considered 
treatment decisions.
    Mr. Stupak. And before you grant the patent extension like 
we did here and we find these drugs are not effective and in 
some cases not safe, what the heck are we doing granting 
extensions to a drug?
    Ms. Woodcock. That is how these statutory provisions are 
set up.
    Mr. Stupak. But in hindsight, is that not incorrect? 
Shouldn't we really change that statute? Isn't that one of the 
examples you could give to Ms. DeGette of some of the things we 
should do here in Congress when she asked you?
    Ms. Woodcock. Again, we would be happy to work with you on 
this.
    Mr. Stupak. All right. Well, you said that this information 
should be available for physicians and families and patients. 
We talked about labeling here today. The labeling we are 
discussing really goes just to the physicians, does it not?
    Ms. Woodcock. Yes.
    Mr. Stupak. So all this labeling we have heard for the last 
couple of hours really never gets to the American people, to 
the patients and to the families unless it is on package 
labeling, and package labeling is much different than just what 
you call labeling; isn't that correct?
    Ms. Woodcock. Yes, and in fact for many drugs, as you know, 
if you go to the drug store, you get a bottle prepared by the 
local pharmacy.
    Mr. Stupak. Sure.
    Ms. Woodcock. And it has information sheet that the local 
pharmacy gives you, information for a patient.
    Mr. Stupak. That is really a summary. What the labeling 
that we have been talking about here for the last few hours 
really deals with between manufactured notice, as required by 
the FDA, to the physicians, not to the American people.
    Ms. Woodcock. That is correct.
    Mr. Stupak. And the only place the American people are 
really going to find it is on the package because when you go 
there you may get a little slip that has the price of your drug 
and gives a quick overview of things on it. You don't get the 
whole label that the physician has; isn't that correct?
    Ms. Woodcock. Well, patients may get the label. We 
certainly get the label at my pharmacy. It is folded up inside 
the pill bottle. It depends on how the drug is dispensed. But 
your point is, I think, that that label is written for a 
professional audience; it is not really accessible to patients 
and consumers.
    Mr. Stupak. And you would agree with me when the American 
people take their pills they don't go and unwrap these little 
things and read it all the way through. They look at the box, 
they look at the bottle and they say, ``Okay. I take this three 
times a day. I have to take it with food, I don't have to take 
it with food.'' That is the labeling the American public relies 
upon, is it not?
    Ms. Woodcock. Yes.
    Mr. Stupak. Okay. On these antidepressant behaviors, you 
have got the British who reached a conclusion that said it was 
not good for young people, you have the Columbia report which 
shows it is 1.8 times greater chance of suicidal behavior with 
these antidepressants, and you have Dr. Mosholder that reached 
the conclusion that these should not be used for young people 
because there may be--they are not effective and they are not 
safe. So you said in your testimony to the other members here 
that the SRI these studies are inconclusive. How can the 
British be conclusive, how can Columbia University be 
conclusive, how can Dr. Mosholder be conclusive but yet the FDA 
isn't conclusive? So what does it take to get the FDA to be 
conclusive on this issue?
    Ms. Woodcock. As I said, the jury is still out on the 
effectiveness of these drugs. Some of the studies were not 
conclusive. It is very common for effective drugs when they are 
tested in adult depression to show no effect.
    Mr. Stupak. We are not talking about adult depression; we 
are talking about young people here.
    Ms. Woodcock. I understand.
    Mr. Stupak. We are talking about adolescents.
    Ms. Woodcock. I agree.
    Mr. Stupak. Who is the jury? Who is the member of this jury 
that makes this decision on whether or not this is conclusive 
and these drugs should be--actions should be taken, either 
pulled or removed or further warnings? Who is this jury?
    Ms. Woodcock. The members of the Center for Drugs who are 
the regulators of this class of drugs are evaluating that 
issue.
    Mr. Stupak. And when will that jury reach its 
deliberations?
    Ms. Woodcock. The FDA is seeking advice from its Advisory 
Committee, as I said, next week on the question of the 
interpretation of the adverse events, the psychiatric adverse 
events and the trials. And questions are posted on the Internet 
as far as what we are going to be asking the committee about.
    Mr. Stupak. Well, is the Advisory Committee because of the 
pressure put forth from the Members of Congress and the press? 
Is that why you are having an Advisory Committee?
    Ms. Woodcock. No. We are trying to wrestle with this 
scientific question about the potential benefits and the 
potential risks of this type of intervention.
    Mr. Stupak. Let me go to the Best Pharmaceuticals Act, 
okay? Section 17. Since I couldn't get the pediatric 
exclusivity amendment I wanted, I did a couple other amendments 
to this bill. No. 1, it says that all adverse events should be 
reported, and to help people understand how to report it, we 
have to put in a 1-800 number so people could report adverse 
events. And it says that is where pediatric drugs or use in 
pediatric population, regardless of the date of approved, it 
would include a toll free number maintained by the Secretary. 
And this was supposed to be done here within, I believe, 1 year 
of enactment of this law. Has that been done?
    Ms. Woodcock. I am sorry, I don't know the answer to that 
question.
    Mr. Stupak. The answer is no. It was December 2001. It is 
now 2004; still not done. Not only that, we gave you something 
else. Drugs dealing with pediatric market exclusivity. During 1 
year, beginning the date on which the drug receives a period of 
market exclusivity, you have a right to put together a 
Pediatric Advisory Subcommittee to review the adverse effects 
and to look at these drugs for their safety. Has that Pediatric 
Advisory Subcommittee for any of these antidepressant drugs we 
have been talking about here today been convened?
    Ms. Woodcock. Yes. In June 2003, Sertraline adverse events 
were reported to the Pediatric Advisory Subcommittee as part of 
this mandate under Best Pharmaceuticals.
    Mr. Stupak. For what drug was that for?
    Ms. Woodcock. Sertraline.
    Mr. Stupak. What is Sertraline?
    Ms. Woodcock. It is one of the antidepressants.
    Mr. Stupak. Not Paxil? Not Effexor? Not Prozac? Not any of 
these, just one of them?
    Ms. Woodcock. Correct.
    Mr. Stupak. What about the rest of them? How come the 
Advisory Committee was not put forth for them?
    Ms. Woodcock. We will be having, I believe, Advisory 
Committee meetings on these additional products.
    Mr. Stupak. Well, geez, it says here you have to do it 
within 1 year, so you missed that date too.
    Ms. Woodcock. Well, we did--the Sertraline one was 
completed.
    Mr. Stupak. We missed it on the other ones. The point being 
you are telling Mr. Waxman that you do not have any mechanisms. 
The mechanisms are built there if they were utilize and if they 
were used by the FDA. You responded to Mr. Bass that we have 
made progress with this hearing and all that, but the progress, 
if you will say because we had this hearing, is not because of 
anything the FDA did, it is because of pressure from the media 
and pressure from Congress to do something on this issue. So I 
go back to my question, where is the FDA in all this? You said 
you saw these signals, you informed the British and that had to 
be in 2002, 2003. And the jury is still out. How many years is 
this jury going to be out? When are we going to have some 
decisions?
    Ms. Woodcock. We saw the signals and informed the company 
and requested additional analyses. We have been trying to look 
at these data ever since and make some sense out of the data. 
The information has been made public on the adverse events in 
suicidality. What wasn't made public was the information on 
effectiveness of the products.
    Mr. Stupak. Okay. So if the information was made public on 
suicidality and it shows that these antidepressants increase 
the likelihood of suicide behavior, then why are these drugs 
being still used and prescribed for young people?
    Ms. Woodcock. Because when faced with a depressed young 
person who has perhaps a life-threatening illness, there are 
not that many choices available to clinicians.
    Mr. Walden. The gentleman's time has expired. I appreciate 
the gentleman's line of questioning. The Chair now recognizes 
the gentleman from New Jersey, Mr. Ferguson.
    Mr. Ferguson. Thank you, Mr. Chairman. I appreciate the 
opportunity, and I appreciate Dr. Woodcock answering many, many 
questions. I have just a few more.
    Would you turn to tab 69, please? I want to refer to this 
Powerpoint presentation which was given at the Advisory 
Committee meeting on February 2. It is about the use of 
antidepressants in the pediatric population. Just so we are 
perfectly clear, I think this has been referred to earlier, but 
Prozac is the only antidepressant that is approved for 
pediatric depression; is that correct?
    Ms. Woodcock. That is correct.
    Mr. Ferguson. The only drug that the FDA has approved for 
pediatric depression. On page 13, there is a chart showing that 
the highest prescribed antidepressants for kids from 1 to 17 
years old.
    Ms. Woodcock. Yes.
    Mr. Ferguson. And it goes through and names several of the 
drugs. Is FDA concerned at all about your own analysis? These 
are your numbers. These are numbers that were given to us, 
compiled by someone else but provided to us by FDA. Are you at 
all concerned about your analysis that shows that kids are 
being prescribed these drugs, Zoloft and Paxil and Celexa, all 
antidepressants that unapproved for kids because they haven't--
I mean why haven't these drugs been approved by the FDA for use 
in children?
    Ms. Woodcock. Because they haven't met the FDA standards 
for effectiveness.
    Mr. Ferguson. Okay. So FDA says these drugs are not 
approved for use with children because they haven't been shown 
to be effective, yes FDA knows by the data that have been 
submitted to us that they are being prescribed a lot for 
children. Is there any concern at FDA about the increasing 
prescriptions for these drugs that are not approved for kids to 
children?
    Ms. Woodcock. Of course, and this has been the whole 
impetus for the Best Pharmaceuticals Act and everything that 
went before it. In fact, until very recently most of the 
prescribing of any drugs for children was off-label and the 
drugs had not been studied in that age group. So this is 
something that the clinical community is very used to doing 
because studies were simply not done in kids. This is a 
problem. We still don't know. As I said, the jury is still out 
on these drugs whether or not they work for depression in 
children, and of course this is a great concern.
    Mr. Ferguson. What about labeling? What about letting 
people know, perhaps pointing out to doctors and the kids' 
parents and families? Wouldn't FDA want some stronger labeling? 
Wouldn't drawing attention to the fact that even though this 
drug may be being prescribed for your child, it has not been 
approved by the FDA for use with children or adolescents 
because they have not shown to be effective? What about no 
efficacy labeling, some stronger labeling? Has that been 
considered, and, if not, why not?
    Ms. Woodcock. Well, we certainly in our warning that we put 
out in March had some language about the side effects and the 
need for caution and everything, but because the jury is still 
out on this class of drugs, I think disclosure of the 
information is very important, but I think the way the message 
is given is also very important, if that answers your question.
    Mr. Ferguson. Important, why? I agree with you. Why do you 
think it is important?
    Ms. Woodcock. I think it is important because pediatric 
depression is a life-threatening illness. I believe that 
clinicians and patients deserve to have information, reliable 
information on which to base prescribing decisions. I believe 
this is what we have got now, this is what we know. We have 
several positive trials for Prozac, we know these drugs are 
effective in adults, we know they have not been effective in 
some of the trials, a number of the trials that have been done. 
That is the state of the science, and we know the information 
about the suicidality and other psychiatric side effects from 
these analyses that have been done. This will all be discussed 
next week at our Advisory Committee meeting.
    Mr. Ferguson. Yes. Well, I agree with you on the need and 
the importance of making this information available. It seems 
to me that enough of this information hasn't been made 
available enough or clear enough or translated into something 
that kind of regular people, non-clinicians, non-doctors, non-
scientists can understand, particularly parents who are 
concerned about perhaps their child's affliction or illness and 
need the information to know that the drug they are giving 
their child hasn't been shown to be effective in children. It 
just seems to me if the FDA acknowledges and knows that there 
is skyrocketing off-label prescriptions being done with drugs 
on kids and some cases that have been shown not only to be not 
effective but in some cases were known to--or at least 
anecdotally are known to be dangerous, it seems to me there is 
a huge responsibility that the FDA needs to make that 
information more available to parents and families. Let me move 
to another question.
    Let me talk about who is prescribing these drugs, and I 
want to ask you to turn to page 15 in the tab. My question is 
if FDA sees a problem with pediatricians and family 
practitioners, folks who are not specialists, writing 
prescriptions for antidepressants in kids? So it is not just--
we are not talking about--in referring to my previous line of 
questioning, we are not just talking about specialists who are 
prescribing drugs off-label for kids when they haven't been 
shown to be effective in kids. We have family practitioners and 
pediatricians, and if you look at the numbers, we see a trend 
where pediatricians are prescribing more and more over the last 
few years of antidepressants for kids. Is there a concern at 
FDA that you have folks who are not experts in childhood 
depression, they are not experts in psychiatry or psychology, 
they are not specialists in this field, yet they are 
responsible for more and more of the off-label prescriptions 
for kids to receive anti-
depressants? Is that a concern at FDA?
    Ms. Woodcock. Yes, it is a concern, and it isn't a concern 
only in the area of pediatric antidepressants. Some of the 
problems that our health care system has around mental health 
care and other care are reflected in problems with drug 
utilization. And the current system of prescription medication 
in this country is predicated on the ``learned intermediary,'' 
that that prescriber has all the information needed to make 
that benefit/risk choice of therapies. And if that prescriber 
does not have all the information, then the system is not 
working effectively.
    Mr. Ferguson. Yes. Well, clearly, I agree with you that the 
learned intermediary is key to the kind of functioning of our 
system properly, but the learned intermediary, if they are not 
really learned, they are not a very effective intermediary.
    Ms. Woodcock. I agree.
    Mr. Ferguson. It just seems to me if you have got a quarter 
of the prescriptions for antidepressants to adolescents are 
being written by pediatricians and family practitioners, 
nothing against those good folks, I mean they are doing the 
very best they can to care for their patients, but they are not 
specialists.
    Ms. Woodcock. That is correct.
    Mr. Ferguson. They are not experts in this field, and, 
gosh, if they are--this is an alarming trend when you see the 
increases in the rates of folks who are not specialists, who 
are not experts in this particular field prescribing drugs that 
are not approved by the FDA for this particular use and then 
are being given to kids and are having incredibly adverse 
reactions and sometimes unpredictable reactions which are, as 
you stated, quite literally life-threatening. That is very, 
very alarming, I know, to many on the panel and I am sure to 
you as well.
    I would just, I guess, ask and urge that you and your 
colleagues at FDA continue to be imaginative and continue to 
redouble and retriple your efforts in terms of labeling, in 
terms of efficacy, making that is understandable to normal 
folks, folks who don't have a degree in this stuff and, 
frankly, depending on where we go after this hearing in terms 
of our discussions on the committee, there may be additional 
steps that we need to take and work that we need to do with you 
all and the companies and the health care professionals to make 
sure that folks are getting the information that they need, 
because, clearly, right now they are not. And part of that 
responsibility, as I said in my opening statement, there is 
plenty of responsibility to go around, but, clearly, some of 
that responsibility falls with FDA, and we would certainly 
appreciate your cooperation and your help and your partnership 
as we continue to address that. Thank you, Mr. Chairman.
    Mr. Walden. Thank you, Mr. Ferguson. We appreciate your 
participation in this hearing. Dr. Woodcock, as we wrap up this 
panel, please know, I think it has been obvious, we are very 
concerned about what has happened at the FDA or what has not 
happened. We are very concerned about the lack of candor and 
cooperation, as evidenced by certainly this May 3 email from 
Mr. McGarey to others. We expect on September 23, when this 
subcommittee reconvenes, that the FDA's witnesses will be fully 
prepared to answer our questions, and we intend then to be 
probably just as tough as we have been today.
    Ms. DeGette. Mr. Chairman, would you yield for one moment?
    Mr. Walden. Yes.
    Ms. DeGette. I would also supplement that request with the 
request that all of the information that the panel has asked 
for today in writing be submitted before that hearing so that 
we may be able to actually use the information at the hearing.
    Mr. Walden. Absolutely. And, in fact, as I think our 
standard procedure, the record will be open for additional 
questions of the agency, and we would appreciate those being 
responded to before September 23. I think you have heard, 
Doctor, the seriousness of what we are hearing from our 
constituents and our views on this committee, and we want to 
get to the bottom of this, we want to know answers to our 
questions. This is too big of a health care issue not to be 
addressed appropriately. And if the law is preventing you from 
acting, then we need to know that and you need to tell us where 
you are handcuffed and shouldn't be. If it is your own rules, 
then you need to fix them. And we are going to be one this one. 
So I appreciate your coming today, and you are now excused.
    Ms. Woodcock. Thank you.
    Mr. Walden. We will call up the second panel to testify. 
Dr. David Wheadon, senior vice president, Regulatory Affairs 
for GlaxoSmithKline; Dr. John R. Hayes, product team leader for 
Eli Lilly Company; Dr. Cathryn Clary, U.S. Medical for 
Psychiatry and Neurology for Pfizer, Incorporated; Dr. Joseph 
S. Camardo, senior vice president, Wyeth Pharmaceuticals; Dr. 
Lawrence Olanoff, executive vice president, Scientific Affairs, 
Forest Laboratories, Incorporated; Patrick Osinsky, esquire, 
general counsel, Organon USA; and Dr. Ronald N. Marcus, 
Neuroscience Global Clinical Development, Bristol-Myers Squibb 
Company.
    Ladies and gentlemen, we appreciate your attending our 
hearing and your willingness to testify before the Subcommittee 
on Oversight and Investigations. You might wait to take your 
seats. As you are aware, the committee is holding an 
investigative hearing, and when doing so has had the practice 
of taking testimony under oath. Do you have any objection to 
testifying under oath? Anyone have objection to that? Let the 
record show no one objects to that. 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? 
Does anyone--okay. Let us go first, Dr. Wheadon? No. Dr. 
Camardo?
    Mr. Camardo. Yes.
    Mr. Walden. And who is your counsel? Could you speak--
somebody turn on one of the microphones, if you would there, 
sir.
    Mr. Camardo. My counsel is Ms. Feliciano who is in the 
second row in the back here.
    Mr. Walden. All right. Thank you very much. Dr. Olanoff?
    Mr. Olanoff. Yes. And my counsel--I wish to be advised, and 
my counsel is Mr. Jim Johnson, James Johnson, behind me.
    Mr. Walden. Okay. Thank you, sir. Dr. Hayes, are you 
represented by counsel? Oh, I am sorry, we have our names 
flopped around here. It is the name tags we need to get 
straightened out there. All right. Dr. Marcus?
    Mr. Marcus. Yes, please.
    Mr. Walden. And you are represented by counsel today?
    Mr. Marcus. Yes, I am.
    Mr. Walden. And could you identify your counsel, sir?
    Mr. Marcus. Mary Alice Barrett.
    Mr. Walden. Thank you. Dr. Osinsky?
    Mr. Osinsky. No.
    Mr. Walden. Okay. Dr. Clary?
    Ms. Clary. Yes. And it is Justin McCarthy who is in the 
room.
    Mr. Walden. Okay. Thank you very much. In that case, if 
then you would please rise and raise your right hand and I will 
swear you in.
    [Witnesses sworn.]
    Mr. Walden. Okay. Let the record show the witnesses all 
answered in the affirmative. You are now under oath, and you 
may give a 5-minute summary of your written statement. And we 
will start with Dr. Wheadon.
    Try it now. Third time.

     TESTIMONY OF DAVID E. WHEADON, SENIOR VICE PRESIDENT, 
  REGULATORY AFFAIRS, GLAXOSMITHKLINE; JOHN R. HAYES, PRODUCT 
TEAM LEADER, ELI LILLY COMPANY; JOSEPH S. CAMARDO, SENIOR VICE 
    PRESIDENT, WYETH PHARMACEUTICALS; LAWRENCE S. OLANOFF, 
     EXECUTIVE VICE PRESIDENT, SCIENTIFIC AFFAIRS, FOREST 
  LABORATORIES, INCORPORATED; RONALD N. MARCUS, NEUROSCIENCE 
  GLOBAL CLINICAL DEVELOPMENT, BRISTOL-MYERS SQUIBB COMPANY; 
 PATRICK J. OSINSKY, GENERAL COUNSEL, ORGANON USA; AND CATHRYN 
   M. CLARY, U.S. MEDICAL, PSYCHIATRY AND NEUROLOGY, PFIZER, 
                          INCORPORATED

    Mr. Wheadon. Should be a charm.
    Mr. Walden. There you go.
    Mr. Wheadon. Mr. Chairman, ranking member and members of 
the committee, good afternoon. I am David Wheadon, senior vice 
president for U.S. Regulatory Affairs at GlaxoSmithKline. I am 
a psychiatrist by training and have held various positions in 
clinical development at both Eli Lilly Company and 
GlaxoSmithKline. At Lilly, I was involved in the development of 
Prozac and have worked extensively on Paxil during my tenure at 
GlaxoSmithKline.
    It is appropriate for GlaxoSmithKline to testify on the 
subject of this hearing; namely, publication and disclosure 
issues in antidepressant pediatric trials. A fact that has been 
obscured in all the recent publicity is that in 2003 it was 
GlaxoSmithKline that voluntarily brought the potential issue of 
suicidality in pediatric patients being treated with 
antidepressants to the attention of the FDA and to the 
attention of other regulatory agencies.
    Another important point that gets lost in the discussion is 
the fact that there were no suicides in our nine trials 
studying pediatric patients who suffer from depression, 
excessive-compulsive disorder or social anxiety disorder. 
Furthermore, we did not see a statistically significant signal 
of increased suicidality in any of these individual trials. It 
was only when we combined the performed analyses on all nine 
studies together, a procedure known as a metaanalysis, that we 
saw a possible signal primarily in adolescent patients with 
depression.
    After completing these analyses in 2003, we proactively 
sought the advice of external experts and regulatory agencies, 
including the FDA. The FDA issued a talk paper in June 2003 
which addressed this issue. More broadly, it has been the 
practice of GlaxoSmithKline to communicate to the medical 
community safety and efficacy data from our clinical trials 
through posters, abstracts presented at medical conferences, 
peer review journal articles and through medical information 
letters provided to physicians upon request. We have not 
stopped there, however. In the interest of full transparency 
and because we felt it was important to clarify the data 
related to GlaxoSmithKline's clinical trial results regarding 
Paxil and children and adolescents, on June 14 of this year, we 
took the unprecedented and extraordinary step of providing 
access via our web site to clinical trial reports and other 
information concerning Paxil studies in children and 
adolescents.
    GSK has since gone even further. We have created the 
GlaxoSmithKline clinical trial register which provides online 
access to summaries of trial protocols and corresponding 
results for GlaxoSmithKline-sponsored trials for all products 
marketed since the date of our merger in 2000.
    Just as the FDA and the public are struggling with this 
issue with pediatric suicidality, GlaxoSmithKline has struggled 
with understanding the data and its implications. The FDA has 
recently required a new warning for products in the newer 
antidepressant classes, including Paxil, that expands upon the 
disease-related risk of suicidality that has been an 
antidepressant labeling factor for many years. Both the new and 
old language reflect the phenomenon that during early treatment 
and recovery symptoms such as lack of energy and motivation may 
improve ahead of depressive and suicidal thinking with the 
result that still depressed patients may now have the energy 
and the motivation to act on their suicidal thoughts. This new 
language underscores the complexity of treating depression and 
the need for physicians and family members to observe patients 
for worsening depression or signs of suicidality, whether or 
not they are taking antidepressants.
    It is critical to recognize that studying, diagnosing and 
treating depression is extraordinarily complex. As a 
psychiatrist, one of my greatest fears is that all of the 
publicity about suicidality associated with antidepressant 
treatment will discourage families from seeking treatment of 
depression for their affected children. This would truly be an 
unacceptable and devastating outcome for these children. The 
end result of this and many other deliberations on this matter 
must be a greater appreciation of safely and effectively 
tackling this significant and potentially devastating disease 
in children. Thank you.
    [The prepared statement of David E. Wheadon follows:]

 Prepared Statement of David E. Wheadon, M.D., Senior Vice President, 
                U.S. Regulatory Affairs, GlaxoSmithKline

    Mister Chairman, Ranking Member and Members of the Committee, good 
morning.
    My name is Dr. David Wheadon, and I am Senior Vice President for 
U.S. Regulatory Affairs at GlaxoSmithKline. I appreciate the 
opportunity to appear before the Subcommittee today and look forward to 
answering your questions.
    As a bit of background, I am a psychiatrist by training, and have 
held various positions in Clinical Development at both Eli Lilly and 
Company and GlaxoSmithKline, primarily focusing on central nervous 
system products. While at Lilly, I was involved in the development of 
Prozac for the treatment of depression as well as other psychiatric 
disorders, and have worked extensively on Paxil during my tenure at 
GlaxoSmithKline. In my current position, I am responsible for 
GlaxoSmithKline's interactions with the FDA on all of our prescription 
drug and vaccine products.
    I appreciate this opportunity to describe to you GlaxoSmithKline's 
continuing efforts to share information to ensure that our 
antidepressant paroxetine hydrochloride, known under the brand name 
Paxil ', is used appropriately by all patients.

                          BACKGROUND ON PAXIL

    Paxil is a member of a class of antidepressants called selective 
serotonin reuptake inhibitors, or SSRIs. Paxil was launched in the U.S. 
market in 1993 for the treatment of depression in adults, also known as 
major depressive disorder. Since its launch, as is the case with all 
new drugs, we have continued to study Paxil's safety and efficacy and 
have sought, and received approval for, additional indications for its 
use. Currently, the FDA has approved Paxil and/or Paxil CR as safe and 
effective to treat depression, generalized anxiety disorder, social 
anxiety disorder, panic disorder, obsessive compulsive disorder, pre-
menstrual dysphoric disorder and posttraumatic stress disorder in adult 
patients. Paxil has never been licensed in North America or Europe for 
use in pediatric patients, and GlaxoSmithKline does not promote Paxil 
for use in this age group.
    GlaxoSmithKline is committed to the research and discovery of 
medicines to improve human health and fill unmet medical needs. The 
unmet need in child and adolescent depressive and anxiety disorders is 
substantial; the consequences of not adequately recognizing and 
treating such disorders include significant morbidity, disability and 
indeed death. Suicidal behavior, suicide attempts and completed suicide 
can all be extremely unfortunate complications of childhood and 
adolescent depression. We have studied Paxil in pediatric patients who 
suffer from depression, obsessive compulsive disorder and social 
anxiety disorder. We conducted eight major safety and efficacy trials, 
and one pharmacokinetics study. Seven of these studies were conducted 
under an Investigational New Drug application with the FDA, and the 
other two were conducted under similar applications in Canada or 
France.

                        COMPLEXITY OF DEPRESSION

    As a psychiatrist, I would like to take a moment to talk about some 
unique characteristics of depression and similar psychiatric disorders. 
Depression is a complex and devastating disease, and one of its 
cardinal symptoms is suicidality--defined as suicidal thinking, suicide 
attempts, or completed suicides. It is well recognized that suicide can 
be a tragic outcome of depression, and it is one of the leading causes 
of death among young people. According to researchers supported by the 
National Institute of Mental Health, among adolescents who develop 
major depressive disorder, as many as 7% may commit suicide in their 
young adult years. Tragically, suicide is the third leading cause of 
death among young people.
    Although most antidepressants are not approved for use in the 
pediatric population, physicians sometimes will prescribe these drugs 
to depressed children ``off-label.'' We are aware that prescriptions 
have been written for children for the various products represented by 
the companies here today, that may or may not be indicated for their 
use. It is important to recognize that the increased use of 
antidepressants among children 10-19 years of age has been accompanied 
by a decrease in the suicide rate in this age group. According to a 
study published in the Archives of General Psychiatry in October 2003, 
for each 1 percent increase in the use of SSRIs among adolescents, 
there was a decrease of 0.23 suicides per 100,000 adolescents per year. 
Although this is an epidemiologic association that does not necessarily 
prove cause-and-effect, it does suggest that we as a society are 
beginning to recognize and appropriately treat depression in children 
and adolescents.
    While physicians have found antidepressants to be useful in 
treating pediatric patients with depression, these drugs have 
historically been very challenging to study in clinical trials. Not 
only is demonstration of efficacy a challenge due to the particularly 
high placebo-response rates in pediatric depression, but evaluation of 
safety and tolerability is confounded by the fact that cardinal 
symptoms of the disease such as anxiety, sleep disturbance and 
suicidality may masquerade as side-effects of treatment. It is 
precisely for this reason that the symptom complex of suicidal 
thinking, suicide attempts, and completed suicides--which we refer to 
as suicidality--is particularly difficult to assess in antidepressant 
clinical trials. Not all acts of self-destructive behavior often seen 
in adolescents are associated with real suicidal intent. GSK's meta-
analysis of the pediatric clinical trial data described below utilized 
an algorithm approach, evaluating adverse event reports and classifying 
them as ``possibly suicide-related'' and/or as a ``suicide attempt''. 
This could be imprecise; for example, one classification of 
``suicidality'' in one of our trials consisted of a subject slapping 
her face.
    Paxil is an effective and generally well-tolerated drug for adults 
with depression and other psychiatric disorders. Given the unmet 
medical need in children and adolescents with depression, 
GlaxoSmithKline undertook to study Paxil in pediatric populations in 
the hope that it might help some of these young patients. Our three 
trials in pediatric depression as a group did not, however, provide 
sufficient evidence that Paxil is more effective than placebo, although 
we did see some signs of efficacy in our first pediatric depression 
trial. It is important to note that even for known effective, approved 
antidepressants, 4 out of 10 studies failed to demonstrate efficacy 
because of the high placebo response rates seen in these studies. Given 
those statistics, we were encouraged by the results of our first trial.
    One possible explanation for the outcome of our pediatric 
depression trials was the high placebo response rate, which made it 
difficult for the drug to show statistically significant efficacy. Our 
trials showed a high response rate to Paxil but also a high response 
rate to placebo--as is common in clinical trials for depression--so it 
was difficult to demonstrate a statistically significant difference 
between the two. Another impediment to measuring efficacy in the 
pediatric population is the need for more refined scales for measuring 
antidepressant efficacy in this population.
    Of note, in our studies of pediatric patients with obsessive-
compulsive disorder and social anxiety disorder, Paxil did demonstrate 
statistically significant evidence of efficacy.

                        COMMUNICATION OF RESULTS

    GlaxoSmithKline's policy is to ensure transparency of the clinical 
data the company collects on its marketed medicines. Specifically, we 
endorse the principles of our trade association, the Pharmaceutical 
Research and Manufacturers of America, also known as PhRMA, that call 
for timely publication of meaningful trial results. In fact, we helped 
to draft the PhRMA principles.
    Although we were not able to demonstrate efficacy in pediatric 
depression, data from clinical trials was shared with the healthcare 
community. Over the past six years or so, data from the pediatric 
depression studies has been communicated through peer-reviewed 
journals, poster presentations at scientific meetings, and medical 
letters to health care professionals--all of which are accepted 
standard practices for making data available to prescribers. A 
bibliography of publications and posters derived from these studies was 
posted to the GlaxoSmithKline corporate website on June 14, 2004.
    As for our safety data concerning suicidality in pediatric patients 
treated with Paxil, I should first point out a few issues that seem to 
get lost in the discussion surrounding the pediatric use of 
antidepressants. Firstly, not a single person committed suicide in any 
of our pediatric trials, which included over 1,000 patients treated 
with Paxil. Secondly, we did not see a statistically significant signal 
of increased suicidality in any of the trials individually. However, 
when, as part of our standard internal process of continuing ongoing 
safety reviews, we combined and performed analyses on all nine 
completed studies together--the meta-analysis--we did see a possible 
signal, primarily in adolescent patients with depression. On completion 
of those analyses in 2003, GlaxoSmithKline proactively sought the 
advice of external experts and regulatory agencies including the FDA. 
The FDA promptly issued a Talk Paper and brought this issue to the 
attention of the medical community and the public in June 2003. 
Thirdly, it is important to note that the possible signal of 
suicidality seen in the adverse event data was not confirmed by 
analysis of the data from the depression rating scales. In all of our 
depression studies, the depression rating scales used contained a 
``suicidality'' question, a physician rated score of suicidality. 
Analysis of this data showed no signal of suicidality associated with 
Paxil in pediatric patients.
    The FDA is in the midst of further considering this issue, 
recognizing that any such review must be done thoroughly and be guided 
by the best scientific and clinical research that exists. Thus, we 
welcome the FDA's approach of asking researchers at Columbia University 
to undertake an independent evaluation of the data on all 
antidepressants, including SSRIs. As I am sure you are all aware, the 
agency will convene a meeting of experts next week to review the 
outcome of this evaluation. Given the complexity of this matter, we 
believe the FDA's approach has been appropriate.
    Concurrent with this review and with our support, the FDA has 
required a new warning on all products in the newer antidepressant 
class, including Paxil. This new labeling expands upon--and gives more 
prominence to--language regarding the disease-related risk of 
suicidality that has been in antidepressant labeling for many years. 
Both the new and old language reflect the phenomenon that, during early 
treatment and recovery, symptoms such as lack of energy and motivation 
may improve ahead of depressive and suicidal thinking. The possible 
consequence of this is that these still-depressed patients may now have 
the energy and motivation to act on their suicidal thoughts. The new 
language underscores the need for physicians and family members to 
observe the patients for worsening depression or signs of suicidality--
whether or not they are taking antidepressants. We support this new 
warning, and we have included it in our labeling.
    Finally, as noted above, in the interest of full transparency, and 
because we feel it is important to clarify the data related to 
GlaxoSmithKline's clinical trial results regarding Paxil in children 
and adolescents, on June 14, 2004, we took the unprecedented and 
extraordinary step of providing access via our website to the clinical 
trial reports and other information about Paxil data in children and 
adolescents. We hope this information will be useful and informative to 
all those who access it.

                        CLINICAL TRIAL REGISTER

    It has been the practice of GlaxoSmithKline to communicate to the 
medical community safety and efficacy data from our clinical trials 
through posters and abstracts presented at medical conferences, through 
peer-reviewed journal articles, and through medical information letters 
provided to physicians upon request.
    GlaxoSmithKline has also recently taken the additional step in on-
line access to clinical trial information by beginning to put study 
summaries of our marketed pharmaceutical products on a single Internet 
site accessible to physicians and the public. The database, called the 
GlaxoSmithKline Clinical Trial Register, provides summaries of trial 
protocols and corresponding results for GlaxoSmithKline-sponsored 
trials of marketed medicines. In addition, the register provides 
citations to publications that have appeared in the medical literature. 
Just last week we began posting data for our antidiabetic Avandia--one 
of the company's most important products--and we will begin posting 
summaries for other products in the near future.
    This Clinical Trial Register had been under consideration and 
development for several months. Our company acts in the interests of 
physicians and patients, and we will take whatever measures are 
necessary to maintain their trust.
    Of course, we will also continue to communicate clinical data in 
journals, at scientific meetings, and in letters to healthcare 
professionals. It is also important to emphasize that while we are 
pleased that we will be able to provide this clinical data online, it 
is the prescribing information approved by regulatory agencies that 
must continue to guide the appropriate use of our medicines.

                               CONCLUSION

    We strongly believe that GSK acted appropriately in analyzing, 
interpreting and communicating data from Paxil trials in children and 
adults given the information available at any given time over the last 
11 years.
    Thank you for your time. I look forward to answering any questions 
you may have.

    Mr. Walden. Thank you, Dr. Wheadon.
    Dr. Hayes.

                   TESTIMONY OF JOHN R. HAYES

    Mr. Hayes. Thank you. I am John Hayes. I am a licensed 
physician and board certified psychiatrist. I work for Lilly 
and have since 1998. Before that I was a health system 
administrator, president of St. Vincent Hospital and Health 
Services and the CEO of Seton Health of Indiana, and I had a 
long career before that as an academic psychiatrist with 
appointments at Indiana University School of Medicine in 
Internal Medicine and Psychiatry, and I still hold those 
appointments.
    I am happy to be here because we think that this is a very 
important set of issues to discuss. That seems obvious. 
Depression is a very serious illness. It is a very serious 
burden for the individuals who have it and for our society. The 
lost opportunities for children and adolescents with depression 
are a tragedy, and the major lost opportunity, which would be 
the death of such a person, is, as Dr. Woodcock said, one of 
the top three reasons for the death of children and adolescents 
in our country.
    Lilly has been for a long time really committed to 
discovering and developing medications to help people with 
serious mental illnesses, certainly including depression and of 
course Prozac, which is arguably the world's most widely 
recognized antidepressants. It has been marketed since 1987 and 
is the drug which, as several people have noted this morning, 
is the first and the only antidepressant which actually has a 
labeled indication for the treatment of children who are 
depressed.
    That labeled indication is based on a body of data that 
includes five studies. One of those was a pharmacokinetics 
study, and of the other four, three of them had positive 
outcomes, and one of them was a failed study or did not show 
effectiveness. All five of those have been published, including 
the negative study.
    The other thing that is important to say is that this 
indication to treat children is in the context of a massive 
amount of data about Prozac, its efficacy and its safety. Fifty 
million people have taken Prozac to this date. There have been 
400 or so clinical trials and over 30,000 people have 
participated in some kind of research as subjects with Prozac. 
If you punch fluoxetine into a search engine on the net, you 
will get 15,000 or so articles, citations, and 7,500 of those 
are articles that have fluoxetine as the major object of the 
study. It is one of the most analyzed and scrutinized drugs in 
history.
    The issue of Prozac and suicidality is perhaps the most 
analyzed and scrutinized issue about Prozac and has been 
examined continuously and repeatedly for years. The recent FDA 
analysis and the reanalysis with the Columbia criteria, as 
people have discussed this morning, has again shown no signal 
for suicidality induced by Prozac in children and adolescents, 
and that collaborates our belief that there are no credible 
data that show such a signal in adults either.
    I noted that all the Prozac studies have been published, 
but, obviously, this hearing is not just about the content of 
those things but whether or not information is disclosed 
appropriately. Lilly has a long-standing history of such 
disclosure, has, I think, been very diligent in populating the 
current clinicaltrials.gov site with our serious or life-
threatening illness trials. Since its inception--and we have 
recently enhanced our policy to create, as we announced several 
weeks ago, a new web site of Lilly's for complete disclosure of 
all of our clinical trial results.
    On that web site, which we hope to bring online in the 
fourth quarter of this year at www.lillytrials.com, we will 
post, first of all, the initiation of all of our trials and all 
phases in all countries, phase one, two, three or four, with an 
identifier so that people can see what trials are going on. As 
those trials are completed and as new indications are approved, 
we will populate those identified study trial titles with the 
results, with methodology, with primary and secondary outcomes. 
We intend to do that at the time of the approval of any new 
indication for all phase one, two and three trials, and for 
phase four trials, we will do it as soon as possible after the 
completion of the trial but not more than 1 year afterwards. We 
are going to do that prospectively starting with trials ending 
July 1, 2004 and retrospectively will populate the data base to 
1994, and we will have third party objective and independent 
auditing of this trial to assure our own compliance with our 
intentions.
    I think our logo says, ``Answers that Matter.'' We believe 
in that strongly and applaud the committee's wish to supply 
answers that matter to everyone who cares, and I am happy to be 
here to help.
    [The prepared statement of John R. Hayes follows:]

 Prepared Statement of John R. Hayes, Product Team Leader, Eli Lilly & 
                                Company

    My name is John R. Hayes. I am a licensed physician, Board-
Certified in Psychiatry, and a product team leader for Eli Lilly and 
Company. I joined Eli Lilly and Company in 1998. Prior to joining 
Lilly, I was president of St. Vincent Hospital and Health Services in 
Indiana and CEO of Seton Health Corporation of Indiana for several 
years, after having a long career in clinical and academic psychiatry 
as a consultation-liaison psychiatrist. I was a tenured member of the 
faculty at the Indiana University School of Medicine in both the 
departments of Psychiatry and Medicine. I continue to hold appointments 
in those departments.
    It is a privilege to appear before you on behalf of Eli Lilly and 
Company. My testimony before your Subcommittee is focused on the issue 
of publication and disclosure of data from clinical trials with 
antidepressant medications in children and adolescents, and in 
particular, our experience with, and data concerning, Prozac.
    Everything I have to say is based in Lilly's belief that all 
pharmaceutical companies have a public health responsibility to:

1. Provide safe and efficacious medications with supporting usage 
        information to adults and children.
2. Monitor the safety and efficacy of these medications and their 
        effects throughout the life cycle of the product, from the time 
        it is initially tested in humans, until it is no longer 
        marketed.
3. Disclose the results of clinical trials and safety monitoring 
        efforts to clinicians and patients in a timely and accurate 
        manner.
    In that context, then, there are four main themes that I will cover 
in today's oral testimony:

1. Depression is a devastating illness for not only adults, but also 
        for children and adolescents. This is a serious public health 
        issue.
2. Fortunately for those suffering with depression, there are 
        treatments available, both pharmacological therapies and ``talk 
        therapies,'' that have proven beneficial in research studies. 
        Among the pharmaceutical therapies, Prozac was the first 
        antidepressant to be approved by the FDA for use in children 
        and adolescents. That approval was based on extensive studies 
        submitted to the FDA for their review. Prozac is also approved 
        for use in adult and geriatric patients. It is reasonable and 
        ethical to make available appropriate treatments for patients 
        with depression, which can be a life-threatening illness, 
        regardless of the patient's age.
3. There is an abundance of clinical data supporting the safety and 
        efficacy of Prozac. Prozac is available to patients in over 100 
        countries. It is estimated that there have been over 50 million 
        patients who have taken Prozac; including over 400 clinical 
        trials in which more than 30,000 patients have participated. 
        These clinical trial data have been supplemented by safety data 
        reported to Lilly's pharmacovigilance databases and regulatory 
        authorities around the world since 1983, updated at least 
        annually in a comprehensive manner.
4. Finally, I will share with you Lilly's policy regarding the 
        disclosure of clinical trial results across all areas of study. 
        Lilly is committed to publicly disclose all medical research 
        results that are significant to patients, healthcare providers 
        or payers--whether favorable or unfavorable to a Lilly 
        product--in an accurate, objective and balanced manner in order 
        for patients and health practitioners to make more informed 
        decisions about our products.

A. DEPRESSION IS A DEVASTATING ILLNESS FOR ADULTS AND FOR CHILDREN AND 
                              ADOLSECENTS

    Prevalence estimates for Major Depression in all children range 
from 16% to 22 % (Costello et al, 1996; Roberts et al, 1998). According 
to a report from the United States Surgeon General (Report of the 
Surgeon General's Conference on Children's Mental Health, 2000, p. 11), 
at least ``one in ten children and adolescents suffer from mental 
illness severe enough to cause some level of impairment.'' 
Additionally, it states ``recent evidence compiled by the World Health 
Organization indicates that by the year 2020, childhood 
neuropsychiatric disorders will rise proportionately by over 50 
percent, internationally, to become one of the five most common causes 
of morbidity, mortality, and disability among children.'' In this same 
report, it was noted that, in the United States, for children between 
the ages of 1 and 19 years, the group of conditions that lowers the 
quality of life and reduces life chances (opportunities) the most are 
emotional and behavioral problems and associated impairments. Children 
with these disorders are at an increased risk for dropping out of 
school, and of not being fully functional members of society in 
adulthood. The cost to society is high in both human and fiscal terms 
(Id. p. 17). There is also the significant role that stigma plays in 
inhibiting parents from seeking, and children from receiving, 
appropriate mental health care. Untreated depression can result in poor 
social and school performance, family problems, interpersonal 
difficulties, alienation, isolation, and sometimes, suicide. It is not 
well appreciated that more teenagers and young adults die from suicide 
than from cancer, heart disease, AIDS, birth defects, stroke, pneumonia 
and influenza, and chronic lung disease combined. Suicide is also the 
fourth leading cause of death among children between the ages of 10 and 
14 years. (CDC. National mortality statistics. http://www/cdc/gov/
ncipc/osp/usmort.htm.)
    Lilly is dedicated to discovering and developing medications to 
help all patients, including children and adolescents, who suffer from 
mental health disorders, including Major Depression.

 B. THERE ARE TREATMENTS AVAILABLE THAT HAVE BENEFIT; OF THESE, PROZAC 
 WAS THE FIRST ANTIDEPRESSANT APPROVED BY FDA FOR USE IN CHILDREN AND 
                              ADOLESCENTS

    Fortunately, there are several treatments currently available for 
children and adolescents with depression, including pharmacological and 
``talk therapies,'' that appear to have benefit. One of these is the 
medication, fluoxetine, or Prozac.
    After reviewing the clinical trial data submitted by Lilly in 
September 2000, the FDA approved Prozac for the treatment of Major 
Depressive Disorder in children and adolescents on January 3, 2003. 
Prozac was the first and continues to be the only antidepressant 
approved by the FDA for the safe and effective treatment of depression 
in children and adolescents. Prozac has also been approved by FDA for 
use in children and adolescents to treat Obsessive-Compulsive Disorder, 
a potentially disabling and life-threatening condition.
    Lilly is committed to providing patients, prescribers and payers 
with all medical data that may influence the health care decision 
process. All five Lilly-sponsored clinical trials using Prozac in 
children and adolescents were not only submitted to, and thoroughly 
reviewed by, the FDA but also published in peer-reviewed medical 
journals upon the completion of the trials. This information is readily 
accessible to patients, health care providers and payers. [See Table of 
Fluoxetine Pediatric Studies and Related Publications. Attachment 1.] 
Four of the five trials demonstrated the efficacy and safety of Prozac 
in children and adolescents. One of the trials, a pilot study, did not 
demonstrate a significant effect. It is important to note that on 
August 3, 2004 the Wall Street Journal erroneously reported that Lilly 
had failed to disclose some of the results from its Prozac pediatric 
studies. Lilly contacted the author who acknowledged she had 
misinterpreted information she obtained from the Lancet. The article 
was subsequently corrected. Results from all five of the Lilly-
sponsored pediatric Prozac trials have in fact been published.
    Beyond these five trials, Lilly continues to monitor the safety of 
children and adolescents being treated with Prozac. Data are collected 
from patients and healthcare providers, reviewed by Lilly and submitted 
to the FDA. Any significant findings result in a label change, which 
may be initiated by Lilly or the FDA. Lilly also continues to conduct 
studies in adolescents and children using Prozac in order to understand 
the long-term effects of its use. We are doing this to honor 
commitments we have to children and their physicians as well as the 
FDA, despite the fact that Prozac's patent has expired and generic 
fluoxetine has been available for some time. For instance, Lilly is in 
discussion with the FDA for an additional study of the long-term 
effects of Prozac on growth in adolescents. It should be noted that 
Prozac has not been and will not be actively promoted by Lilly sales 
force or advertised for use in children.

  C. THERE IS ABUNDANT DATA, BOTH FROM CONTROLLED CLINICAL TRIALS AND 
FROM SPONTANEOUS REPORTS IN OUR PHARMACOVIGILANCE DATABASE, WITH WHICH 
             TO EVALUATE THE SAFETY AND EFFICACY OF PROZAC.

    Prozac was first marketed in 1987, and is now available to patients 
in over 100 countries. It is estimated that Prozac has been used to 
treat over 50 million people worldwide, improving the lives of millions 
of people suffering from depression and other disorders. Prozac has 
been the subject of more than 400 clinical trials, and has been studied 
in more than 30,000 patients worldwide. There are more than 15,000 
articles in medical and scientific literature with fluoxetine (Prozac) 
in the title, and over 7,500 in which Prozac is the primary topic of 
the article. Lilly has maintained pharmacovigilance databases on Prozac 
since 1983, in which all manner of events reported while patients have 
taken Prozac are recorded. This database, together with controlled data 
from clinical trials and pre-clinical studies, form the basis for our 
assessment of safety and efficacy of this product.

              D. LILLY DATA DISCLOSURE POLICY INFORMATION

    Lilly has had a long-standing commitment to provide our customers 
with ``answers that matter.'' We strive to provide information about 
all of our products, and clear responses to questions that add value to 
the healthcare decision process, just as I have outlined in the Prozac 
example.
    Lilly has internal standards for conducting, funding and 
communicating the results of our medical research. In these standards, 
Lilly commits to publicly disclose all medical research results that 
are significant to patients, health care providers or payers--whether 
favorable or unfavorable to a Lilly product--in an accurate, objective 
and balanced manner in order for our customers to make more informed 
decisions about our products. Lilly understands that patients and 
health care providers are looking for transparent answers, therefore, 
Lilly has enhanced recently its internal standards by committing to 
disclose publicly the results of all Lilly-sponsored clinical trials of 
its marketed products. [See Principles of Medical Research--Clinical 
Trial Registry. Attachment 2] This includes the results of all Phase I 
(early exploratory), Phase II (proof of concept), Phase III 
(registration), and Phase IV (post marketing) trials conducted anywhere 
in the world.
    Lilly commits to disclose the clinical trial results of the primary 
and secondary outcome measures that are specified in the study 
protocol, as well as additional safety and efficacy results that impact 
patient care and the use of our products. Also, Lilly commits to 
disclose a comprehensive description of the trial design and 
methodology for each study. Results which do not support the hypothesis 
being tested, or which are contrary to the intended outcome, will be 
disclosed.
    Lilly further understands that patients and health care providers 
are not only looking for the results of our clinical trials, but they 
also want to be assured that they are not just receiving select 
results. Therefore, Lilly also commits to publicly report the 
initiation of all Phase III and Phase IV clinical trials, with an 
identifier assigned to each trial. When the trial is completed and the 
drug is commercially available, the results of the trial will be 
appended to its identifier in order to assure patients and providers 
they are receiving full transparency. Beyond that, Lilly will assign an 
independent third party to audit and verify adherence by Lilly to these 
standards for results disclosure.
    Lilly is committed to providing answers in a timely manner. For 
Phase I, II and III studies, Lilly will disclose clinical trial results 
when a drug's indication is approved and it is commercially available. 
For Phase IV studies, Lilly will disclose clinical trial results as 
soon as possible after the data analysis is completed but no later than 
one year after the trial has completed.
    In all cases, Lilly will disclose clinical trial results on a 
publicly available, on-line registry. Lilly also will seek to disclose 
results through a peer-reviewed medical journal, subject to the 
discretion of the journal editors. For studies that are under review by 
a peer-reviewed journal that prohibits pre-publication disclosure of 
results, the results will be posted on the registry at the time of the 
publication. Lilly commits to providing a reference in the clinical 
trial registry for study results that are disclosed in a peer-reviewed 
journal. In addition, Lilly's clinical trial results may be disclosed 
through presentations or abstract submissions at professional 
scientific meetings.
    Implementation of these standards will begin with all clinical 
trials of marketed products that are completed after July 1, 2004. In 
addition, the registry will be populated retrospectively with results 
of core efficacy and safety registration trials of marketed compounds 
approved since July 1, 1994.
    Lilly is interested in disclosing clinical trial results and the 
initiation of trials through an industry-wide registry. However, 
because of the importance of this issue, we have chosen a Lilly-
sponsored registry at this time to disclose our clinical trial 
information. Beginning in the forth quarter of this year, our 
information will be publicly available at www.lillytrials.com.
    Lilly has been actively engaged in PhRMA's efforts to create a 
results disclosure database and fully supports this initiative. In 
fact, Lilly was a leader in developing the PhRMA Principles on Conduct 
of Clinical Trials and Communication of Clinical Trial Results 
originally adopted by member companies in 2002. Lilly also led the 
recent development of clarifying Questions and Answers that were 
adopted by member companies in June 2004 and now append the PhRMA 
Principles text. These principles reinforce each PhRMA member's 
commitment to the safety of research participants, integrity and 
objectivity of clinical research and public disclosure of clinical 
trial results. Among other things, these Q&A clarify that member 
companies commit to disclose the results of all hypothesis-testing 
clinical trials of marketed product. Lilly's active involvement in 
shaping the content and rigor of such efforts has contributed to making 
these Principles more specific and affirmative on the publication of 
clinically meaningful study results than anything the trade association 
has set forth before.
    Additionally, we continue to be actively engaged in the posting of 
information on the initiation of clinical trials for serious and life-
threatening diseases via the U.S. government web site, 
www.clinicaltrials.gov. This website gives the patients and the general 
public a central place--to learn about what potential life-saving 
clinical trials are underway involving those disease states. Lilly met 
the U.S. Food and Drug Administration timeline in 2002--to post the 
required trials and continues to regularly update its list. Lilly has 
been so proficient at site participation, with--dozens of Lilly 
clinical trials listed on clinicaltrials.gov,--that we recently 
provided a speaker--on the topic for the--Drug Information Association 
conference at--the FDA moderator's invitation.
    In closing, Eli Lilly and Company thanks the Subcommittee for the 
opportunity to participate in this important dialog. The issue of data 
disclosure of child and adolescent antidepressant clinical trials is 
ultimately an issue of public health responsibility in which we all, as 
regulators, legislators, antidepressant manufacturers and the medical 
community have a role to play. For Lilly, that role is to provide safe 
and effective medications for the people who need them; to continue to 
monitor the safety of those medications and to share information 
promptly about the safe use of its products with the community. Thank 
you.

                              References:

    Costello EJ, Angold A, Burns BJ, et al. (1996) The great smokey 
mountains study of youth: functional impairment and serious emotional 
disturbance. Arch of Gen Psychiatry, 53(12): 1137-1143.
    Roberts RE, Attkisson CC, Rosenblatt A (1998). Prevalence of 
psychopathology among children and adolescents. Amer J Psychiatry, 
155(6): 715-25.
    U.S. Public Health Service, Report of the Surgeon General's 
Conference on Children's Mental Health: A National Action Agenda. 
Washington, D.C.: Department of Health and Human Services, 2000.
    CDC. National mortality statistics. (http://www/cdc/gov/ncipc/osp/
usmort.htm.)

    Mr. Walden. Thank you for your testimony.
    Dr. Camardo.

                 TESTIMONY OF JOSEPH S. CAMARDO

    Mr. Camardo. Good afternoon, Mr. Chairman and members of 
the subcommittee. I am Dr. Joseph Camardo, head of Medical 
Affairs for Wyeth Pharmaceuticals. venlafaxine, an 
antidepressant drug, also called Effexor, is our product. It is 
a dual reuptake inhibitor that has been used successfully in 
adults for over 10 years.
    Our policy at Wyeth is to communicate the meaningful 
results of our clinical studies regardless of the outcomes. So 
we appreciate the opportunity to testify at this hearing about 
this topic.
    I want to first highlight three facts about depression and 
venlafaxine. First, depression in children is a tragic medical 
condition, and some children with depression may commit 
suicide. Second, venlafaxine has never been indicated for 
children, and Wyeth did not recommend or promote venlafaxine 
for pediatric patients. Nevertheless, physicians have used the 
newer antidepressants, including venlafaxine, cautiously to 
help relieve depression in individual children because 
depression is a serious problem. And, third, the label for 
venlafaxine advises that there is a risk of suicide in 
depressed patients and recommends supervision of high-risk 
patients when drug treatment is initiated.
    Now, I want to tell you about our pediatric studies. We 
performed five studies of safety and efficacy of venlafaxine 
for depression and anxiety disorder in children. The data were 
collected, analyzed and compiled into reports within about a 
year after completing the last study. Our internal Executive 
Safety Committee reviewed all the study results in June 2002. 
This is a committee of senior physicians at Wyeth and at this 
meeting were two psychiatrists, one of whom is a specialist in 
child psychiatry. This committee concluded that while the 
children in the depression studies improved during the study 
period, the main analyses did not show a statistically 
significant difference between the active and placebo-treated 
children. For anxiety, one study showed a clear benefit of 
venlafaxine over placebo, and a second study showed a 
difference favoring venlafaxine that did not reach statistical 
significance.
    This committee also reviewed the safety data and discussed 
the reports of suicidal ideation, hostility and self-harm. No 
child committed suicide. The small number of reports and the 
facts of each report did not demonstrate to us a clear and 
unambiguous relationship between venlafaxine use and suicide-
related events. Nevertheless, despite the lack of a clear 
relation, we decided that this information should be posted to 
our product label to advise of the reports of suicide ideation 
and to advise that venlafaxine had not been demonstrated to be 
effective for depression in children in these two studies. We 
disclosed all the data along with our recommendations for the 
label change to FDA in September 2002. Also in September 2002, 
our Medical Department prepared letters to provide information 
to physicians who called to inquire about pediatric use of 
venlafaxine. These letters explained the results of the studies 
and the safety information.
    In March 2003, the FDA review of our pediatric data was 
posted on the FDA web site. Reflecting a lack of certainty 
about the reports of suicide ideation, FDA at this time did not 
approve our proposal to amend the product label. In April 2003, 
we presented the pediatric data to outside expert 
psychiatrists, and these experts suggested that the information 
about suicidal ideation should be communicated. We also learned 
about similar reports with paroxetine, another manufacturer's 
antidepressant.
    Our Safety Committee met again and recommended that we do 
the following, which we did: First, in August 2003, we 
published an amended label to include the reports of suicidal 
ideation, hostility and self-harm; second, we sent a letter to 
more than 450,000 physicians and other health care 
professionals in the United States. The letter disclosed the 
reports of suicidal ideation and hostility and reminded 
practitioners that venlafaxine was not demonstrated to be 
effective in clinical studies in children with depression. I 
want to emphasize that changing the label and notifying 
physicians directly is a most effective and timely way to 
provide new information. Third, we posted the information on 
the physician and consumer web sites for venlafaxine, so it was 
widely available. And, fourth, the Medical Department updated 
the letters to respond to any direct physician inquiries.
    Most recently, in April 2004, Wyeth adopted the 
antidepressant class label concerning suicide risk, as 
recommended by FDA, and we again notified physicians by letter. 
The pediatric study results were presented in May at the 
American Psychiatric Association meeting.
    We continue to operate our safety oversight process to 
assure that new information is reviewed and that medically 
important information is communicated. Thank you.
    [The prepared statement of Joseph S. Camardo follows:]

Prepared Statement of Joseph Camardo, Senior Vice President of Medical 
                     Affairs, Wyeth Pharmaceuticals

    Good morning, Mr. Chairman. I am Dr. Joseph Camardo, Senior Vice 
President of Medical Affairs for Wyeth Pharmaceuticals based in 
Collegeville, Pennsylvania. Wyeth developed and has marketed 
venlafaxine, an antidepressant that is a dual reuptake inhibitor, under 
the brand name Effexor, since 1994. We appreciate this opportunity to 
testify before the Subcommittee.
    It is Wyeth's policy to communicate meaningful clinical results of 
studies of our products regardless of the trial outcome, consistent 
with the Principles on the Conduct of Clinical Trials put forth by the 
Pharmaceutical Research and Manufacturers Association.
    I want to highlight three facts about depression and venlafaxine.

 First, depression in children is a tragic medical condition 
        associated with a significant incidence of suicide. Physicians 
        need to find ways to treat individual children and they have 
        cautiously used the newer antidepressants.
 Second, venlafaxine has never been indicated for children and Wyeth 
        did not recommend or promote its use in children.
 Third, the product's label has always included a precaution that the 
        possibility of a suicide attempt is inherent in depression, and 
        that close supervision of high-risk patients should accompany 
        initial drug therapy.
    Wyeth performed five safety and efficacy studies of venlafaxine for 
depression and generalized anxiety disorder in children according to a 
written request by the Food and Drug Administration (FDA). At the 
conclusion of each study, in accordance with standards of Good Clinical 
Practice,1 the data were collected from the various clinical 
sites, entered into our database, and verified for accuracy. The data 
were analyzed for efficacy and safety and compiled into a study report. 
For the five studies in this program, these activities took one year 
after completion of the last study which is about average for a program 
of this size.
---------------------------------------------------------------------------
    \1\ ICH Harmonised Tripartite Guideline for Good Clinical Practice.
---------------------------------------------------------------------------
    In preparation for submitting an application to the FDA, our 
internal Executive Safety Committee reviewed the study results in June 
2002. Our reviewers included senior, experienced physicians from our 
medical, clinical research, safety surveillance, and regulatory affairs 
departments and two experienced psychiatrists, one of whom is a 
specialist in child psychiatry. This committee concluded that while the 
children in the studies of depression showed improvement during the 
study period, the main analyses did not find a statistically 
significant difference between children with depression treated with 
venlafaxine or placebo. One study of anxiety in children showed a clear 
benefit of venlafaxine over placebo in the main analyses, and the 
second study showed a non-significant difference favoring venlafaxine.
    In reviewing the collective data from these studies, the committee 
discussed the reports of suicidal ideation, hostility, and suicide 
attempts. None of the children in these studies committed suicide. The 
numbers of reports and the facts surrounding each report did not 
demonstrate a clear relation between venlafaxine use and suicide-
related events.
    Nevertheless, despite the lack of a clear relation we decided that 
our label should be amended to add a precaution to advise of the 
reports of suicidal ideation and hostility and to state that studies 
had not demonstrated venlafaxine to be effective in children with 
depression. In September 2002 Wyeth disclosed all data to FDA in a 
pediatric NDA supplement that included recommended label changes.
    At the same time, our medical department prepared letters to 
respond to physicians who called us to inquire about pediatric use. 
These letters included detailed information about the efficacy results 
and the safety information from these pediatric studies.2 In 
March 2003, the FDA informed Wyeth that our supplemental application 
was not approved. Subsequently, the FDA posted its clinical review of 
this supplement on the FDA website.3 Reflecting the lack of 
certainty about the reports of suicidal ideation, FDA did not approve 
our proposed label additions concerning suicidal ideation in children.
---------------------------------------------------------------------------
    \2\ A copy of Wyeth's response letter from October 2002 is 
Attachment A.
    \3\ A copy of FDA's clinical review is Attachment B.
---------------------------------------------------------------------------
    In April 2003 we reviewed our pediatric data with outside expert 
psychiatrists who had not been involved with the studies. These experts 
concurred that the information about suicidal ideation should be 
disseminated. We learned of similar observations with paroxetine and we 
judged that these findings raised the level of importance of our own 
findings. At this time, our Executive Safety Committee recommended and 
we took the following actions:

 First, in August 2003 Wyeth published an amended label to notify 
        health professionals about the reports of suicidal ideation, 
        hostility, and self-harm.
 Second, also in August 2003, we sent a letter to more than 450,000 
        physicians and other health care practitioners in the United 
        States. This letter disclosed the reports of suicidal ideation 
        and hostility and reminded practitioners that venlafaxine was 
        not demonstrated to be effective in children and was not 
        approved for use in children.4 Changing the label 
        and notifying physicians directly is the most effective and 
        timely way to get the information to physicians.
---------------------------------------------------------------------------
    \4\ A copy of Wyeth's August 2003 Dear Healthcare Provider Letter 
is Attachment C.
---------------------------------------------------------------------------
 Wyeth posted the information on the physician and consumer sections 
        of the Effexor website.
 Our medical department's inquiry responses were updated to include 
        this information.5
---------------------------------------------------------------------------
    \5\ A copy of Wyeth's response letter from August 2003 is 
Attachment D.
---------------------------------------------------------------------------
    In April 2004 on the basis of FDA's recommendation, Wyeth 
incorporated class label changes to the warnings section concerning 
suicide risk. In addition, the pediatric data, including the results of 
the depression studies showing no difference from placebo, have been 
presented at the American Psychiatric Association.
    We continue to operate under our safety review process in which new 
information from any source is reviewed by our Executive Safety 
Committee and, if warranted, by outside experts. Medically important 
new drug information is disseminated.
    Again, Mr. Chairman, we thank you for this opportunity to appear 
before the Subcommittee.
                                 ______
                                 
                              ATTACHMENT A
                      October 2002 Response Letter

           THE USE OF VENLAFAXINE IN CHILDREN OR ADOLESCENTS

    Venlafaxine is a serotonin and norepinephrine reuptake inhibitor 
(SNRI).\1\,\2\ Its active metabolite, O-desmethylvenlafaxine 
(ODV), also inhibits serotonin and norepinephrine reuptake, with 
similar potency to venlafaxine. Venlafaxine and ODV are weak inhibitors 
of dopamine reuptake and have no significant affinity for muscarinic 
cholinergic, H1-histaminergic, or a1adrenergic 
receptors in vitro. Effexor XR Capsules are indicated for the treatment 
of depression and Generalized Anxiety Disorder (GAD). Effexor Tablets 
are indicated for the treatment of depression. Please see the enclosed 
prescribing information for the recommended dosage and administration.

Summary Points
 The safety and efficacy of venlafaxine in children and adolescents 
        less than 18 years of age have not been established; therefore, 
        we cannot recommend the use of these products in this patient 
        population.\3\,\4\
 The safety and efficacy of venlafaxine extended-release (XR) for the 
        treatment of GAD in children and adolescents was assessed in 2 
        double-blind, 8-week, placebo-controlled 
        trials.\5\,\6\,\7\ In the first 
        randomized controlled trial, patients in the venlafaxine XR 
        group had a mean decrease of 18.6 points on the Columbia-Kiddie 
        Schedule for Affective Disorders and Schizophrenia (C-KIDDIE-
        SADS) GAD (9 delineated items) compared to a 12.4 point 
        decrease in the placebo group (P < .001).\5\,\6\ In 
        the second randomized controlled trial, the decrease from 
        baseline in the C-KIDDIE-SADS GAD was greater in venlafaxine 
        XR- compared with placebo-treated patients (15.8 versus 13); 
        however, this difference did not reach statistical significance 
        (P = .060).\7\
 Several randomized placebo controlled trials assessed the safety and 
        efficacy of venlafaxine for the treatment of depression in 
        children and adolescents.\8\-\11\ Data from these 
        clinical trials indicated that venlafaxine was well-tolerated 
        but not efficacious for the treatment of depression in children 
        and adolescents.
 In a 5-week, open trial of 16 children (aged 8-16) with ADHD, 44% (7/
        16) of the subjects responded favorably to venlafaxine therapy 
        based on the Conners Parent Rating Scale (CPRS), while no 
        significant effects were found on the Continuous Performance 
        Test (CPT).\12\ Treatment was initiated at a dose of 12.5 mg/
        day and gradually increased to a target dose of 75 mg/day.
 In an open-label, retrospective evaluation of 10 patients (aged 3-21) 
        with autism, 60% (6/10) of the patients were rated as sustained 
        responders with a Clinical Global Impression (CGI) improvement 
        score of 1 or 2 and showed improvement of symptoms in 
        autism.\13\ Treatment was initiated at a dose of 12.5 mg/day 
        and gradually increased based on clinical response and adverse 
        events.
 Pharmacokinetic studies demonstrated that the mean clearance 
        (normalized-body weight) of venlafaxine and ODV was 2.5-fold to 
        3.0-fold higher, and plasma concentrations lower, in children 
        and adolescents compared to adults who received the same mg/kg 
        dose.\14\,\15\

GAD
    The safety and efficacy of venlafaxine XR for the treatment of GAD 
in children and adolescents was assessed in 2 double-blind, 8-week, 
placebo-controlled trials that evaluated 158 and 164 patients, 
respectively.\5\,\6\,\7\ For both trials, 
patients had symptoms of anxiety for  6 months and met the Diagnostic 
and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and C-
KIDDIE-SADS criteria for GAD. All patients in the active-treatment 
groups started venlafaxine at 37.5 mg/day for the first week. Primary 
efficacy assessments were obtained on days 7, 14, 21, 42 and 49, and 
safety assessments were obtained at each visit. The primary efficacy 
variable was the C-KIDDIE-SADS GAD (9 delineated items). The dose was 
then titrated according to weight and response, according to a 
flexible-dosing regimen.
    In the first randomized controlled trial, patients in the extended-
release venlafaxine group had a mean decrease of 18.6 points on the 
primary efficacy variable compared to the 12.4 point decrease in the 
placebo group (P < .001).\5\,\6\ The discontinuation rate 
for adverse events between extended-release venlafaxine (3%) and 
placebo (9%) was not significant. The most common treatment-emergent 
adverse events were asthenia, anorexia, weight loss, thinking abnormal, 
hyperkinesia and epistaxis.
    In the second randomized controlled trial, the decrease from 
baseline in the C-KIDDIE-SADS GAD was greater in venlafaxine XR- 
compared with placebo-treated patients (15.8 versus 13); however, this 
difference did not reach statistical significance (P = .060).\7\ The 
adverse events observed in venlafaxine XR-treated patients were similar 
to that observed in adult patients with GAD. Adverse events were the 
primary or secondary cause of discontinuation in 4% of venlafaxine-
treated patients compared with 2% of placebo-treated patients.
    These trials suggested that venlafaxine-XR is an efficacious and 
well-tolerated treatment for children and adolescents with 
GAD.\5\-\7\

Depression
    The safety and efficacy of venlafaxine XR for the treatment of 
depression in children and adolescents was assessed in 2 double-blind, 
8-week, placebo-controlled trials,\8\,\9\ and one open-label 
6-month trial.\10\ The double-blind trials included 161 and 193 
patients,\8\,\9\ respectively, that were evaluated for 
efficacy; the open-label trial evaluated 85 patients.10 For all 3 
trials, patients met DSM-IV and Kiddie Schedule for Affective Disorders 
and Schizophrenia, Present and Lifetime Version (KIDDIE-SADS-PL) 
criteria for major depressive disorder. Patients also had a Childhood 
Depression Rating Scale, Revised (CDRS-R) score > 40 at baseline, with 
no greater than a 30% decrease during screening; a Clinical Impressions 
Severity of Illness (CGI-S) score  4; and depressive symptoms for at 
least 1 month prior to entry into the study. All patients in the 
active-treatment groups started venlafaxine at 37.5 mg/day for the 
first week. The dose was then titrated according to weight and 
response, according to a flexible-dosing regimen. The primary efficacy 
variable was the CDRS-R total score.
    There was no significant difference between venlafaxine XR- and 
placebo-treated patients for CDRS-R scores in either of the placebo-
controlled trials. Venlafaxine XR was found to be safe and well 
tolerated in all 3 trials, with a safety profile that was similar to 
that seen in adults with major depression. No patients died in any of 
the studies. In one placebo-controlled trial,\8\ adverse events were 
the primary or secondary cause for discontinuation of study drug in 13% 
of venlafaxine XR-treated patients compared with 5% of placebo-treated 
patients. The adverse events that most frequently caused 
discontinuation of treatment in the venlafaxine XR group were manic 
reaction (3%) and suicidal ideation (3%). In the other placebo-
controlled trial,\9\ adverse events were the primary cause for 
discontinuation of study drug in 8% of venlafaxine XR-treated patients 
compared with 1% of placebo-treated patients. The adverse events that 
most frequently caused discontinuation of treatment in the venlafaxine 
XR group were hostility (2%) and suicidal ideation (2%).
    In a separate preliminary double-blind, placebo-controlled, 6-week 
study, Mandoki et al \11\ evaluated the effectiveness of venlafaxine 
immediate-release (IR) in the treatment of depression in children or 
adolescents. The study involved 33 patients (age range, 8-17 years) who 
met DSM-IV criteria for major depression. Suicidal patients were 
excluded from the study. Patients were randomized to receive either 
venlafaxine or placebo (n = 20 each group). The children (aged 8-12) 
randomized to venlafaxine were titrated during the first week to 12.5 
mg t.i.d.; adolescents (aged 13-17) in the venlafaxine group were 
titrated to 25 mg t.i.d.
    Efficacy assessments were obtained weekly by administering the 
Hamilton Psychiatric Rating Scale for Depression (HAM-D), the Child 
Depression Rating Scale (CDRS), the Child Behavior Checklist (CBCL), 
and the Child Depression Inventory (CDI).\11\ Safety data were also 
obtained on a weekly basis.
    Both the venlafaxine and placebo groups improved significantly (P 
.05) as measured by the HAM-D, the CDRS, and the CBCL.\11\ Significant 
improvement was not obtained by any group on the CDI. There were no 
significant differences between treatment groups for any rating scale. 
In addition, the pattern of improvement over the treatment period was 
similar for both groups, indicating that there was not a faster onset 
of action in the venlafaxine group.
    A higher percentage of venlafaxine-treated patients reported 
adverse events than the placebo group at almost every weekly 
assessment.\11\ However, only the incidence of nausea at week 2 (all 
ages compared) and increased appetite (only adolescents compared) were 
statistically significantly different from placebo.
    Data from these clinical trials indicate that venlafaxine is well-
tolerated but is not efficacious for the treatment of depression in 
children and adolescents.\8\-\11\

ADHD
    Olvera et al \12\ conducted a 5-week, open trial of venlafaxine in 
the treatment of ADHD. Sixteen children and adolescents (ages 8-16 
years; mean 11.6 years) meeting DSM-III-R criteria for ADHD (based on 
the Diagnostic Interview Schedule for Children) participated in the 
study. The child was also required to have a score of at least 1.5 
standard deviations above the mean for the patient's age and sex on the 
Inattention or Impulsivity/Hyperactivity factor of the CPRS. 
Venlafaxine was initiated at a dose of 12.5 mg/day for the first week. 
Based on the patient's tolerability, the daily dose was increased by 25 
mg each week until a target dose of 75 mg/day was achieved. For 
children weighing less than 40 kg, daily venlafaxine doses were 
increased by 12.5 mg weekly up to a maximum of 50 mg. If a patient 
experienced side effects, the dosage was reduced to the previous level. 
The child's parent completed the CPRS, and the child performed the CPT 
at baseline and at the end of the 5-week trial. In addition, telephone 
interviews of the child and parent were conducted weekly to assess the 
effects of venlafaxine treatment on ADHD symptoms.
    Of the 16 enrolled patients, 10 patients completed the study (mean 
venlafaxine dose, 60 mg/day).\12\ Two patients were lost to follow-up, 
3 discontinued therapy due to an increase in hyperactivity, and one 
discontinued due to nausea. Of the evaluable patients, treatment with 
venlafaxine resulted in significant improvement (P < 01) in the 
Impulsivity/Hyperactivity Factor and Hyperactivity Index of the CPRS. 
However, there were no significant changes in the Conduct Index Factor, 
nor were there any significant effects of venlafaxine therapy on the 
CPT. Overall, 44% (7/16) subjects responded favorably to venlafaxine 
therapy based upon the CPRS.
    There were no significant adverse events noted.\12\ The most common 
adverse experiences were drowsiness, nausea, irritability, and 
worsening of hyperactivity. Other reported adverse events included 
insomnia, dizziness, decreased appetite, dry mouth, anxiety, and 
headache. No appreciable effects on blood pressure or heart rate were 
noted.
    The preliminary findings of this study suggest that low doses of 
venlafaxine appeared to be effective in reducing behavioral but not 
cognitive symptoms of ADHD in some patients.\12\ Further study is 
necessary to confirm these results.
Autism
    Hollander et al \13\ conducted an open-label, retrospective 
evaluation of the treatment responses to venlafaxine in children, 
adolescents or young adults with autistic spectrum disorders. Ten 
patients between the ages of 3 and 21 (mean 10.5  5.5) years old who 
met the DSM-IV criteria for pervasive developmental disorders, 
including autism and Asperger's Syndrome, were included in the study. 
Five patients had comorbid disorders including ADHD, body dysmorphic 
disorder, separation anxiety, obsessive-compulsive disorder, and 
Tourette's syndrome. Patients were treated with an initial dose of 
venlafaxine 12.5 mg/day. The venlafaxine dose was gradually increased 
based on clinical response and adverse events. Efficacy was assessed 
using the CGI improvement scale. Responders were defined as those 
patients who obtained a score of 1 (very much improved) or 2 (much 
improved).
    Six of the 10 patients were rated as sustained responders with a 
CGI improvement score of 1 or 2.\13\ The mean endpoint venlafaxine dose 
in these patients (25  14 mg/day) did not differ from that of the 
nonresponders. The mean duration of treatment was 4.8  2.5 months. 
Venlafaxine treatment was noted to improve symptoms in all 3 core 
dimensions of autism (social deficits, language and communication 
impairment, restricted interests and repetitive behaviors). Patients 
were observed to show a decrease in repetitive behaviors and 
obsessional symptoms. Improvements were also noted in eye contact, 
socialization, complexity of play, contextual language use, and 
abnormal vocalizations. According to the investigators, 5 of the 6 
responders also showed signs of improvement in features of ADHD 
including inattention, lack of focus, impulsivity, and hyperactivity.
    Venlafaxine appeared well tolerated with the low doses used.\13\ 
Adverse events included polyuria, nausea, inattention and behavioral 
activation. According to the authors, the behavioral activation 
symptoms were transient or disappeared with dose reduction in 3 
patients, but resulted in withdrawal from the study for 2 patients 
because of persistent symptoms.
    While these preliminary results were positive, randomized 
controlled studies are necessary to adequately evaluate the safety and 
efficacy of venlafaxine for autism spectrum disorders.

Conduct Disorder
    A randomized, double-blind, third party unblinded, placebo lead-in 
study of 25 patients (6-16 years of age) was conducted to determine the 
safety and tolerability of venlafaxine in children with conduct 
disorder, as well as to evaluate preliminary pharmacokinetic data for 
venlafaxine in children or adolescents.\15\ All patients met the DSM-
III R diagnostic criteria for conduct disorder. The study duration was 
6 weeks. Venlafaxine was titrated up to targets of 1 mg/kg/day or 2 mg/
kg/day.
    There were no serious adverse events or deaths reported in this 
study. There was no significant difference between the venlafaxine- and 
placebo-treated patients in this trial; however, this was a preliminary 
trial with insufficient power to detect differences between the 
treatment groups.

Pharmacokinetics
    In an open-label, single-dose study, 18 subjects diagnosed with ADD 
or ADHD were enrolled to evaluate the pharmacokinetic profile of a 
single dose of extended-release venlafaxine in pediatric patients.\14\ 
There were 6 subjects each in 3 age groups (6-7 years, 8-11 years, and 
12-17 years). The single-dose clearance (normalized-body weight) of 
venlafaxine and ODV was 2.5-fold to 3.0-fold higher, and plasma 
concentrations lower, in children and adolescents compared to a 
historical control of adults who received the same mg/kg dose. It was 
calculated that children who receive 3.1 mg/kg and adolescents who 
receive 2.0 mg/kg would have plasma concentrations of venlafaxine and 
ODV similar to typical adult populations that received 150 mg.
    A pharmacokinetic study in 25 children and adolescents with conduct 
disorder with or without major depression or ADD demonstrated similar 
findings.\15\ The oral-clearance values (normalized for body weight) 
for venlafaxine were approximately 2.5-fold higher in children and 
adolescents with conduct disorder that in a historical control of 
healthy adult subjects who received similar mg/kg doses. It was 
calculated that children who received3.3 mg/kg/day and adolescents who 
receive 2.8 mg/kg/day had plasma concentrations of venlafaxine and ODV 
similar to typical adult populations that received 150 mg 
(approximately 2.0 mg/kg/day).

Summary/Conclusion
    The safety and efficacy of venlafaxine in children or adolescents 
less than 18 years of age has not been established; therefore, we 
cannot recommend the use of venlafaxine in this patient population. One 
randomized controlled trial demonstrated that venlafaxine XR was an 
effective and well-tolerated treatment for children and adolescents 
with GAD.\5\,\6\ In a second randomized controlled trial, 
the improvement in the primary endpoint was greater in the venlafaxine 
XR group; however, this difference did not reach statistical 
significance.\7\ Data from clinical trials in patients with depression 
indicated that venlafaxine was well-tolerated but not efficacious for 
the treatment of depression in children and 
adolescents.\8\-\11\ Several preliminary investigations into 
the safety and efficacy of venlafaxine for various other disorders in 
children and adolescents have been 
reported.\12\,\13\,\15\ Larger randomized 
controlled trials are necessary to establish the safety and efficacy of 
venlafaxine in these populations.

                              References:

    1. Muth EA, Haskins JT, Moyer JA, Husbands GEM, Nielsen ST, Sigg 
EB. Antidepressant biochemical profile of the novel bicyclic compound 
Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol. 
1986;35:4493-4497.
    2. Muth EA, Moyer JA, Haskins JT, Andree TH, Husbands GEM. 
Biochemical, neurophysiological, and behavioral effects of Wy-45,233 
and other identified metabolites of the antidepressant venlafaxine. 
Drug Dev Res. 1991:23:191-199.
    3. Effexor ' Tablets--current US prescribing 
information, Wyeth Pharmaceuticals.
    4. Effexor ' XR Capsules--current US prescribing 
information, Wyeth Pharmaceuticals.
    5. Khan A, Kunz NR, Nicolacopoulos E, Jenkins L, Yeung PP. 
Venlafaxine extended release for the treatment of children and 
adolescents with generalized anxiety disorder [poster]. American 
Psychiatric Association 2002 Annual Meeting, Philadelphia, 
Pennsylvania, May 2002.
    6. Data on file (Protocol 0600B2-397-US, CSR-44734, 2002), Wyeth 
Pharmaceuticals.
    7. Data on file (Protocol 0600B2-396-US, CSR-44723, 2002), Wyeth 
Pharmaceuticals.
    8. Data on file (Protocol 0600B1-382-US, CSR-43456, 2002), Wyeth 
Pharmaceuticals.
    9. Data on file (Protocol 0600B1-394-US, CSR-44693, 2002), Wyeth 
Pharmaceuticals.
    10. Data on file (Protocol 0600B1-395-US, CSR-44610, 2002), Wyeth 
Pharmaceuticals.
    11. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL. 
Venlafaxine in the treatment of children and adolescents with major 
depression. Psychopharmacol Bull. 1997;33:149-154.
    12. Olvera RL, Pliszka SR, Luh J, Tatum R. An open trial of 
venlafaxine in the treatment of attention-deficit/hyperactivity 
disorder in children and adolescents. J Child Adolesc Psychopharmacol. 
1996;6:241-250.
    13. Hollander E, Kaplan A, Cartwright C, Reichman D. Venlafaxine in 
children, adolescents, and young adults with autism spectrum disorders: 
An open retrospective clinical report. J Child Neurol. 2000;15:132-135.
    14. Data on file (Protocol 0600B1-169-US, CSR-44894, 2002), Wyeth 
Pharmaceuticals.
    15. Data on file (Protocol 0600A-126-US, CSR-26710, 2002), Wyeth 
Pharmaceuticals.

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                              ATTACHMENT D
                      August 2003 Response Letter

             USE OF VENLAFAXINE IN CHILDREN OR ADOLESCENTS

    Venlafaxine is a serotonin and norepinephrine reuptake inhibitor 
(SNRI).\1\,\2\ Its active metabolite, O-desmethylvenlafaxine 
(ODV), also inhibits serotonin and norepinephrine reuptake, with 
similar potency to venlafaxine. Venlafaxine and ODV are weak inhibitors 
of dopamine reuptake and have no significant affinity for muscarinic 
cholinergic, H1-histaminergic, or a1-adrenergic receptors in vitro. 
Effexor XR Capsules are indicated for the treatment of major depressive 
disorder (MDD), generalized anxiety disorder (GAD) and social anxiety 
disorder (SAD). Effexor Tablets are indicated for the treatment of MDD. 
Please see the prescribing information for recommended dosage and 
administration.

Summary Points
 The safety and effectiveness of venlafaxine in children and 
        adolescents less than 18 years of age have not been 
        established; therefore, venlafaxine is not recommended in this 
        patient population.\3\,\4\
 In pediatric clinical trials, there were increased reports of 
        hostility and, especially in MDD, suicide-related adverse 
        events such as suicidal ideation and self-
        harm.\3\,\4\
 The safety and efficacy of venlafaxine XR for the treatment of MDD in 
        children and adolescents was assessed in 2 randomized, placebo-
        controlled trials.\5\,\6\ Venlafaxine XR did not 
        separate from placebo on the primary efficacy variable in 
        either study.
 The safety and efficacy of venlafaxine extended-release (XR) for the 
        treatment of GAD in children and adolescents was assessed in 2 
        randomized, placebo-controlled 
        trials.\7\,\8\,\9\ Venlafaxine XR was 
        significantly (P < .001) better than placebo on the primary 
        efficacy variable in only 1 of these studies.
 The most common adverse events leading to discontinuation in at least 
        1% of venlafaxine XR-treated pediatric patients and at a rate 
        twice that of placebo were as follows (percentages listed for 
        venlafaxine XR and placebo, respectively): GAD studies: 
        abnormal/changed behavior (1%, 0%); MDD studies: hostility (2%, 
        <1%) and suicidal ideation (2%, 0%).\10\ In addition, the 
        following adverse events were observed at higher incidences 
        than in adult patients: abdominal pain, agitation, dyspepsia, 
        ecchymosis, epistaxis, and myalgia.
 The long-term safety of venlafaxine XR in pediatrics with MDD was 
        evaluated in a 6-month open-label study.\11\ Adverse events 
        were the primary cause of discontinuation for 17% of patients, 
        with hostility (3%) being most common.
 In a 5-week, open trial of 16 patients (ages 8-16) with attention 
        deficit hyperactivity disorder (ADHD), 44% of the patients 
        responded to venlafaxine therapy based on the Conners Parent 
        Rating Scale (CPRS), while no significant effects were found on 
        the Continuous Performance Test (CPT).\12\
 In an open-label, retrospective evaluation of 10 patients (ages 3-21) 
        with autism, 60% of the patients were rated as sustained 
        responders with a Clinical Global Impression (CGI) improvement 
        score of 1 or 2 and showed improvement of symptoms in 
        autism.\13\
 Pharmacokinetic studies demonstrated that the mean clearance 
        (normalized-body weight) of venlafaxine and ODV was 2.5-fold to 
        3.0-fold higher, and plasma concentrations lower, in children 
        and adolescents compared to adults who received the same mg/kg 
        dose.\14\,\15\
 The safety concerns and adverse event profile for venlafaxine in 
        pediatric patients are generally similar to those described for 
        adult patients.\10\ As with adults, decreased appetite and 
        weight loss, increased blood pressure, and increased 
        cholesterol have been observed. Consequently, the warnings and 
        precautions as described in the prescribing information for 
        adults apply to pediatric patients, including the 
        recommendation for regular monitoring of blood pressure.
 The risks that may be associated with long-term use of venlafaxine in 
        children and adolescents have not been systematically 
        evaluated. In particular, there are no studies that directly 
        evaluate the effects of long-term venlafaxine use on growth, 
        development, and maturation.

Depression
    The safety and efficacy of venlafaxine XR for the treatment of 
depression in pediatric patients ages 6-17 years was assessed in 2 
double-blind, 8-week, placebo-controlled trials,\5\,\6\ and 
one open-label 6-month trial.\11\ The double-blind trials included 166 
and 201 patients, respectively,\5\,\6\ the open-label trial 
included 87 patients.\11\ For all 3 trials, patients met DSM-IV and 
Kiddie Schedule for Affective Disorders and Schizophrenia, Present and 
Lifetime Version (KIDDIE-SADS-PL) criteria for major depressive 
disorder. Patients also had a Childhood Depression Rating Scale, 
Revised (CDRS-R) score  40 at baseline, with no greater than a 30% 
decrease during screening; a Clinical Impressions Severity of Illness 
(CGI-S) score  4; and depressive symptoms for at least 1 month prior 
to entry into the study. All patients in the active-treatment groups 
started venlafaxine at 37.5 mg/day for the first week. The doses were 
then titrated according to weight and response, as per the same dosing 
protocol as the GAD studies described above. The primary efficacy 
variable was the CDRS-R total score.
    There was no significant difference between venlafaxine XR- and 
placebo-treated patients in CDRS-R scores in either of the placebo-
controlled trials. Venlafaxine XR was found to be well tolerated in all 
3 trials, with a safety profile that was generally similar to that seen 
in adults with major depression. No patients died in any of the 
studies. In one placebo-controlled trial,\5\ adverse events were the 
primary or secondary cause for discontinuation of study drug in 13% of 
venlafaxine XR-treated patients compared with 5% of placebo-treated 
patients. The adverse events that most frequently caused 
discontinuation of treatment in the venlafaxine XR group were manic 
reaction (3%) and suicidal ideation (3%). In the other placebo-
controlled trial,\5\ adverse events were the primary cause for 
discontinuation of study drug in 8% of venlafaxine XR-treated patients 
compared with 1% of placebo-treated patients. The adverse events that 
most frequently caused discontinuation of treatment in the venlafaxine 
XR group were hostility (2%) and suicidal ideation (2%). In the open-
label 6-month trial, adverse events were the primary reason for 
discontinuation for 17% of patients, with hostility (3%) being the most 
commonly cited event.\11\
    In a pooled analysis of the 2 randomized controlled trials in MDD, 
the most common adverse events leading to discontinuation in at least 
1% of venlafaxine XR-treated patients and at a rate twice that of 
placebo were (percentages listed for venlafaxine XR and placebo, 
respectively): hostility (2%, <1%) and suicidal ideation (2%, 0%).\10\ 
The most common treatment-emergent adverse events with venlafaxine XR 
(incidence  5% and at least twice that of placebo were abdominal pain 
(21%) and anorexia (7%).
    In another double blind, placebo-controlled, study (N = 40), 
Mandoki et al \16\ found no efficacy difference between venlafaxine 
immediate-release (IR) and placebo in the treatment of depression in 
pediatric patients (ages 8-17 years). A higher percentage of 
venlafaxine-treated patients reported adverse events than the placebo 
group at almost every weekly assessment.\16\ However, only the 
incidence of nausea at week 2 (all ages compared) and increased 
appetite (only adolescents compared) were significantly different from 
placebo.

GAD
    The safety and efficacy of venlafaxine XR for the treatment of GAD 
in pediatric patients ages 6-17 years was assessed in 2 double-blind, 
8-week, placebo-controlled trials that evaluated 158 and 164 patients, 
respectively.\7\,\8\,\9\ For both trials, 
patients had symptoms of anxiety for  6 months and met the Diagnostic 
and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and 
Columbia-Kiddie Schedule for Affective Disorders and Schizophrenia (C-
KIDDIE-SADS) criteria for GAD. Primary efficacy assessments were 
obtained on days 7, 14, 21, 42 and 49, and safety assessments were 
obtained at each visit. The primary efficacy variable was the C-KIDDIE-
SADS GAD (9 delineated items).
    All patients in the active-treatment groups started venlafaxine XR 
at 37.5 mg/day for the first week. The doses were then titrated 
according to weight and response using a flexible-dosing regimen. On 
study day 8, the doses were increased to 75 mg/day for all patients 
weighing  40 kg; the dose increase was optional for patients in the 
25-39 kg group. On study day 15, the doses were titrated to a maximum 
of 75 mg, 112.5 mg, or 150 mg daily for the 25-39 kg group, 40-49 kg 
group, and  50 kg group, respectively. On day 29, the doses were 
further titrated to a maximum of 112.5 mg, 150 mg, and 225 mg, 
respectively, for the 25-39 kg, 40-49 kg, and  50 kg patient weight 
groups.
    In the first randomized controlled trial, patients in the 
venlafaxine XR group had a significant mean decrease at week 8 of 18.6 
points on the primary efficacy variable compared to the 12.4 point 
decrease in the placebo group (P < .001).\7\,\8\ Adverse 
events were cited as a cause of discontinuation in 3% and 9% of 
venlafaxine XR- and placebo-treated patients, respectively. The most 
common treatment-emergent adverse events for venlafaxine XR (incidence 
 5% and at least twice the placebo rate) were: asthenia (10%), 
anorexia (10%), hyperkinesia (6%), epistaxis (6%), thinking abnormal 
(5%), and weight loss (5%).
    In the second trial, the decrease from baseline in the C-KIDDIE-
SADS GAD was greater in venlafaxine XR- compared with placebo-treated 
patients (15.8 versus 13); however, this difference did not reach 
statistical significance (P = .060).\9\ The adverse events observed in 
venlafaxine XR-treated patients were similar to that observed in adult 
patients with GAD. Adverse events were the primary or secondary cause 
of discontinuation in 4% of venlafaxine-treated patients and 2% of 
placebo-treated patients. The most common treatment-emergent adverse 
events for venlafaxine XR (incidence  5% and at least twice the 
placebo rate) were: anorexia (15%), nausea (13%), pain (9%), somnolence 
(8%), nervousness (8%), dizziness (6%), and dry mouth (5%).
    In a pooled analysis of the 2 GAD studies, the most common adverse 
event leading to discontinuation in at least 1% of venlafaxine XR-
treated patients and at a rate twice that of placebo was (percentages 
listed for venlafaxine XR and placebo, respectively): abnormal/changed 
behavior (1%, 0%).\10\
    Anorexia/Weight Loss in MDD and GAD Trials
    In a pooled analysis of the 4 randomized controlled trials of 
venlafaxine XR in pediatric patients (2 in MDD and 2 in GAD), 
treatment-emergent anorexia was reported in 10% and 3% of patients 
(ages 6-17) receiving venlafaxine XR and placebo for up to 8 weeks, 
respectively.\10\ A loss of 5% or more of body weight occurred in 14% 
of the venlafaxine XR-treated and 1% of the placebo-treated patients in 
these trials.

ADHD
    Olvera et al \12\ conducted a 5-week, open trial of venlafaxine in 
the treatment of ADHD. Sixteen children and adolescents (ages 8-16 
years; mean 11.6 years) meeting DSM-III-R criteria for ADHD (based on 
the Diagnostic Interview Schedule for Children) participated in the 
study. The patient was also required to have a score of at least 1.5 
standard deviations above the mean for the patient's age and sex on the 
Inattention or Impulsivity/Hyperactivity factor of the CPRS. 
Venlafaxine was initiated at a dose of 12.5 mg/day for the first week. 
Based on the patient's tolerability, the daily dose was increased by 25 
mg each week until a target dose of 75 mg/day was achieved. For 
children weighing less than 40 kg, daily venlafaxine doses were 
increased by 12.5 mg weekly up to a maximum of 50 mg. If a patient 
experienced side effects, the dosage was reduced to the previous level. 
The child's parent completed the CPRS, and the child performed the CPT 
at baseline and at the end of the 5-week trial. In addition, telephone 
interviews of the child and parent were conducted weekly to assess the 
effects of venlafaxine treatment on ADHD symptoms.
    Of the 16 enrolled patients, 10 patients completed the study (mean 
venlafaxine dose, 60 mg/day).\12\ Two patients were lost to follow-up, 
3 discontinued therapy due to an increase in hyperactivity, and 1 
discontinued due to nausea. Of the evaluable patients, treatment with 
venlafaxine resulted in significant improvement (P < .01) in the 
Impulsivity/Hyperactivity Factor and Hyperactivity Index of the CPRS. 
However, there were no significant changes in the Conduct Index Factor, 
nor were there any significant effects of venlafaxine therapy on the 
CPT. Overall, 44% (7/16) subjects responded favorably to venlafaxine 
therapy based upon the CPRS.
    The most common adverse experiences were drowsiness, nausea, 
irritability, and worsening of hyperactivity.\12\ Other reported 
adverse events included insomnia, dizziness, decreased appetite, dry 
mouth, anxiety, and headache. No appreciable effects on blood pressure 
or heart rate were noted.

Autism
    Hollander et al \13\ conducted an open, retrospective evaluation of 
the treatment responses to venlafaxine in children, adolescents or 
young adults with autistic spectrum disorders. Ten patients between the 
ages of 3 and 21 (mean 10.5  5.5) years old who met the DSM-IV 
criteria for pervasive developmental disorders, including autism and 
Asperger's Syndrome, were evaluated. Five patients had comorbid 
disorders including ADHD, body dysmorphic disorder, separation anxiety, 
obsessive-compulsive disorder, and Tourette's syndrome. Patients were 
treated with an initial dose of venlafaxine 12.5 mg/day. The 
venlafaxine dose was gradually increased based on clinical response and 
adverse events. Efficacy was assessed using the CGI improvement scale. 
Responders were defined as those patients who obtained a score of 1 
(very much improved) or 2 (much improved).
    Six of the 10 patients were rated as sustained responders with a 
CGI improvement score of 1 or 2.\13\ The mean endpoint venlafaxine dose 
in these patients (25  14 mg/day) did not differ from that of the 
nonresponders. The mean duration of treatment was 4.8  2.5 months. 
Venlafaxine treatment was noted to improve symptoms in all 3 core 
dimensions of autism (social deficits, language and communication 
impairment, restricted interests and repetitive behaviors). 
Improvements were also noted in eye contact, socialization, complexity 
of play, contextual language use, and abnormal vocalizations. According 
to the investigators, 5 of the 6 responders also showed signs of 
improvement in features of ADHD including inattention, lack of focus, 
impulsivity, and hyperactivity.
    Adverse events included polyuria, nausea, inattention and 
behavioral activation.\13\ According to the authors, the behavioral 
activation symptoms were transient or disappeared with dose reduction 
in 3 patients, but resulted in withdrawal from the study for 2 patients 
because of persistent symptoms.
    While the results of this retrospective evaluation were generally 
positive, randomized controlled studies are necessary to adequately 
evaluate the safety and efficacy of venlafaxine for autism spectrum 
disorders.

Pharmacokinetics
Venlafaxine IR
    The oral-clearance values (normalized for body weight) for 
venlafaxine IR were approximately 2.5-fold higher in children and 
adolescents with conduct disorder than in a historical control of 
healthy adult subjects who received similar mg/kg doses.\14\ It was 
calculated that children who received 3.3 mg/kg/day and adolescents who 
receive 2.8 mg/kg/day had plasma concentrations of venlafaxine and ODV 
similar to typical adult populations that received 150 mg 
(approximately 2.0 mg/kg/day).

Venlafaxine XR
    In an open-label, single-dose study, 18 subjects were enrolled to 
evaluate the pharmacokinetic profile of a single dose of venlafaxine XR 
in pediatric patients.\15\ There were 6 subjects each in 3 age groups 
(6-7 years, 8-11 years, and 12-17 years). The results of this study are 
similar to those reported above for venlafaxine IR. The single-dose 
clearance (normalized-body weight) of venlafaxine and ODV was 2.5-fold 
to 3.0-fold higher, and plasma concentrations lower, in children and 
adolescents compared to a historical control of adults who received the 
same mg/kg dose. It was calculated that children who receive 3.1 mg/kg 
and adolescents who receive 2.0 mg/kg would have plasma concentrations 
of venlafaxine and ODV similar to typical adult populations that 
received 150 mg.

Summary/Conclusion
    The efficacy of venlafaxine in children or adolescents less than 18 
years of age has not been established for any indication; therefore, we 
cannot recommend the use of venlafaxine in this patient 
population.\3\,\4\
    In depression studies, suicidal ideation and hostility were the 
most common reasons for discontinuation that occurred at a rate 1% and 
at least 2 times that for placebo.\5\,\6\
    Based on studies in MDD and GAD, the safety profile for venlafaxine 
in pediatric patients is generally similar to those described for adult 
patients; consequently, the contraindications, warnings and precautions 
for adults apply to pediatric patients (consult prescribing 
information).
    Preliminary investigations into the safety and/or efficacy of 
venlafaxine for various other disorders in children and adolescents 
have been reported.\12\,\13\,\15\ Larger 
randomized controlled trials are necessary to establish the safety and 
efficacy of venlafaxine in these populations.

                              References:

    1. Muth EA, Haskins JT, Moyer JA, Husbands GEM, Nielsen ST, Sigg 
EB. Antidepressant biochemical profile of the novel bicyclic compound 
Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol. 
1986;35:4493-4497.
    2. Muth EA, Moyer JA, Haskins JT, Andree TH, Husbands GEM. 
Biochemical, neurophysiological, and behavioral effects of Wy-45,233 
and other identified metabolites of the antidepressant venlafaxine. 
Drug Dev Res. 1991:23:191-199.
    3. Effexor '--current US prescribing information, Wyeth 
Pharmaceuticals.
    4. Effexor ' XR--current US prescribing information, 
Wyeth Pharmaceuticals.
    5. Data on file (Protocol 0600B1-382-US, CSR-43456, 2002), Wyeth 
Pharmaceuticals.
    6. Data on file (Protocol 0600B1-394-US, CSR-44693, 2002), Wyeth 
Pharmaceuticals.
    7. Khan A, Kunz NR, Nicolacopoulos E, Jenkins L, Yeung PP. 
Venlafaxine extended release for the treatment of children and 
adolescents with generalized anxiety disorder [poster]. American 
Psychiatric Association 2002 Annual Meeting, Philadelphia, 
Pennsylvania, May 2002.
    8. Data on file (Protocol 0600B2-397-US, CSR-44734, 2002), Wyeth 
Pharmaceuticals.
    9. Data on file (Protocol 0600B2-396-US, CSR-44723, 2002), Wyeth 
Pharmaceuticals.
    10. Data on file (Pediatric Integrated Summary of Safety), Wyeth 
Pharmaceuticals.
    11. Data on file (Protocol 0600B1-395-US, CSR-44610, 2002), Wyeth 
Pharmaceuticals.
    12. Olvera RL, Pliszka SR, Luh J, Tatum R. An open trial of 
venlafaxine in the treatment of attention-deficit/hyperactivity 
disorder in children and adolescents. J Child Adolesc Psychopharmacol. 
1996;6:241-250.
    13. Hollander E, Kaplan A, Cartwright C, Reichman D. Venlafaxine in 
children, adolescents, and young adults with autism spectrum disorders: 
An open retrospective clinical report. J Child Neurol. 2000;15:132-135.
    14. Data on file (Protocol 0600A-126-US, CSR-26710, 2002), Wyeth 
Pharmaceuticals.
    15. Data on file (Protocol 0600B1-169-US, CSR-44894, 2002), Wyeth 
Pharmaceuticals.
    16. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL. 
Venlafaxine in the treatment of children and adolescents with major 
depression. Psychopharmacol Bull. 1997;33:149-154.

    Mr. Walden. Thank you, Dr. Camardo.
    Dr. Olanoff, thanks for being here.

                TESTIMONY OF LAWRENCE S. OLANOFF

    Mr. Olanoff. Mr. Chairman, members of the subcommittee, I 
am Dr. Lawrence Olanoff, executive vice president of Forest 
Laboratories and head of the Forest Research Institute. I thank 
the subcommittee for the opportunity to discuss Forest's views 
on the issues presented in this hearing and in particular to 
describe our clinical trial registry.
    I am a medical doctor. My medical specialty is in clinical 
pharmacology, and I have devoted my entire career to the 
development of pharmaceuticals. The topic of today's hearing is 
the disclosure of clinical trial results. Forest routinely 
discloses the results of its sponsored clinical trials and 
believes its practices in this regard have been entirely 
appropriate and in full compliance with the law.
    We also recognize there is great interest in the results of 
clinical trials by the medical community, and we realize that 
new approaches are needed to provide physicians and patients 
with all available relevant efficacy and safety information in 
a timely manner. To this end, Forest has announced its 
commitment to make its clinical trial results publicly 
available on its web site. We have worked with staff of the 
committee, members of the industry and with the New York State 
attorney general in developing this approach. Our policy of 
disclosure is reflected in our recent agreement with the New 
York State attorney general. We are pleased with the result.
    On this registry, Forest will list key ongoing trials for 
its investigational products. If we are running a trial, the 
public will know. Forest will provide the results of phase 
three and four trials for its marketed products regardless of 
study outcome. When we have results for studies of new uses on 
products on the market, we will post those results on the web. 
This registry will include both results for studies going as 
far back as January 1, 2000 and safety information for even 
older studies where the information is important to the use of 
the product. As some physicians may find it cumbersome to 
research individual company web sites, Forest is also willing 
to support an industry-wide centralized registry.
    Let me now comment about depression in children and Forest 
actions following the completion of two placebo-controlled 
trials with Celexa, a drug approved for the treatment of adult 
depression. Depression, in particular depression in children, 
is a terrible and dangerous disease which inflicts pain, robs 
victims of their ability to enjoy their lives and presents a 
substantial risk of suicide. The loss of a child by suicide is 
an issue about which Forest and its most senior executives have 
painful and personal experience. Our personal experience has 
fueled our commitment to developing and providing the most 
effective possible treatments for this horrible disease. This 
is why Forest is continuing to study its antidepressants in 
children.
    Forest has indicated its serious intent to disclose the 
results of its clinical trials in a detailed and timely manner. 
This issue first arose due to questions regarding the past 
disclosure of pediatric depression trials by the industry. I 
would like to talk about two studies involving Forest's 
antidepressant product Celexa. Forest became aware of the 
results of a European Celexa pediatric depression trial 
sponsored by its licensor, Lundbeck, and the Forest-sponsored 
U.S. trial about the same time. The U.S. trial clearly showed 
that Celexa was superior to placebo treatment whereas the 
Lundbeck study did not show effectiveness for Celexa. The 
positive efficacy result achieved for the Forest-sponsored U.S. 
trial was a significant event. There were 15 placebo-controlled 
pediatric antidepressant trials reviewed by the FDA. Of these 
only three were positive, one of which was the U.S. study 
conducted by Forest with Celexa. It was the importance of the 
U.S. study outcome and our confidence in the results that led 
to its presentation and professional meetings and publication 
in the peer review journal. The Lundbeck study was 
substantially different in its design compared to the U.S. 
study, and its unique design features ultimately made it more 
difficult to fully assess the safety and effectiveness of the 
drug in this trial.
    Despite these differences, Forest determined there were no 
clinically relevant safety signals in the overall results, 
including any clinically important or statistically significant 
increase in suicide-related events. We presented all these data 
to the FDA, and the FDA reached the same conclusion in its 
review of our submission. The results of both studies were 
presented at a prestigious scientific meeting in 2003. Further 
details of these two studies are provided in my written 
statement, and the results of both studies will be posted on 
our clinical trial registry in early 2005.
    Mr. Chairman and members of the subcommittee, we at Forest 
have a deep commitment to doing what is best for patients, 
particularly children suffering from depression. Forest will 
continue to search for more effective ways to inform physicians 
about the clinical trial data on its products. Again, I thank 
the subcommittee for inviting me to speak, and I am happy to 
address any questions the subcommittee may have.
    [The prepared statement of Lawrence S. Olanoff follows:]

 Prepared Statement of Lawrence S. Olanoff, Executive Vice President, 
                       Forest Laboratories, Inc.

    Mr. Chairman and Members of the Subcommittee, I am Dr. Lawrence 
Olanoff. I am Executive Vice President of Forest Laboratories and head 
of the Forest Research Institute. On behalf of Forest, I would like to 
thank the Subcommittee for the opportunity to discuss our views on the 
issues presented in this hearing. Among other things, I will discuss 
our new Clinical Trial Registry.
    I am a medical doctor and I have trained as a clinical 
pharmacologist. I have chosen to devote my career to the development of 
human pharmaceuticals.
    Depression--and in particular depression in children and young 
people--is a terrible and dangerous disease. It is terrible in that it 
inflicts terrible pain and it robs victims of the ability to enjoy 
their lives. It is dangerous because it also presents a substantial 
risk of suicide. This is an issue about which Forest, and its most 
senior executives, have painful and personal experience. The book, THE 
NOONDAY DEMON, authored by Andrew Solomon, is a seminal study of 
depression and his own depression and in that book Andrew describes his 
own near suicide. That book won the National Book Award and is 
dedicated to his father, who helped to bring him back from the brink of 
suicide. Andrew's book is dedicated to his father and the dedication 
reads ``for my father who gave me life not once but twice''. Andrew's 
father is our Chairman and Chief Executive Officer, Howard Solomon. In 
the case of the two most senior executives responsible for the launch 
and marketing of Celexa ', an antidepressant marketed by us, 
their child's depression took an even greater toll. Both lost young 
sons to suicide. One is still a member of our Board and has retired 
from Forest and now devotes his time to a foundation started by him to 
prevent suicide among young people.
    So we at Forest know all too well that depression, without proper 
therapy, can be a devastating illness. I tell you about these personal 
experiences to emphasize our motivation at Forest. We strive to develop 
and provide the best possible treatment for this horrible disease. Our 
mission is to alleviate depression and thus help to prevent suicide.
    Forest is a medium size pharmaceutical company that primarily 
markets drugs in the United States. Also, unlike the larger 
pharmaceutical companies who are members of PhRMA, which we are not, we 
do not conduct drug discovery activities in-house, but license all our 
products from other companies, usually European companies which sell 
the same products in their own markets. Our licensors often have 
already completed some clinical studies before we license the drug and 
continue to do studies after we license the drug. In the case of 
Celexa, for example, the drug was already approved in Europe for six 
years when we first licensed it. We have also, in the case of most of 
the drugs we have licensed, performed the additional necessary 
development activities and clinical trials in the United States to 
obtain FDA approval of these products.
    The basis for a drug's evaluation are the clinical trials in which 
it is tested. A controlled clinical trial is a method for providing 
objective evidence about the safety and effectiveness of a drug. In a 
controlled clinical trial, subjects are divided into different test 
groups. Most commonly, one group will receive a placebo (a pill with no 
active drug), while another group will receive the test drug. We 
attempt to design these studies to assure, to the greatest extent 
possible, that the only thing that will cause a different result 
between the two groups is the drug itself. It is essential therefore 
that the patients in each study group be carefully balanced from the 
start in as many respects as possible to avoid distorted results. If, 
for example, one group included more patients with more severe illness, 
that might affect the results and make it difficult to know whether or 
not the drug itself was the cause of the study outcome or whether any 
observed differences arose simply because the study groups were 
different from the onset. Similar considerations apply in comparisons 
of the results across different clinical trials if there are different 
study designs and different patient populations. In addition, the terms 
that investigators use to describe adverse events and outcome measures 
may vary among different trials, particularly studies in different 
countries.
    I want to make one additional point about clinical trials of 
depression and many other psychiatric diseases where the endpoints are 
not objective measurements like blood pressure but more subjective in 
nature like, for example, mood. It is well known and accepted in the 
scientific community that there is typically a relatively high 
proportion of placebo-treated patients who respond favorably (also 
called a high placebo response rate) in these studies, particularly 
because in the environment of a clinical trial, as distinct from 
clinical practice, drug therapy is accompanied by greater attention to 
the patient by the investigator and his staff, especially where this 
was not part of the patient's experience before entering the study. 
This means that some patients may improve from their condition at the 
start of the study even though they are not receiving active drug 
treatment. The high placebo response rate can make demonstration of a 
therapeutic effect for the test drug difficult when the overall 
response difference between test groups is compared by statistical 
analysis. Dr. March, the author of the NIH supported Treatment for 
Adolescents with Depression Study (TADS), involving Eli Lilly's Prozac 
and described in the recent JAMA publication, comments in regards to 
other SSRI/SNRI pediatric depression studies that, ``In the 2 earlier 
fluoxetine studies, the placebo response rates were lower than placebo 
response rates seen in other pediatric antidepressant trials. Because 
the response to active drug was comparable, it was the placebo response 
rate that generally determined the effect size and hence whether a 
trial was positive or negative.'' Thus, in many cases studies of drugs 
intended for the treatment of depression fail to demonstrate a 
response: i.e., those studies are referred to as ``negative'' in the 
scientific literature, although they might be more logically termed 
``no-effect'' studies. In fact, the vast majority of these no-effect 
studies do show some modest advantage of the test drug compared to the 
placebo treatment. It is just that the difference between the groups 
fails to meet the required statistical hurdle that confirms that the 
benefit observed did not simply occur by chance. For the reasons I 
stated above, the attainment of a positive study is especially notable 
and this explains why it may take more than one study to achieve a 
study with a positive outcome. Of the 15 placebo controlled studies in 
pediatric depression submitted to the FDA, only 3 were considered 
positive: two fluoxetine studies (which led to the approval of Prozac 
for pediatric depression) and the Forest sponsored U.S. study with 
Celexa which is discussed below.
    It is clearly essential to determine whether drugs that are safe 
and effective for use in adults can also be appropriately used in 
children. This is an important inquiry, because children may be 
physiologically and psychologically different from adults and they 
therefore may react differently to drugs. The law therefore currently 
requires the conduct of pediatric studies where the indications sought 
for in adults may be applicable to the pediatric population.
    Forest supports the goals of the pediatric study law and FDA's 
implementation of that law with respect to antidepressant drugs. If a 
drug should not be used in children, doctors should know that. 
Conversely, if a drug can help some children suffering from depression, 
it would be a tragedy if doctors and patients were discouraged from its 
use in that population, condemning those children and their families to 
unnecessary misery and to a possibly preventable risk of suicide. This 
places a heavy responsibility on the FDA as it has in so many areas. In 
our experience we have found the FDA to be unbiased and expert.
    So far as we are aware, based on the data available to us and the 
complexity of the subject, we believe that FDA is trying to achieve the 
right result.
    I want to emphasize that, because the FDA has not approved 
pediatric labeling for our products, Forest has always been scrupulous 
about not promoting the pediatric use of our antidepressant drugs, 
Celexa and Lexapro '. That is the law, and we follow it.
    Prior to approval, companies are required to fully disclose the 
results of all studies related to the indication sought in the NDA to 
the FDA regardless of their outcome, and Forest has always done so. The 
FDA reviews those studies and decides what information is necessary in 
the package labeling which is the ultimate source of information for 
the physician. The FDA may approve a drug based on two positive studies 
even if there are negative or no-effect studies in the application, and 
it may or may not require mention of the no-effect studies in the label 
because, in large part, the scientific community has accepted that 
positive studies are generally more informative than no-effect studies. 
Companies frequently continue to develop drugs despite no-effect 
studies; the FDA approves drugs even when there are no-effect studies; 
and journals will often reject no-effect studies for publication.
    That brings us to the question of publication and disclosure of the 
results of clinical trials, both those that show a positive effect and 
those that fail to detect a positive effect. Aside from the review by 
the FDA itself, perhaps the most objective review of a pharmaceutical 
company's clinical studies is the peer review system of prestigious 
medical journals. It is our experience that journals publish only a 
small portion of the studies conducted or submitted to their editors, 
and that they are usually interested in reporting positive studies and 
are often not interested in publishing studies which are not positive. 
Positive studies may be breakthrough studies; they are likely to be of 
greater interest to physicians. No-effect or negative studies, 
particularly if there are a number of known prior such studies in the 
same drug category, are often considered of less interest to their 
physician audience. That is certainly not always the case, but it is 
understandable that medical journals, like the media in general, want 
to publish what they believe their readers would be most interested in.
    The next question relates to studies for new therapeutic uses 
completed after the FDA has initially approved the drug for a 
particular indication. There is no established procedure for disclosure 
of such study results. The general principle observed by Forest is that 
information that better enables physicians to treat their patients 
should be available to them.
    Recently much public attention has been directed towards approaches 
to achieve the timely and full disclosure of all clinical study results 
for approved and unapproved uses of marketed products. Many have 
recognized that scientific publications alone cannot serve as the sole 
vehicle for this purpose for the reasons I have cited above.
    Forest has focused on this complicated issue and announced this 
week the development of detailed procedures to assure that all results 
of Phase III and IV trials are reported in a Clinical Trial Registry. 
Forest's Clinical Trial Registry will contain the following 
information:

Ongoing Studies
    Forest's Clinical Trial Registry will include a listing of Forest-
sponsored ongoing phase III and phase IV clinical studies for all 
Forest drugs. In particular, when Forest initiates a Phase III or Phase 
IV clinical study, the number, title, start date and key objectives 
will be posted to the Clinical Trial Registry.

Completed Studies
    For all phase III and phase IV Forest-sponsored studies relating to 
currently-marketed Forest products completed since January 1, 2000, 
Forest will by December 31, 2005 post summaries of the results of these 
studies on the Clinical Trial Registry. This will include summaries of 
clinical study reports for clinical studies of the use of Celexa and 
Lexapro by pediatric patients. These summaries will include results for 
the protocol-defined efficacy and safety outcomes, as well as a 
description of the trial design and methodology.
    For all phase III studies relating to Forest products completed 
after today, Forest will post summaries of the results on the Clinical 
Trial Registry upon the commercial introduction of the product in the 
United States. For phase IV trials conducted for the approved 
indications completed after today, Forest will post summaries of the 
results within a year of study completion.
    For studies submitted to scientific peer-reviewed journals whose 
policies do not permit disclosure of study results prior to publication 
in these journals, the clinical study summary will be posted at the 
time of publication. Also, Forest will post a summary on the Clinical 
Trial Registry of: (a) those Forest-sponsored phase I and phase II 
studies completed after January 1, 2000 for products which Forest 
currently markets, and (b) those Forest-sponsored studies completed 
prior to January 1, 2000 for products which Forest currently actively 
promotes, which provide additional important information for physicians 
and the care of patients.
    In addition to our own activities in this regard, Forest will 
participate in and be guided by any industry, legislative, regulatory 
or medical association initiatives to facilitate this effort.
    Now that I have provided the details of our recently announced 
Clinical Trial Registry, I want to comment on Forest's past practices 
in disclosing clinical trial results by referring to our three 
principal products. The first is Namenda, our recently approved drug 
for the treatment of moderate-to-severe Alzheimer's disease. The 
product was approved in October, 2003. We have released information on 
four placebo controlled studies relating to unapproved uses, in each 
case promptly after we received the study results as these results were 
judged to be material to investors. In the case of use of this drug in 
the treatment of patients with mild-to-moderate Alzheimer's disease, we 
disclosed that one study was positive and that two studies (one of 
which was performed by a European licensee) showed no effect. We hope 
to ultimately obtain FDA approval for Namenda in the treatment of mild-
to-moderate Alzheimer's disease. The other study related to use of the 
active ingredient in Namenda in the treatment of neuropathic pain and 
it also failed to meet the FDA standard for approval even though an 
earlier study had shown promising results. Again, we promptly disclosed 
these results. We are continuing to study the drug for that indication 
and likewise ultimately hope to be able to meet FDA requirements for 
that indication.
    The second drug is Celexa, which was approved for depression in 
adults in the U.S. in 1998 and which had been first approved in Europe 
as early as 1989. For this product there are two placebo controlled 
studies in pediatric-adolescent population. One was a study conducted 
by our licensor in Europe over a five year period which recruited 
patients from seven different countries and underwent various 
modifications in the test protocol over the course of the study in an 
attempt to improve its slow enrollment rate. We did not originate, 
design or monitor that study. This study included patients with 
characteristics that we and other sponsors would not use in our studies 
of depression and which we believe caused a substantial degree of 
patient variability and potentially important differences in disease 
severity between the active and placebo group from the very start of 
the study. Specifically, the European study allowed for the enrollment 
of patients without regards to a past history of hospitalization due to 
psychiatric illnesses, past history of suicide related events or a 
history of a failure to respond to other antidepressants.
    Further, patients were allowed to enter into the study with other 
co-morbid psychiatric illnesses or on other concomitant psychotropic 
medications or receiving psychotherapy. This study was unique across 
the experience of placebo-controlled pediatric trials in that it 
allowed both hospitalized patients and outpatients to be enrolled. In 
fact, a third of the patients enrolled had a past history of suicide 
related events and the patients in the Celexa group had a higher rate 
of previous psychiatric hospitalizations and a greater number of the 
Celexa treated patients were hospitalized due to psychiatric illnesses 
at the start of the study compared to the placebo group. These design 
features and potential imbalances between groups make it very difficult 
to interpret any resultant differences in the incidence of relatively 
infrequent events such as suicidal ideation or behavior as related to a 
particular treatment assignment. Finally, this study did not 
demonstrate effectiveness of Celexa for pediatric use which we believe 
was due largely to a high placebo response rate, amounting to some 60% 
of the placebo treated patients.
    The second trial was a well-controlled study, designed and 
monitored by Forest in the United States with investigators and trial 
centers determined by us, which did demonstrate the efficacy of Celexa 
for pediatric patients. In contrast to the European study, the U.S. 
Celexa study was more typical of other pediatric depression studies in 
that it enrolled only outpatients, did not allow patients to enter with 
a history of suicidal behavior or treatment resistance, did not allow 
for concurrent psychotherapy and was far more restrictive in the use of 
concomitant psychotropic drugs or the presence of comorbid psychiatric 
illnesses. We felt that this study was important to the medical 
community as it was the first and only positive study after a string of 
no-effect studies for all the other modern antidepressants except for 
two previous positive studies for fluoxetine, which has been approved 
for the treatment of pediatric depression. When we first unblinded 
these Celexa studies in 2001, we looked carefully at all the safety 
data combined across the two studies. We did not see in these results 
any evidence of a statistically significant or clinically relevant 
increase in suicide related events (SREs). We fully reported what we 
believed to be suicide related events under appropriate adverse event 
descriptive terms in our submission to the FDA in 2002 and the FDA in 
its review of our submission, while not granting approval for a 
pediatric indication, did conclude that there were no new safety issues 
identified in this population which would require labeling. When this 
issue was raised again in 2003 due to potential concerns over the SSRI/
SNRI class as a whole, we reviewed our entire pediatric safety database 
for any SREs using the FDA's provided algorithm. Our conclusion and the 
conclusion of the FDA in early 2004, as reflected in the August 16, 
2004 memo by Dr. Mosholder, of the FDA, was that the difference between 
the citalopram and placebo groups in the incidence of SREs was 
relatively small (risk ratio of approximately 1.4) and not 
statistically significant. The FDA conducted a new analysis in August 
based on a reclassification of SREs by experts at Columbia University. 
After their elimination of questionable cases, this reclassification 
reduced the number of SREs by some 40% for the citalopram group 
compared to our own earlier classification. This reclassification led 
to a new FDA calculated risk ratio of 1.37, also not statistically 
significant and the lowest of all the risk ratios among the SRI/SNRIs 
except for Prozac. After adding to this overall Celexa database, the 
safety experience from the Forest-sponsored and the only pediatric 
placebo-controlled trial with Lexapro (escitalopram, which is the 
therapeutically active enantiomer of citalopram), this risk ratio would 
be reduced to approximately 1.2. The Lexapro trial is relevant as it 
was conducted in the U.S. according to a protocol design very similar 
to that of the earlier U.S. pediatric trial for Celexa. When these two 
U.S. studies are taken together, and separate from the European Celexa 
trial, the risk of suicide related events is actually two-fold higher 
in the placebo group compared to these two related SSRIs; however, the 
numbers of events in these U.S. trials were too low to demonstrate any 
statistical differences.
    As I have previously indicated, these two U.S. trials are in 
substantial contrast by design to the European trial where event rates 
were higher in both treatment groups. As stated by the FDA medical 
reviewer, Dr. Hammad in his review of August 16, 2004, in describing 
the U.S. and European Celexa trials, ``These two Celexa trials varied 
in almost every aspect. The combination of the differences might have 
led to higher probability of having higher risk patients in trial 
94404.''
    Forest conducted further analyses to attempt to better understand 
why certain patients in the Celexa trials experienced SREs. The 
analyses revealed that such patients generally experienced numerous 
antecedent psychosocial stress factors and as a group responded 
substantially less well to treatment, whether they were treated with 
placebo or active drug, compared to the patients who did not experience 
SREs.
    It was these psychosocial factors and the lack of therapeutic 
response that appeared to better predict whether a given patient would 
experience an SRE, rather than their drug or placebo treatment 
assignment or any prior activation-like side effects.
    Dr. March in his recent publication of the TADS results makes the 
same observation of the patients who experienced what he described as 
``harm-related adverse events'' which included suicide related adverse 
events. Dr. March states that, ``Incident narratives indicate that 
irritability, agitation/ restlessness, and anxiety were not commonly 
reported in association with harm-related adverse events, suggesting 
that other factors, such as substance use and psychosocial stressors, 
may be more important in mediating the risk of harm-related adverse 
events.''
    Both Celexa studies were completed at virtually the same time, 
despite the fact that the European study was started four years before 
our study. In fact, the results of both studies were obtained shortly 
before we terminated virtually all promotion of Celexa for any use. We 
stopped promoting Celexa because we had obtained approval for Lexapro, 
a more potent antidepressant which we considered a superior product. 
However, the fact that we had a successful study demonstrating efficacy 
in a pediatric population, after there have been so many no-effect 
studies for so many other similar antidepressant products was important 
and something the study investigators felt should be made available to 
the medical profession. This study was therefore presented at several 
scientific meetings and accepted by and published in a prominent peer 
reviewed journal in June, 2004. The no-effect or negative European 
study results were not hidden by us and were available in several 
sources including a 2003 presentation at a prestigious meeting of 
psychiatrists specializing in the care of pediatric and adolescent 
patients, at which the safety and efficacy findings of both studies 
were described.
    The final example is Lexapro, the antidepressant drug that Forest 
is currently promoting. We performed a clinical trial of this drug in a 
pediatric population and that trial failed to show a statistically 
significant therapeutic effect but did not demonstrate any safety 
issues for Lexapro in these pediatric patients. We promptly issued a 
press release disclosing the results of that study. Based on our 
overall analysis of the study results we are continuing to study 
Lexapro for that indication. That press release also discussed the 
positive and no-effect trials of Celexa.
    We understand that there is great interest in the issue of 
disclosure of the results of clinical trials. With respect to Forest, 
we believe we have consistently acted appropriately and in compliance 
with all legal and regulatory requirements when informing physicians 
about out products. As I stated earlier, we are prepared to put into 
effect a publicly accessible clinical trial registry to facilitate the 
timely disclosure of our phase III and IV clinical study results for 
our marketed products.
    We at Forest have a deep--and deeply personal--commitment to doing 
what is best for patients, and particularly children suffering from 
depression. Our mission is to help heal and treat young people. Forest 
will continue to search for more effective ways to inform physicians 
about clinical trial data on its products. I look forward to today's 
discussion of these important issues.

    Mr. Walden. Thank you, Doctor.
    Dr. Marcus.

                  TESTIMONY OF RONALD N. MARCUS

    Mr. Marcus. Good afternoon, Mr. Chairman and members of the 
subcommittee. My name is Dr. Ron Marcus, and I am the executive 
director of Neuroscience Global Clinical Research at the 
Bristol-Myers Squibb Pharmaceutical Research Institute. I am 
also a board certified psychiatrist. Today, I am representing 
my company to briefly describe our efforts to responsibly 
report the results of pediatric clinical trials involving our 
antidepressant, nefazodone, which is also known by its branded 
commercial name, Serzone.
    Serzone was approved almost 10 years ago by FDA. Upon 
approval, FDA requested the Bristol-Myers Squibb conduct 
studies to evaluate the use of Serzone in children and 
adolescents with depression. In response to this request, 
Bristol-Myers Squibb initiated two pediatric clinical studies 
involving Serzone. One was a pharmacokinetic and safety study 
in children and adolescents, and the other was an efficacy and 
safety study in adolescents. Additionally, in 1999, FDA issued 
a written request for pediatric studies with Serzone. In 
response to this request, Bristol-Myers Squibb initiated a 
third post-approval study, one that examined Serzone's efficacy 
and safety in pediatric patients.
    Bristol-Myers Squibb fulfilled its commitment to FDA and 
completed all three pediatric trials of Serzone. Each of these 
studies was carefully designed and the protocols were reviewed 
by FDA. The results of the three studies were disclosed in a 
manner that would appropriately inform the psychiatric 
community of the studies' results. Specifically, the results of 
the pharmacokinetic study in children and adolescents were 
published in the well-respected journal of the American Academy 
of Child and Adolescent Psychiatry. The results of our efficacy 
and safety study in adolescents were presented in scientific 
posters at the annual meeting of the American Psychiatric 
Association, the premier psychiatric conference in this 
country, as well as the New Clinical Drug Evaluation Unit 
conference, otherwise known as NCDEU. Finally, the results of 
our third study that looked at Serzone's efficacy and safety in 
pediatric patients were included in the posters detailing the 
adolescent study presented at the APA and NCDEU meetings.
    Bristol-Myers Squibb also submitted the clinical trial 
results to FDA. After reviewing the clinical trial data, FDA 
advised the company that the safety and efficacy of Serzone in 
individuals below 18 years of age had not been established 
through the clinical trials. The Serzone product label 
specifically states that the safety and effectiveness in 
individuals below 18 years of age have not been established.
    Bristol-Myers Squibb is committed to the principle that 
clinical trial results that could have a bearing on patient 
care and treatment should be made available to physicians 
making medical decisions regarding the use of our medicines. 
Our commitment to this principle was most recently highlighted 
by a response to results of the TIMI-22, or PROVE-IT trial. The 
trial demonstrated that patients with a recent acute coronary 
syndrome benefited significantly when treated with an intensive 
statin regimen using high doses of a competitor's drug when 
compared to a regiment using standard doses of Bristol-Myers 
Squibb's statin drug. Clearly, the results could be interpreted 
as favoring the competitor's product, but because the study 
data could have an immediate impact on patient care, we worked 
closely with the investigators to ensure that the presentation 
and publication of the data were achieved in the shortest 
possible time.
    Consistent with our company's commitment to the principle 
of disclosure described above, we support the PhRMA principles 
on the conduct of clinical trials and disclosure of results. 
Further, we are in the process of developing a mechanism for 
making these clinical results publicly available. In addition, 
Bristol-Myers Squibb also registers clinical trials on 
www.clinicaltrials.gov for life-threatening or serious 
diseases.
    Regarding Serzone, clearly, our company disclosed the 
results of our pediatric trials in an appropriate manner, and 
Serzone's label continues to provide a warning to physicians 
regarding Serzone's use with pediatric patients. Beyond 
Serzone, Bristol-Myers Squibb is absolutely committed to open 
and timely reporting of clinical trial results of our medicines 
when the welfare of patients could be affected. As demonstrated 
by the company's approach to the TIMI-22 trial on statin drugs, 
BMS will openly disclose important data, regardless of result, 
that can have a real impact on patient care.
    Thank you for the opportunity to testify on this important 
issue, and I will be happy to answer any of your questions.
    [The prepared statement of Ronald N. Marcus follows:]

      Prepared Statement of Ronald N. Marcus, Executive Director, 
   Neuroscience Global Clinical Development, Pharmaceutical Research 
                Institute, Bristol-Myers Squibb Company

    Good morning Mr. Chairman and members of the Subcommittee on 
Oversight and Investigations.
    My name is Dr. Ron Marcus, and I am an executive director of 
neuroscience global clinical development at the Bristol-Myers Squibb 
Company's Pharmaceutical Research Institute. I am also a board 
certified clinical psychiatrist. Today, I am here representing my 
company to briefly describe our efforts to responsibly report the 
results of pediatric clinical trials involving our anti-depressant 
nefazodone, which is also known by its branded commercial name--
Serzone.
    Serzone was approved almost ten years ago by the FDA. Upon 
approval, FDA requested that Bristol-Myers Squibb conduct studies to 
evaluate the use of nefazodone in children and adolescents with 
depression. In response to this request Bristol-Myers Squibb, initiated 
two pediatric clinical studies involving Serzone. One was a 
pharmacokinetic and safety study in children and adolescents, and the 
other was an efficacy and safety study in adolescents. Additionally, in 
1999 FDA issued a Written Request for pediatric studies with Serzone. 
In response to this request, Bristol-Myers Squibb initiated a third 
post-approval study--one that examined Serzone's efficacy and safety in 
pediatric patients.
    Bristol-Myers Squibb fulfilled its commitment to the FDA and 
completed all three pediatric studies of Serzone. Each of these studies 
was carefully designed and their protocols were reviewed by the FDA.
    The results of the three studies were disclosed in a manner that 
would appropriately inform the psychiatric community of the studies' 
results. Specifically, the results of the pharmacokinetic study in 
children and adolescents were published in the well-respected Journal 
of the American Academy of Child Adolescent Psychiatry. The results of 
our efficacy and safety study in adolescents were presented in 
scientific posters at the Annual Meeting of the American Psychiatric 
Association--the premier psychiatric conference in this country, as 
well as at the New Clinical Drug Evaluation Unit conference. Finally, 
the results of our third study that looked at Serzone's efficacy and 
safety in pediatric patients were included in the posters detailing the 
adolescent study presented at the APA meeting.
    Bristol-Myers Squibb also submitted the clinical trial results to 
the FDA. After reviewing the clinical trial data, the FDA advised the 
company that the safety and efficacy of Serzone in individuals below 18 
years of age had not been established through the clinical trials. The 
Serzone product label expressly states that the ``safety and 
effectiveness in individuals below 18 years of age have not been 
established.''
    Bristol-Myers Squibb Company is committed to the principle that 
clinical trial results that could have a bearing on patient care and 
treatment should be made available to physicians making medical 
decisions regarding the use of our medicines. Our commitment to this 
principle was most recently highlighted by our response to the results 
of the TIMI-22, or ``PROVE-IT,'' trial. The trial demonstrated that 
patients with a recent acute coronary syndrome benefited significantly 
when treated with an intensive statin regimen using high doses of a 
competitor's drug when compared to a regimen using standard doses of--
Bristol-Myers Squibb's statin drug. Clearly, the results could be 
interpreted as favoring the competitor's product. But because the study 
data could have an immediate impact on patient care, we worked closely 
with the investigators to ensure that presentation and publication of 
the data were achieved in the shortest possible time.
    Consistent with our company's commitment to the principle of 
disclosure described above, we support the PhRMA Principles on the 
Conduct of Clinical Trials and Disclosure of Results. Further, we are 
in the process of developing a mechanism for making these clinical 
results publicly available. Bristol-Myers Squibb also registers 
clinical trials on www.clinicaltrials.gov for life-threatening or 
serious diseases.
    Regarding Serzone, clearly our company disclosed the results of 
pediatric trials in an appropriate manner, and Serzone's label 
continues to provide a warning to physicians regarding Serzone's use 
with pediatric patients.
    Beyond Serzone, Bristol-Myers Squibb's is absolutely committed to 
open and timely reporting of clinical trial results of our medicines 
when the welfare of patients could be affected. As demonstrated by the 
company's approach to the TIMI-22 trial on statin drugs, Bristol-Myers 
Squibb will openly disclose important data, regardless of result, that 
could have a real impact on patient care.1
---------------------------------------------------------------------------
    \1\ In a letter dated March 24, 2004, the Committee on Energy and 
Commerce requested data and background information from BMS from any 
published and unpublished nefazodone clinical trials involving 
depressed children. On April 12, 2004, BMS submitted the requested data 
and background information; a copy of that submission (without 
attachments) is provided as Attachment A.
---------------------------------------------------------------------------
                         ADDITIONAL BACKGROUND

1 OVERVIEW OF THE NEFAZODONE PEDIATRIC STUDIES
    On December 22, 1994, FDA approved Serzone ' (nefazodone 
hydrochloride) with a post-approval commitment to conduct studies to 
evaluate the use of nefazodone in children and adolescents with 
depression. In response to this commitment and a written Request for 
pediatric studies with Serzone issued by FDA in 1999, BMS has conducted 
three nefazodone pediatric studies: CN104-136, CN104-141 and CN104-187.

Study CN104-136: ``An Open Label Pharmacokinetic Trial of Nefazodone in 
        Depressed Children and Adolescents''
    CN104-136 was a trial designed primarily for the evaluation of 
pharmacokinetics and the assessment of safety and tolerability in 
children and adolescents; it is uninformative on the evaluation of 
efficacy because it is an open-label, uncontrolled trial (i.e., no 
placebo or comparator arms). BMS submitted the Final Study Report for 
the Acute Phase to FDA on August 21, 1997; the results were presented 
at the Annual Meeting of the American Academy of Child and Adolescent 
Psychiatry in October, 1997. The Final Study Report for the Extension 
Phase was submitted to FDA on January 20, 1999; these results were 
published in August, 2000. Findling R.L., Preskorn S.H., Marcus R.N., 
et al., Nefazodone pharmacokinetics in depressed children and 
adolescents, J. American Academy Child Adolescent Psychiatry 2000; 
39;1008-16.

Study CN104-141: ``A Multicenter, Double-Blind, Placebo-Controlled 
        Trial of Nefazodone in Depressed Adolescents''
    CN104-141 was a double-blind, placebo-controlled trial involving 
only adolescents designed primarily for the evaluation of efficacy and 
safety in pediatric patients. The Final Study Report of the Acute Phase 
and the Ongoing Study Report of the Extension Phase were submitted to 
FDA on April 16, 2002. The study results were presented in a poster at 
the Annual Meeting of the American Psychiatric Association, the premier 
psychiatric conference, on May 20, 2002. M.A. Rynn, R.L. Findling, G.J. 
Emslie, R.N. Marcus, L.A. Fernandes, M.F. D'Amico, S.A. Hardy, Efficacy 
and Safety of Nefazodone in Adolescents with MDD. The study results 
were also presented in a poster at the New Clinical Drug Evaluation 
Unit conference on June 12, 2002. G.J. Emslie, R.L. Findling, M.A. 
Rynn, R.N. Marcus, L.A. Fernandes, M.F. D'Amico, S.A. Hardy, Efficacy 
and Safety of Nefazodone in the Treatment of Adolescents with Major 
Depressive Disorder.

Study CN104-187: ``A Multicenter, Double-Blind, Placebo-Controlled 
        Trial of Two Dose Ranges of Nefazodone in the Treatment of 
        Children with a Major Depressive Episode''
    CN104-187 was a double-blind, placebo-controlled trial involving 
children and adolescents designed primarily for the evaluation of 
efficacy and safety in pediatric patients. BMS submitted to FDA the 
Final Study Report of the Acute Phase and the Ongoing Study Report of 
the Extension Phase on April 16, 2002. While the results of the study 
were not formally presented nor published, the two posters for CN104-
141 stated: ``In a second depression trial in pediatric patients (aged 
7-17), nefazodone did not differentiate from placebo.'' BMS submitted 
to FDA the Final Study Report of the Extension Phase on September 3, 
2004.

2 ADVERSE EVENTS IN THE PEDIATRIC STUDIES

Adverse Events Concerning Worsening Depression, Suicidal Ideation, and 
        Rate of Self-Injury
    The risk of worsening depression, suicidal ideation, and rate of 
self-injury can only, truly, be assessed in the double-blind, placebo-
controlled efficacy studies, such as CN104-141 and CN104-187. BMS 
assessed these risks through the tabulation of adverse events and an 
analysis of a CDRS-R item related to suicidal ideation.
    A review of patient-reported adverse events in the short-term and 
long-term phases of CN104-141 and CN104-187 was done to evaluate the 
incidence of worsening depression. Altogether there were two reports of 
worsening depression in the nefazodone group and no reports in the 
placebo group, on therapy, in the short-term phase of the efficacy 
studies; this finding was not statistically significant and therefore 
did not provide evidence that there is an increased risk of depression 
with short-term use of nefazodone. In the long-term phase of CN104-141, 
there was one patient with worsening depression in the placebo group 
and no patients in the nefazodone group.
    The risk of worsening suicidal ideation was assessed by evaluating 
the incidence of patients with a baseline score of 1 or 2 on item 13 of 
the CDRS-R (Suicidal Ideation) that increased to a score of 3 or 
higher. The results of this analysis show no statistical difference in 
the incidence of worsening suicidal ideation between nefazodone-treated 
patients and placebo-treated patients in the short-term phases of 
CN104-141 and CN104-187. In the long-term phase of CN104-141, no 
patients on either nefazodone or placebo had worsening suicidal 
ideation as assessed on item 13 of the CDRS-R.
    BMS received a number of requests from FDA beginning on July 2, 
2003 for data and information on nefazodone and suicidality in 
pediatric patients. In response to those requests, BMS has made four 
submissions to FDA. The review revealed that no suicides occurred in 
either study. Two nefazodone patients and no placebo patients had on-
therapy suicide-related or self-injury events during the short-term 
phase of the study. One nefazodone patient had self-injurious behavior 
(minor self-mutilation), during the screening phase, prior to dosing. 
There were no statistically significant differences between nefazodone 
and placebo on the incidence of suicidal-related adverse events.

3 COMMUNICATIONS WITH FDA
    As discussed above, BMS conducted nefazodone pediatric studies in 
response to a request from FDA. BMS submitted to FDA the Final Study 
Reports for CN104-136 on August 21, 1997, and January 20, 1999. BMS 
submitted to FDA the Final Study Reports for the Acute Phases and the 
Ongoing Study Reports of the Extension Phases for CN104-141 and CN104-
187 on April 16, 2002. Based upon the results of these studies, FDA 
told BMS that nefazodone is not indicated for use in pediatric patients 
and the product label specifically notes that the safety and efficacy 
in individuals below 18 years of age has not been established.
    Thank you for the opportunity to testify on this important issue 
this morning.

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    Mr. Walden. Thank you, Dr. Marcus.
    Mr. Osinsky.

                 TESTIMONY OF PATRICK J. OSINSKY

    Mr. Osinsky. Good afternoon, Congressman Walden, 
Congresswoman DeGette and members of the subcommittee. I am 
Patrick J. Osinsky, vice president and general counsel of 
Organon USA, Inc., on whose behalf I appear before you today.
    At the outset, Organon would like to thank the subcommittee 
for inviting us to participate in today's hearing. Organon 
shares the subcommittee's concern about the safety of 
antidepressants in children. In response to the subcommittee's 
letter of March 24, Organon compiled data and other information 
about clinical trials involving the use of Organon's Remeron, 
mirtazapine tablets, for the treatment of major depressive 
order in children.
    On April 14, Organon submitted this information to the 
subcommittee and updated it on July 16. The following is a 
brief summary of that information. Organon conducted two 
studies, both of which were subsequently submitted to FDA on 
May 1, 2001 as part of Organon's supplemental new drug 
application for pediatric exclusivity of Remeron tablets. One 
of these two studies was a safety and efficacy study of the use 
of Remeron for the treatment of depression in pediatric 
patients. In terms of safety, the conclusion was that Remeron 
was well tolerated and safe. In terms of efficacy, however, 
there was no statistically significant difference detected 
between the placebo and treatment groups. That study was the 
subject of two presentations, one made in September of 2001 in 
Pittsburgh at a consortium entitled, ``Pharmacological Update 
in Children and Adolescents,'' and one made at a symposium held 
at American Academy of Child and Adolescent Psychiatry 
Conference in October 2001.
    The second study that Organon sponsored and submitted to 
FDA as part of its supplemental NDA was a pharmacokinetic 
study. The conclusion of that study was that Remeron was 
relatively well tolerated and safe. That study was the subject 
of a manuscript, portions of which were presented at a March 
2002 annual meeting of the American Society of Clinical 
Pharmacology and Therapeutics in an abstract entitled, ``Single 
Dose Pharmacokinetics and Mirtazapine and Demethyl Metabolite 
in Depressed Children and Adolescents,'' which was published in 
a 2002 issue of Clinical Pharmacology Therapeutics. A summary 
of the PK study was also disseminated as part of a poster 
session at the October 2001 American Academy of Child and 
Adolescent Psychiatry Conference and subsequently included in 
the compilation of conference materials.
    Grants were provided for two additional studies conducted 
on the use of Remeron in children. The first was an open label 
study that was conducted in Finland to evaluate the 
antidepressant efficacy and safety of Remeron in adolescents 
suffering from major depression. Based on the results of that 
study, it was concluded that Remeron may be a safe and 
effective treatment for major depression adolescents. This 
study is the subject of an article entitled, ``Mirtazapine in 
the Treatment of Adolescents with Major Depression,'' in an 
open label multicenter pilot study, which is expected to be 
published in the third week of this month in the Journal of 
Child and Adolescents Psychopharmacology.
    The study subject to a grant was a study on the safety and 
efficacy of Remeron for the treatment of social phobia in 
children. The conclusion of that study was that Remeron was 
associated with significant improvement in social phobia and 
was well tolerated. This study was the subject of an abstract 
provided at two separate conferences: The Society of Biological 
Psychiatry in May 2003 and the New Clinical Drug Evaluation 
Unit, a scientific conference sponsored by the National 
Institute of Mental Health in June 2003.
    And, finally, Organon is aware of one additional study in 
pediatric patients. That study, though neither sponsored nor 
funded by the company, was the subject of an abstract at the 
21st CINP Congress in Glasgow, Scotland in 1992. That abstract 
states that significant improvements of depressive symptoms on 
nine of the DSM-4 criteria were found with no serious adverse 
effects being reported. This then is a brief summary of the 
information that Organon has concerning studies on the use of 
Remeron in children for the treatment of major depressive 
disorders. Each of the studies was discussed in varying detail 
at scientific and professional meetings and published in 
scientific journals in either abstract or full manuscript form.
    On behalf of Organon, I thank you again for the opportunity 
to be here this afternoon. Organon looks forward to continuing 
to work with you and to provide you with any additional 
information that you might require.
    [The prepared statement of Patrick J. Osinsky follows:]

Prepared Statement of Patrick J. Osinski, on Behalf of Organon USA Inc.

    Good morning Congressman Walden, Ranking Minority Member Deutsch, 
and Members of the Subcommittee. I am Patrick J. Osinski, Vice 
President and General Counsel of Organon USA Inc. (``Organon''). I 
appear before you today on behalf of Organon, in connection with the 
Subcommittee's inquiry concerning the publication and disclosure of 
studies related to the safety of anti-depressants in children.
    At the outset, Organon would like to thank the Subcommittee for 
inviting us to participate in today's hearing. Organon shares the 
Subcommittee's concern about the safety of antidepressants in children.
    By letter dated March 24, 2004, the Subcommittee requested that 
Organon provide it with data and other information of published and 
unpublished clinical trials involving the use of Organon's prescription 
drug product, Remeron ' (mirtazapine) Tablets, for the 
treatment of major depressive disorder in children. In response to the 
Subcommittee's request, on April 14, 2004, Organon compiled and 
submitted this information, which was updated on July 16, 2004. The 
following is a summary of that information.
    Organon conducted two studies--both of which were subsequently 
submitted to FDA on May 1, 2001, as part of Organon's submission of a 
supplemental New Drug Application (sNDA) for pediatric exclusivity of 
Remeron ' Tablets. Neither of these studies raised any 
safety concerns, though it was determined that no efficacy was 
indicated in either trial.
    One of these two studies was a safety and efficacy study of the use 
of Remeron ' for the treatment of depression in pediatric 
patients. In terms of safety, the conclusion was that Remeron 
' was well-tolerated and safe. In terms of efficacy, 
however, there was no statistically significant difference detected 
between the placebo and treatment groups. That study was the subject of 
two oral presentations with slides, one made in September 2001 in 
Pittsburgh, Pennsylvania at a consortium entitled ``Pharmacological 
Update in Children and Adolescents'' and one made at a symposium held 
at an American Academy of Child and Adolescent Psychiatry Conference in 
October 2001.
    The second study that Organon sponsored and submitted to FDA as 
part of its May 2001 sNDA was a pharmacokinetic, or PK, study. The 
conclusion of that study was that Remeron ' was relatively 
well-tolerated and safe. That study was the subject of a manuscript, 
portions of which were presented at a March 2002 annual meeting of the 
American Society of Clinical Pharmacology & Therapeutics, and an 
abstract entitled, ``Single-Dose Pharmacokinetics (PK) of Mirtazapine 
(M) and its Demethyl Metabolite (MET) in Depressed Children and 
Adolescents,'' which was published in a 2002 issue of Clinical 
Pharmacology Therapeutics. A summary of the PK study was also 
disseminated as part of a poster session at the October 2001 American 
Academy of Child and Adolescent Psychiatry Conference, and subsequently 
included in a compilation of Conference materials prepared by the 
Academy.
    Grants were provided for two additional studies conducted on the 
use of Remeron ' in children.
    The first was an open label study that was conducted in Finland to 
evaluate the antidepressant efficacy and safety of Remeron ' 
in adolescents suffering from major depression. Based on the results of 
that study, it was concluded that Remeron ' may be a safe 
and effective treatment for major depression in adolescents. This study 
is the subject of an article entitled ``Mirtazapine in the Treatment of 
Adolescents with Major Depression: An Open-Label, Multicenter Pilot 
Study,'' which is expected to be published in September 2004 in the 
Journal of Child and Adolescent Psycho-pharmacology.
    The second study subject to a grant was a study on the efficacy and 
safety of Remeron ' for the treatment of social phobia in 
children. The conclusion of that study was that treatment with Remeron 
' was associated with significant improvement in social 
phobia and was well-tolerated. This study was the subject of an 
abstract provided at two separate conferences--the Society of 
Biological Psychiatry in May 2003 and the New Clinical Drug Evaluation 
Unit--a scientific conference sponsored by the National Institute of 
Mental Health--in June 2003.
    And finally Organon is aware of one additional study in pediatric 
patients. That study, though neither sponsored nor funded by the 
Company, was the subject of an abstract at the 21st CINP Congress in 
Glasgow, Scotland in 1998. The abstract states that significant 
improvements of depressive symptoms on 9 of the DSM IV criteria were 
found with no serious adverse effects being reported.
    This, then, is a brief summary of the information that Organon has 
concerning studies on the use of Remeron ' in children for 
the treatment of major depressive disorder. Each of the studies was 
discussed in varying detail at scientific and professional meetings and 
published in scientific journals in either abstract or full manuscript 
form.
    On behalf of Organon, I thank you again for the opportunity to be 
here this morning. Organon looks forward to continuing to work with you 
and to provide you with any additional information that you might 
require.

    Mr. Walden. Thank you, Mr. Osinsky.
    Dr. Clary, welcome.

                  TESTIMONY OF CATHRYN M. CLARY

    Ms. Clary. Thank you. Good afternoon, Mr. Chairman and 
members of the subcommittee. I really thank you for the 
opportunity to testify today on this important topic, and I 
respectfully request that this testimony be included in the 
record.
    Mr. Walden. Absolutely.
    Ms. Clary. My name is Cathryn Clary. I am a physician, also 
a board certified psychiatrist and the vice president for 
Psychiatry and Neurology in the U.S. Medical Department at 
Pfizer. I am here today to testify about disclosure and 
communication of results with Pfizer's antidepressant, Zoloft, 
in the pediatric population.
    During my 13 years in private practice of psychiatry before 
joining Pfizer, I treated hundreds of people, both teenagers 
and adults, who were suffering from psychiatric illness, 
including major depression. As you have heard from many others 
today and as some of the subcommittee has also stated, 
pediatric depression is a devastating illness. It is one of the 
most serious public health problems facing the adolescent 
population in America.
    Childhood depression affects 10 percent of all children 
under 18 every year and can result in suicide, tragically. It 
is the third leading cause of death in this age group, as you 
have also heard. I joined Pfizer in 1996 because of its 
commitment to developing innovative medicines to treat 
psychiatric illnesses such as depression as well as its 
commitment to educating physicians about its medicines in a 
full way, such as Zoloft.
    In my testimony today, there are three points that I would 
like to make. First of all, Pfizer has conducted extensive and 
valuable research in the pediatric population with our 
antidepressant, Zoloft. Second, the data from this clinical 
research program has been communicated to the FDA, all of it, 
it has been published in peer review journals, and it has been 
presented at multiple scientific meetings. Third, in 
conjunction with FDA, changes have been made to the Zoloft 
label to reflect the findings from this pediatric research 
program.
    One thing that I wanted to say clearly is that Pfizer began 
studying Zoloft for a disorder called obsessive-compulsive 
disorder back in 1991. This was around the time of the drug's 
approval, and it was not based on any type of legislation or a 
request from FDA. It was based on the fact that Pfizer 
determined there was unmet medical need in children suffering 
from obsessive-compulsive disorder, which can be quite 
debilitating. By the mid-1990's, Pfizer had completed several 
studies, and it obtained safety, tolerability as well as dosing 
information from the studies of these children and teenagers 
suffering from obsessive-compulsive disorder, also called OCD. 
And in 1997, after submitting the results of these studies to 
the FDA, Zoloft was approved by the FDA for treatment of OCD in 
pediatric patients. So since 1997, there has been 
pharmacokinetic dosing data and safety data in the label for 
Zoloft as well as one indication for pediatric obsessive-
compulsive disorder.
    Several years later, with a written request under FDAMA, 
Pfizer began to study Zoloft in pediatric patients who were 
suffering from major depressive disorder, or MDD. From December 
1999 through May 2001, Pfizer conducted, in the terms of the 
written request, two identical placebo-controlled studies in 
children and teenagers with major depression. While the studies 
were underway and before the results were known, the result of 
neither individual study was known, we did not know which 
children were on Zoloft, which children were on placebo, and 
because of new information that was being obtained as the 
results of other studies came in, Pfizer decided to combine 
these two studies for the purpose of the analysis. We felt that 
would provide the most scientifically sound and reliable 
result. It would improve our ability to detect the difference 
between Zoloft and placebo if one existed.
    The combined analysis did demonstrate the benefit of Zoloft 
in treating the symptoms of depression in the pediatric 
population. There was a statistically significant difference 
between Zoloft and placebo, although small. There was a small 
difference. This combined analysis study report was submitted 
to FDA in December 2001 along with the results of the 
individual studies and full individual study reports, as per 
the written request. Although FDA made a determination that the 
submitted data did not support approval for pediatric 
depression, the Zoloft label was updated in September 2003 to 
include additional safety information derived from these 
studies. And in addition, the label did state that efficacy had 
not been established in children under the age of 18 in major 
depressive disorder. I do want to emphasize that Pfizer does 
not promote the use of Zoloft in pediatric MDD. In addition, 
the Zoloft label has recently been updated to reflect the new 
warning.
    In total, Pfizer has completed nine pediatric studies with 
Zoloft. Every one has been submitted to the FDA. In addition, 
seven have been published in peer review journals, including 
our pediatric MDD data, which were published in JAMA. The 
eighth study has been submitted to a peer review journal and is 
undergoing peer review. The only study that Pfizer has 
conducted with Zoloft in the pediatric population not published 
in a peer review journal, although of course submitted to FDA, 
is an open label continuation of a dose finding study, an early 
pharmacokinetic study. We, of course, filed this with FDA. 
Given the current interest in transparency of all results of 
pediatric trials, we are now preparing this study for 
submission to a peer review journal.
    In addition, Pfizer is committed to working with PhRMA, 
with AMA, journal editors and all interested stakeholders to 
determine the optimal means for disseminating information from 
all of our trials that will have an impact on prescribing 
decisions in public health. Pfizer's participation in the 
recently announced PhRMA data base is a first step in that 
direction, and I understand you will hear more about that this 
afternoon.
    In conclusion, I want to emphasize my belief, as a 
physician and vice president at Pfizer, that our company has 
been and continues to be committed to generating and 
communicating meaningful information to physicians about the 
appropriate use of Zoloft in the pediatric population. Thank 
you, and I will be happy to take any questions.
    [The prepared statement of Cathryn M. Clary follows:]

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    Mr. Walden. Thank you very much, Dr. Clary. We appreciate 
all of you being here today and testifying as we look at how 
all this information is made public. Dr. Clary, your company 
performed two pediatric studies with Zoloft in depressed 
children; is that correct?
    Ms. Clary. That is correct.
    Mr. Walden. These study reports were submitted then to the 
FDA in December 2001, right?
    Ms. Clary. Yes, that is correct.
    Mr. Walden. And is it correct that neither study showed 
efficacy?
    Ms. Clary. It is correct that neither study showed a 
statistically significant difference between Zoloft and 
placebo.
    Mr. Walden. And, therefore, Zoloft is not approved, as you 
said, for use in depressed kids, correct?
    Ms. Clary. Yes.
    Mr. Walden. On the label.
    Ms. Clary. Yes.
    Mr. Walden. Neither of these depression studies that you 
did in children were published on a stand-alone basis, right?
    Ms. Clary. That is correct, because Pfizer had made a 
determination before the blinds were broken that the pooled 
analysis was really what was needed in order to really have 
reliable results.
    Mr. Walden. If you always sort of planned on pooling the 
studies, why is the Zoloft pooling article published 1\1/2\ 
years after the study reports were completed?
    Ms. Clary. Well, I would like to just--that brings up 
really a question about sort of the peer review process----
    Mr. Walden. Sure.
    Ms. Clary. [continuing] and the length of time that it can 
take to get an article into publication. It often may take a 
year to a year and a half for submission of a manuscript. Then 
the article is sent out by journal editors to a group of 
anonymous peer reviewers, experts in the field review the 
information, review the study, often will ask for new analyses, 
they may ask for things to be taken out of the article or 
additional information to be placed in the article. It is then 
sent back to the authors, the authors respond and possibly 
rewrite the article. It goes back, it is reviewed again. There 
are still editorial decisions that have to be made. So it can 
take a while for----
    Mr. Walden. And that is what happened in this case?
    Ms. Clary. Yes. Yes.
    Mr. Walden. That is why the delay?
    Ms. Clary. Yes. This manuscript was submitted very soon 
after we had the information.
    Mr. Walden. Could you turn to tab 48, please? This is the 
pooled analysis article that was published in the Journal of 
American Medical Association in August of 2003. Nowhere in this 
article does it make clear that the two separate trials by 
themselves did not show efficacy. Do you know why that wasn't 
included?
    Ms. Clary. That was because Pfizer had made a determination 
that the best way----
    Mr. Walden. Was to pool?
    Ms. Clary. [continuing] was to pool. We have a signed 
analysis plan demonstrating that. This was certainly not 
anything that the editors, the peer reviewers didn't know. As a 
matter of fact, there was a lot of exchange between the editors 
and Pfizer about exactly what should be in the article, as is 
common in these peer reviewed articles.
    Mr. Walden. Sure. Now, I guess as I read the JAMA from 
August 27, 2003, it talks about comment, and it says, ``In the 
trials reported here, Sertraline was found to be more effective 
than placebo for treatment of pediatric MDD with statistically 
greater improvement occurring as early as week 2. Of these 
three randomized double blind placebo-controlled trials of an 
SSRI in pediatric MDD that have been published to date, only 
one,'' that was Prozac, I believe, ``the study by Emslie, et 
al., of fluoxetine reported statistically significantly better 
results for the prospectively defined primary end point, and 
this was a comparatively small single center trial. Thus, our 
trials,'' and these would be the ones Pfizer did, ``describe 
the largest positive psychopharmological study of pediatric MDD 
using an international multicenter study design.''
    Now, when it says here the largest positive study for 
pediatric MDD and yet where I am confused is if the two 
individual studies showed no efficacy, how do you arrive at 
this conclusion that it is the largest positive study for 
pharmacological pediatric MDD?
    Ms. Clary. I think in a paper like this, and, again, in the 
methodology section of the paper, it was described that there 
were two trials that were pooled. This decision was made to 
pool prior to the breaking of the blind, so no one, the 
investigators nor Pfizer statisticians or anyone knew who was 
on medicine----
    Mr. Walden. Sure.
    Ms. Clary. [continuing] and who was on placebo, but the 
word, ``study,'' is often used in an article like this to 
describe the paper was about a combined analysis.
    Mr. Walden. Do you think, though, that that article implies 
that Zoloft works in kids, and, if so, do you think that 
accurately is based on what the two studies showed 
independently?
    Ms. Clary. I think that the article states--in a scientific 
article, what you state is the conclusion from the data that is 
presented in that article, and it states that--I just wanted to 
read you exactly what the last part of that--it talked about 
some limitations, whether there might be lower dosages that 
could be needed or whether longer-term treatment was effective 
or unknown, that was not known. It did say the results reported 
here, so the results in this study, these two pooled studies, 
support the conclusion that Sertraline is an effective, safe 
and well-tolerated short-term treatment. And, indeed----
    Mr. Walden. Treatment for pediatric MDD?
    Ms. Clary. Yes, for children and adolescents with MDD. 
Those are the conclusions from this particular analysis, 
which----
    Mr. Walden. But you said earlier the independent study 
showed it really didn't have an efficacy in pediatric MDD, 
right, the two studies on their own?
    Ms. Clary. There was not a statistical difference. In both 
studies, Zoloft-treated patients showed more improvement than 
placebo-treated patients.
    Mr. Walden. Now, I want to go to tab 67 because this is the 
review and evaluation of clinical data by the Food and Drug 
Administration. The reviewer was Andrew D. Mosholder, MPH, and 
it was completed on August 13, 2002. And in the executive 
summary Dr. Mosholder says, and I quote, ``The sponsor's 
proposed claim for the treatment of pediatric major depressive 
disorder is not supported by the data in this submission. Both 
pivotal studies failed to distinguish Sertraline from placebo 
on the primary outcome measures. The sponsor has proposed 
pooling the data from the two trials to yield a statistically 
significant result on the basis the trials were conducted under 
identical protocols. This, however, would be a major departure 
from our usual policies discouraging pooling of efficacy 
data.'' And then it goes on to say some other things, but that 
is the primary point. How did your company respond to Dr. 
Mosholder's comments?
    Ms. Clary. Well, when we received the indication from the 
FDA that they would not approve the drug for pediatric 
depression, we had to accept that.
    Mr. Walden. Sure.
    Ms. Clary. We believed that the pooled analysis was the 
most valid, scientifically accurate way to show the data, but 
we of course accepted that, and eventually that did end up in 
our label that efficacy was not established. In addition, we 
have not promoted the use of Zoloft for pediatric MDD. 
Physicians who inquire about the use of Zoloft in MDD will 
receive information, medical information letter stating that 
Zoloft is not approved for use in MDD in pediatrics.
    Mr. Walden. And in fact after our conversation yesterday, 
sometime this afternoon, Pfizer provided us with the letter 
that is sent out when someone does inquire about use of Zoloft 
for pediatric depression. And I note that, if I recall 
correctly, at least in the cover letter, it doesn't say that it 
is--it actually says Zoloft is indicated for the treatment of 
major depressive disorder, obsessions and compulsions in 
patients with OCD, panic disorder, et cetera, et cetera. So in 
the cover letter it doesn't say it is not approved for 
pediatric MDD; however, it does say that when you go over to 
the next page. But then it goes on in the summary to talk about 
how well it is tolerated in children and all kinds of open 
label studies and other uses in adolescents. And then it makes 
a reference to a retrospective study. ``Sertraline demonstrated 
clinical benefits in treating depression in children and 
adolescents.'' It sure--I mean I am not a doctor, but it sure 
would leave me with the impression that it is not only safe to 
use in adolescents for pediatric MDD but may actually do some 
good.
    Ms. Clary. So there are a couple of ways I would like to 
respond to that.
    Mr. Walden. Yes, please.
    Ms. Clary. First of all is that, again, going back to 1997, 
the FDA concluded that Zoloft was a safe medication to use in 
the pediatric population, ages 6 to 17. So that has been in the 
label since----
    Mr. Walden. Safe but no efficacy.
    Ms. Clary. Safe and effective for obsessive-compulsive 
disorder.
    Mr. Walden. Okay, for OCD, right.
    Ms. Clary. Right. We have no reason to think the safety--so 
the basic safety information has been there. The way that these 
letters are constructed, and there is a very clear process with 
our Medical Information Department, is that they do a 
literature search of all literature. You will note here that 
there is literature, most of it open label because there really 
haven't been a lot of large placebo-controlled studies until 
FDAMA was passed, which really did encourage controlled studies 
to be done, but a comprehensive search. So every study is put 
into these letters, positive or negative, that is in the 
literature.
    Mr. Walden. I should have submitted this letter for the 
record, and so I would like to do that without objection at 
this time.
    [The information referred to follows:]

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    Mr. Walden. One final question--I have blown past my time 
limit here--do you have--what is the objection to publishing 
studies in full as stand-alone? Some of you, I think, your 
companies at least have begun to do that. It would seem to me 
that it would be in everyone's best interest as we all try and 
get information to make these studies published stand-alone, 
fully available to the public without us having to mandate that 
legislatively. I noted today that the various medical journals 
are now requiring additional standards in terms of what they 
are going to accept to be published, I think, in part, because 
of these hearings, but can you just quickly say if your company 
does support publication of stand-alone studies, making them 
available on your web sites of all pediatric MDD studies? Dr. 
Wheadon?
    Mr. Wheadon. Well, as I think I stated in my opening 
statement, we have taken that process starting in June 2004 to 
post on our web site the study results for the pediatric 
studies. So that is a process that we have undertaken for the--
--
    Mr. Walden. But when you say study results, is that a 
summary of them or will you also make the full study available 
if someone were to want to access that?
    Mr. Wheadon. Actually, on this particular web site, we are 
posting the study reports.
    Mr. Walden. Is that whole thing?
    Mr. Wheadon. The whole thing, right.
    Mr. Walden. Okay.
    Mr. Wheadon. As well as the protocols.
    Mr. Walden. Yes. Dr. Hayes?
    Mr. Hayes. I am not completely clear what you mean by 
stand-alone. Do you mean as----
    Mr. Walden. Some of them are published as summaries or as 
pooled studies.
    Mr. Hayes. I see. So if a study is done, a study with a 
particular identifier, yes, we do that regularly.
    Mr. Walden. So not only just a summary but you also make 
the full study available.
    Mr. Hayes. Yes. In the format which is usually acceptable 
in the scientific journals, is that what you mean? Yes.
    Mr. Walden. Okay. Dr. Hayes?
    Mr. Camardo. I am Dr. Camardo.
    Mr. Walden. I am sorry.
    Mr. Camardo. That is all right.
    Mr. Walden. I keep--these names are all one off, my 
apologies. Dr. Camardo.
    Mr. Camardo. That is okay. At Wyeth, we would like to 
support--we do support the PhRMA proposal and favor having a 
centralized data base which I believe would be somewhat more 
easily searchable for a physician, which is one important 
criteria.
    Mr. Walden. But PhRMA's is a summary, not full data.
    Mr. Camardo. Yes, it is. It is actually designed to be a 
standardized format summary which is pretty extensive and 
readable review of the designs, the methods, the analysis, the 
safety and the efficacy. It is a standardized relatively 
extensive summary. I think if that is found to be inadequate, 
we don't have an objection to publishing, certainly to making 
more available, but, as Dr. Woodcock pointed out, it can get 
pretty wordy if you let it keep going, and this summary is a 
pretty standard format that all of us----
    Mr. Walden. Would that include the Effexor?
    Mr. Camardo. It would, yes. I mean when the data base is 
opened, we can put our summaries on that data base.
    Mr. Walden. And you will do that?
    Mr. Camardo. Yes. Yes.
    Mr. Walden. Okay. Dr. Olanoff?
    Mr. Olanoff. Yes. I would support the previous statements 
and also state we have already committed to doing this by way 
of a clinical trial registry. And, again, I think what we have 
committed to at this point is we are posting summaries. The 
summaries are very extensive. These are under an international 
agreed upon format, and these can run 5 to 10 pages of fairly 
detailed information. As Dr. Woodcock explains, some of our 
study reports run thousands of pages. I am not sure--our 
concern would be that they would actually obfuscate the ability 
of the physician to get to the clear information.
    Mr. Walden. It would seem to me you can publish the study 
summaries and then make available for people who want to do 
that----
    Mr. Olanoff. Clearly, if that is where this is going, we 
have no objection to that.
    Mr. Walden. Dr. Marcus?
    Mr. Marcus. We are committed to following the PhRMA 
proposal and would be putting the Serzone pediatric studies as 
individual summaries on that data base.
    Mr. Walden. Mr. Osinsky?
    Mr. Osinsky. Yes, we support the PhRMA and we would be 
putting our information, which is already published, on that 
web site.
    Mr. Walden. And Dr. Clary?
    Ms. Clary. Yes. Pfizer also worked very closely with PhRMA, 
and we are committed to putting all the individual study 
summaries. We share the concern expressed by Dr. Olanoff that 
perhaps--we really want to have a dialog. What we encourage is 
that everyone get together and really talk about what really is 
the best form of the information that needs to be there. I 
think we have heard that there is a cry for a lot more 
information than there has been, and we really do support 
having that discussion with industry, with government, with 
AMA, with FDA and really all the stakeholders in this.
    Mr. Walden. I appreciate the tolerance of the committee, as 
I have overrun my time. I would now defer to the gentlelady 
from Colorado.
    Ms. DeGette. Thank you, Mr. Chairman. I actually thank the 
chairman because he asked my first question for me. As you can 
see, I have actually got the PhRMA guidelines in my hand, and I 
guess I think it is a commendable first step by the 
pharmaceutical companies and PhRMA to agree to communicate the 
results. I think the concern a lot of us share, and I am sure 
you share it too, is how will those be meaningfully made 
available to patients and their physicians, and that is the 
line of questioning I would like to ask about.
    Dr. Woodcock talked about the number of studies out there. 
She used the number 11,000, and my concern is let us say we get 
this web site set up and there are all these clinical studies 
on it. I want to know how that information is going to be 
meaningful to people. Now, Dr. Wheadon, I think it is your 
organization, as a result of the agreement with Mr. Spitzer, 
the attorney general of New York, you folks are putting now 
information on the web; is that correct?
    Mr. Wheadon. In terms of all of our marketed products since 
the time of the merger, so that is since 2000, we are 
establishing a clinical trial registry that will have studies--
in this case, summaries of studies posted on that particular 
web site.
    Ms. DeGette. And would that include the document I referred 
to earlier during Dr. Woodcock's testimony? I don't know if you 
were in the room and heard about that. There was a summary 
right here. It is a summary about Paxil. We actually got it off 
your web site, so I assume that is kind of the information you 
intend to put----
    Mr. Wheadon. That is the sort of information. Paxil is not 
on that web site yet, because Paxil has its own web site that 
we posted prior to initiation of the clinical trial register 
for all of our marketed products.
    Ms. DeGette. All right. Now, is that also going to be 
posted on this PhRMA web site?
    Mr. Wheadon. Well, the process of how individual web sites, 
our web site in particular, will either populate the PhRMA web 
site or refer to the PhRMA web site or vice versa hasn't been 
worked out yet.
    Ms. DeGette. So it might not be on the PhRMA web site?
    Mr. Wheadon. No. We fully expect that whatever the 
agreement is within the industry and PhRMA about that web site, 
we will either download our information to PhRMA or have a 
link----
    Ms. DeGette. Oh, okay.
    Mr. Wheadon. [continuing] that would link to the web site 
and the information.
    Ms. DeGette. I guess I had thought there was already an 
agreement in place. Is that not accurate? I can ask the PhRMA 
people that when they----
    Mr. Wheadon. Right. I think Dr. Loew will be testifying 
later about that.
    Ms. DeGette. So you don't know--the details haven't been 
worked out; is that fair to say?
    Mr. Wheadon. That is correct.
    Ms. DeGette. Does anybody here know when those details will 
be worked out and all this information will be available 
through the web site?
    Ms. Clary. Well, I do understand the web site should be 
operational in October, but I don't--it will be quite a while, 
I think, before all the results get posted.
    Ms. DeGette. All right. I will ask the PhRMA folks about 
that. Now, Dr. Camardo, you testified that some of the things 
that Wyeth has done on Venlafaxine?
    Mr. Camardo. Venlafaxine.
    Ms. DeGette. Venlafaxine is changing the label and a letter 
to physicians that this drug is really not recommended for a 
prescription to children for depression, correct?
    Mr. Camardo. Yes.
    Ms. DeGette. Now, let me ask the rest of you for whom your 
product has not been indicated for children, have you changed 
your label and have you sent a letter to physicians? And I 
guess we can start with you, Dr. Wheadon.
    Mr. Wheadon. Well, we have amended our label as has 
everyone at the table based upon the FDA class labeling that 
was required of all antidepressant sponsors a few months ago, 
which references the issue of suicidality associated with 
depression, whether or not someone is undergoing antidepressant 
treatment.
    Ms. DeGette. Does it talk about the use in pediatric 
populations?
    Mr. Wheadon. Our labeling indicates that Paxil does not 
have the indication for pediatric depression.
    Ms. DeGette. Does it talk about the studies that you talk 
about on your web site that shows it has some--well, that Paxil 
was not statistically superior to placebo with respect to 
efficacy? Does it say it hasn't been proven to work?
    Mr. Wheadon. The specific references to the individual 
studies are not presently in the label.
    Ms. DeGette. But does it say that it has not been proven to 
work in pediatric populations?
    Mr. Wheadon. I think the language is that it has not been 
shown to be effective or is not an indicator. I can't remember 
the exact language, but it clearly indicates that the FDA has 
not given their regulatory purview that the drug has been shown 
to be effective.
    Ms. DeGette. Now, did you all send a letter out to 
physicians saying the same thing?
    Mr. Wheadon. A letter has gone to physicians on two 
occasions, one with the FDA talk paper in 2003 that initially 
referenced the metaanalysis in terms of the suicidality data, 
and then with the label change, a letter went to health care 
professionals----
    Ms. DeGette. Okay.
    Mr. Wheadon. [continuing] indicating that Paxil is not 
approved for pediatric depression.
    Ms. DeGette. Okay. Who is next? Dr. Hayes? No, you have 
been approved, so you are off the hook. Dr. Camardo, you 
already talked. Dr. Olanoff. This panel is so big it is hard to 
keep all the drugs separate.
    Mr. Olanoff. In response to your question, Congresswoman 
DeGette, we have changed our label. We were very quick to adopt 
the changes.
    Ms. DeGette. And what does your label now say?
    Mr. Olanoff. The label expressly provides warnings 
regarding the potential for suicidality in both adult and 
pediatric patients, especially in the early course of disease, 
with or without antidepressant treatment. In addition, the 
labels has always stated that the drug has not been shown to be 
safe and effective in pediatric patients.
    Ms. DeGette. Okay. Did you send a letter out to physicians?
    Mr. Olanoff. No, we have not as yet.
    Ms. DeGette. Do you intend to do that?
    Mr. Olanoff. We can, yes.
    Ms. DeGette. That would be a good idea. Okay. Next.
    Mr. Marcus. We pretty much made the same change. I think 
all the companies made the same change, so----
    Ms. DeGette. And, again, why did you make that change?
    Mr. Marcus. We were asked by the FDA to make the change as 
part of class labeling.
    Ms. DeGette. Okay. And what does your label now say?
    Mr. Marcus. I can tell you in a second. I think it is 
pretty much standardized across most of the labels.
    Ms. DeGette. Okay. Did you send a letter out to physicians?
    Mr. Marcus. I would have to double check, but I believe we 
did.
    Ms. DeGette. Mr. Stupak points out, and for all of you, 
this label is not actually on the medication itself; it is sent 
out to physicians, right? Dr. Olanoff, you are nodding. Is that 
correct?
    Mr. Olanoff. That is correct. As Dr. Woodcock indicated, 
sometimes when you get your prescription it is attached to the 
bottle. It depends on how the pharmacist packages it. But, yes, 
the primary----
    Ms. DeGette. Well, this is the instructions to the 
physicians. This isn't on the bottle that is given out to the 
patients.
    Mr. Olanoff. That is correct.
    Ms. DeGette. Now, do you have any--Doctor, do you have any 
objection to this language being put on the bottle that is 
given to the patients?
    Mr. Olanoff. I think it is something for consideration. We 
would have to discuss in general how patient labeling would be 
done in this regard for all potential safety or efficacy----
    Ms. DeGette. Well, I mean if you have got a drug that is 
being widely prescribed off-label for a population for which it 
hasn't been shown to be efficacious, for the most part, and, 
worse, could cause increased suicide, it would seem that would 
be a warning that might be appropriate to be put on the label 
for consumers, right?
    Mr. Olanoff. I think in the context of whether the drug was 
approved and being used and utilized in that regard, it could 
be something considered, but the product is not approved for 
use in that pediatric population.
    Ms. DeGette. Right, so given the fact it is being so widely 
prescribed, don't you think that would be a good thing to have 
on the bottle, especially since you have it on the label that 
is given to physicians anyway?
    Mr. Olanoff. I think it is important that that information 
be provided to the physician and the physician so instruct the 
patient in terms of the potential benefits and risks of the 
product. I am not sure that the description in the warning in a 
label, at least in a very limited space on a box or on a 
bottle, would be sufficient to really instruct the patient as 
to all considerations to the benefits and risks of the product.
    Ms. DeGette. Well, I don't know. I mean it hasn't been 
approved by the FDA for us in these populations, and the reason 
is because it hasn't been proven to be efficacious. So what 
would the use be for the pediatric populations? I don't mean to 
be difficult.
    Mr. Olanoff. No, no. I am afraid I am not entirely 
understanding your point either.
    Ms. DeGette. Well, does anybody here think it would be a 
good idea to put it right on the bottle that was given out to 
the patients? Dr. Wheadon? You need to turn your mic. Thanks.
    Mr. Wheadon. I think we need to refer back to the statement 
that Dr. Woodcock made earlier today, and that is it is 
important not to undercut or negate the relationship between 
the prescriber and the patient, the learned intermediary. As we 
all know, and, again, as Dr. Woodcock very, I think, 
appropriately pointed out, the issue of depression in pediatric 
patients is extraordinarily complex and very important to be 
treated in the same way that adults are being treated for 
depression, seriously and by appropriate prescribers. So it is 
our belief that the information concerning the state of affairs 
for the studies is most appropriately in the label for 
physicians that can understand the limitations of the data as 
opposed to potentially sullying the relationship between the 
patient and the physician.
    Ms. DeGette. Well, I hear your point, but part of the whole 
rationale for like these new PhRMA rules and for the things the 
FDA is talking about is so that we can have more information 
out, not just to doctors but also to the families of these 
children who are really suffering some serious psychological 
problems so they can know, they can be a participant. These are 
not adults making independent decisions for themselves. These 
are parents making--as you well know, they are making decisions 
for their kids, and part of the whole goal of getting the 
information out there is to let people know.
    I was talking to some of my colleagues up here. Even some 
Members of Congress who sit on committees like this one were 
under the misimpression that if the FDA does not approve a drug 
for a population, then it can't be prescribed. That is what 
they thought. They were stunned to know that physicians are 
actually prescribing these medications off-label. They wouldn't 
even know for their own children. And that is why part of the 
goal is to get this information out to the general population 
as well as physicians, and it would seem to me if you are 
putting it in the labeling, you wouldn't object to putting it 
on the bottle.
    Mr. Wheadon. Well, unfortunately----
    Ms. DeGette. And let me just add----
    Mr. Wheadon. Unfortunately, in the best of all possible 
worlds, that would be a wonderful thing to do, but let us also 
keep in mind where we are in terms of the acceptance and the 
willingness for people to recognize that children are suffering 
from a mental illness, from a psychiatric illness. So the 
important context is for the physician to be able to counsel 
the parent and the patient about the disorder, about how to 
treat the disorder and about the things that need to be watched 
for in terms of the evolving nature of the disease and the 
potential side effects of the drug.
    Now, by putting a host of very confounded data on a patient 
label about negative studies, that could potentially, 
potentially do more harm than good, and I think that is what we 
are all struggling with----
    Ms. DeGette. Right.
    Mr. Wheadon. [continuing] is how do we do most of all good 
and provide the context for the physician and patient to make 
the right decision for treating the disease.
    Ms. DeGette. And you know what? I agree with you, which is 
why we are giving all this information to the physician, but we 
should give it to the parents too. And let me just make one 
more point. I support pediatric exclusivity, a concept under 
which all of your companies have made a lot of profits. I 
support research for these drugs for juvenile populations. I 
think it is terrible that we only have one drug approved by the 
FDA for treatment of depression. I think we should have more 
drugs, be we need more studies to do that. But in the meantime, 
parents who for whatever reason whose physicians don't 
understand or don't care that these drugs are not indicated for 
pediatric populations, they should also be able to find out. 
That is my only point. Thank you very much for your comity. I 
appreciate it, Mr. Chairman.
    Mr. Bass [presiding]. The Chair thanks the gentlelady from 
Colorado and recognizes himself for 10 minutes. I have a series 
of questions for Dr. Olanoff and before I ask them, though, I 
just want to ask the witnesses to think about a single question 
and perhaps respond at the end of my line of questioning of Dr. 
Olanoff if there is time.
    I don't understand why a pharmaceutical manufacturer 
wouldn't want to put every possible bit of information out on 
the table, be it positive or negative. Certainly, the potential 
liability, legal liability, for withholding bad or negative 
trial studies and so forth exists. I understand that there is 
an interest in expanding markets and sales and so forth and 
finding new and giving doctors the ability to provide these 
medications off-label, but not to be totally forthcoming with 
every conceivable piece of information is beyond me.
    I don't want members to answer now but members of the panel 
can think about that and give me any reason why the public 
shouldn't have access to as much data as possible. When I see 
an ad for a pharmaceutical on television these days, 20 of the 
26 seconds is spent describing how it is going to kill you 
instead of cure you, and I think that is part of the process, 
but in this instance, in the professional community where 
really trained professionals, the people who should be doing 
the prescribing, aren't getting all the information potentially 
that they need in order to make informed decisions.
    Dr. Olanoff, Forest Labs conducted two random controlled 
trials in pediatric patients. One showed no efficacy and one 
showed efficacy. Do you agree with that?
    Mr. Olanoff. I agree with it except for the comment that 
actually one of the studies was conducted by our licensor, 
Lundbeck, independent of Forest.
    Mr. Bass. Fair enough. If you could turn to tab 15 in the--
tab 15, and this is a journal article that was published in 
June 2004 on the one Celexa study that showed efficacy. I want 
to make sure you have the same tab that I do.
    Mr. Olanoff. Yes, we do.
    Mr. Bass. Do you have it?
    Mr. Olanoff. Yes, I do.
    Mr. Bass. Good. Why didn't the article also reference the 
fact that another Celexa study in depressed children showed no 
efficacy? Do you think that admission could be misleading?
    Mr. Olanoff. First of all, let me state that we disclosed 
the results of both studies prior to the publication of this 
journal article. They were disclosed. Both the efficacy and 
safety results of both studies were disclosed by Forest at the 
American Academy of Adolescent and Child Psychiatrists in 2003. 
The focus of this particular article was the U.S. study, and if 
you read through the article and into the discussion section, 
you can see that the tone of the article was more in line with 
what studies are out there that suggest that SRIs might work. 
It wasn't intended as a full review of all studies that have 
been done with antidepressants or all positive or negative 
studies. It really was a focus on one study. And I should state 
that this study was a single study, it was planned as a single 
study, it was unequivocally positive, was so recognized by the 
FDA.
    Mr. Bass. What was the last sentence you said, it was what?
    Mr. Olanoff. It was unequivocally positive and it was so 
recognized by the FDA.
    Mr. Bass. One of the studies was.
    Mr. Olanoff. Yes, that is right.
    Mr. Bass. But in this article it says in the conclusions 
that, ``In this population of children and adolescent treatment 
with,'' whatever it is, ``reduced depressive symptoms to a 
significantly greater extent than placebo treatment and was 
well tolerated. It doesn't say anything about any negative 
trial at all; is that correct?
    Mr. Olanoff. That is correct, but it doesn't say anything 
about any negative data for any of the other antidepressants. 
The focus of the article was more on what data is out there 
that suggests that any of these drugs may work.
    Mr. Bass. But it is about your drug. It is not all drugs, 
it is about your drug.
    Mr. Olanoff. That is correct.
    Mr. Bass. And it only says the good stuff about your drug; 
isn't that true?
    Mr. Olanoff. It was the intent of the authors and the focus 
of the article to concentrate on this particular study. There 
were other venues in which you can talk about the multitude of 
studies that are out there. They could have been referenced in 
this article, there was no prohibition for that, but that 
wasn't the tone and focus of this article. I think that in 
large part addresses why publications on their own are an 
imperfect way of disclosing information and in large part gets 
us back to why we have gone forward and really got out in front 
of the industry in regards to clinical trial disclosure.
    Mr. Bass. Let us finish this up. If you had to do this 
again, would you do it any differently today?
    Mr. Olanoff. I think given the interest and the general 
consensus of the community, we have in fact taken steps 
internally to try to make sure that at least topline results 
are mentioned in all our scientific presentations and 
publications. But that wasn't the general thrust of how these 
papers were put together in the past.
    Mr. Bass. Okay. Why don't we turn to tab 18 for a second, 
if you could? Got it?
    Mr. Olanoff. Yes, I do.
    Mr. Bass. Tab 18 is the slide show presentation by Dr. 
Jonas at Forest Labs, and its presentation is focused more on 
safety results than on efficacy, don't you agree?
    Mr. Olanoff. It is, but as you can see from the speaker 
notes, the speaker specifically referred to the fact that one 
study was positive and one study was negative. I would like to 
put this presentation in context. The presentation was 
primarily focused on safety, and it was really a direct replica 
of what we presented to the FDA in response to their request to 
review all suicide-related events according to an algorithm 
they provided. We thought this was useful information, and we 
wanted to get it out to the specialists in this care are as 
soon as possible. And this came out only a few months after we 
provided the data to the FDA.
    Mr. Bass. Well, as you know, this particular slide show has 
a one-line reference to the fact that the study showed no 
efficacy, and do you think that that is sufficient disclosure 
to the medical community and the public as to the efficacy 
results of Celexa in depressed children?
    Mr. Olanoff. Well, it also has a one-line reference to the 
fact that the U.S. study did show efficacy, and that, again, 
was just because of the way this presentation was put together. 
It was a focus on safety issues, not on efficacy. But we did 
disclose the topline results.
    I think another context which is important is that the 
problem with no-effect studies or sometimes called negative 
studies is that they don't rise to a statistical hurdle that 
demonstrate clear and unequivocal efficacy. We are alone, aside 
from Prozac, in being able to demonstrate case study that does 
show efficacy. When you have a no-effect study it is not 
particularly informative if you can't determine why there was 
no efficacy in that particular study.
    Mr. Bass. Did you make any effort to get the no-efficacy 
study published in any peer review journal?
    Mr. Olanoff. We have asked our colleagues at Lundbeck to do 
so.
    Mr. Bass. Okay. Moving to Lexapro for a second, are you 
attempting to get the Lexapro trial, which did not show 
efficacy and was recently completed and submitted to the FDA, 
published?
    Mr. Olanoff. Yes, we are, and we have disclosed those 
results in a very short time at the time we unblinded the 
study.
    Mr. Bass. How come it took over a year until October 2003--
you may have answered this question with a previous 
questioner--even to mention publicly the fact that one of the 
studies was negative?
    Mr. Olanoff. We didn't put as much emphasis on the European 
study for a number of reasons; main reason being that we didn't 
find the study particularly informative. There was a 60 percent 
placebo response in this study, which makes it very difficult 
to interpret why we didn't show efficacy. We believe there were 
some imbalances in the groups at the beginning, which may have 
explained this, but we couldn't provide useful information on a 
negative study. We also knew that it is very difficult to 
publish negative studies. Just as a coincidence, around the 
same time, we had finished a study in geriatric patients, in 
very old population of geriatric patients, greater than 75 
years old. In many ways, it was a groundbreaking study in that 
it employed many other research techniques, such as MRIs and 
extensive psychometric testing, and we applied to have that 
published in a journal. We gave the data base over to our 
investigators, they send in the publication, and we had great 
difficulty getting that published.
    Mr. Bass. Moving on to your settlement with the AG, is 
there any reason--tell us why you entered into a settlement 
with the New York attorney general when he hadn't even filed a 
complaint against you?
    Mr. Olanoff. We entered into an agreement with the attorney 
general. His office had started an inquiry. We responded to 
that inquiry. It became apparent to us as we were working out 
our own internal policies for a clinical trial registry that 
this was a great interest of the Attorney General's Office. We 
were able to discuss that with the office. They provided 
significant input into what they believed should be in a 
clinical trial registry. We were able to incorporate that 
registry. We are very pleased with the results. That led to the 
core of the agreement.
    Mr. Bass. In a minute or so can you give us a couple of 
specifics on the trial registry that you are obligated to 
create under your consent agreement? What types of trials and 
drugs are included, the timeframe in which results must be 
posted, summaries or are they actual studies and any 
enforcement mechanisms if you don't post something or it is 
incomplete? Can you address those?
    Mr. Olanoff. Under the agreement with the New York Attorney 
General's Office, we will be providing not only summaries of 
our clinical trial results for all our phase three and four 
studies going forward, but also we will be listing online, and 
this was something that we had planned to do independently, all 
our ongoing trials, so that if we are performing a trial in 
phase three population or a phase four trial, people will know 
about it, and it will be identified and it can be tracked to 
its results later on.
    In addition, we have gone even further. We have gone back 
to studies that go back to January 1, 2000 for all our marketed 
products, even before that for any of our promoted products in 
terms of any safety information.
    Mr. Bass. One last question, Dr. Olanoff. Is there anything 
wrong with making available the complete trial, clinical trial, 
publishing the summary but making available the other 
information or the more complete or the thorough information if 
it is requested? Is anything wrong with doing that?
    Mr. Olanoff. Well, you are talking about the protocol 
itself when you say the clinical trial?
    Mr. Bass. Yes.
    Mr. Olanoff. I don't see any major issues there. We 
actually plan to incorporate all the key entry and exit 
criteria or entry criteria for inclusion----
    Mr. Bass. How about the study report?
    Mr. Olanoff. The study report, I think the issue with the 
study report we have no major objection in terms of the 
pediatric studies if that is requested. We provided it to the 
staffers. I think from the standpoint of putting it on a 
clinical trial web site, I am not sure that that serves a great 
deal of purpose because we are talking about in many cases 
thousands of pages of data. Whereas I think the clinical trial 
summary I don't think we should confuse this with a short 
abstract. We are talking about 5 to 10 pages of very detailed 
information that hopefully can be navigated through and 
straightforward to the physician in terms of their 
understanding of the benefits and risks.
    Mr. Bass. Very briefly, and if members of the panel don't 
want to comment, I don't want to force everybody to comment, 
what about my first question? Why would there be any hesitation 
on the part of any pharmaceutical company to publish 
information about the efficacy of a drug given the context of 
the potential issues that might be involved as a result of 
failure to publish information that you know might affect the 
outcome of treatment associated with a drug? Why aren't you 
willing just to publish everything if you are asked because it 
gets you off the hook, to some extent, passes the blame over to 
somebody else? Anybody have any comment about that? It is a 
general question. Why withhold anything? Does anybody have any 
objection to publishing--put it the other way so you don't have 
to say anything, does anybody have any objection to publishing 
everything associated with clinical trials of pharmaceuticals?
    Mr. Wheadon. Well, I think what you have heard from 
everyone at the table is that certainly is the goal, and that 
is what we are working toward. We also have to ask the 
question, and I think Dr. Olanoff refers to that, in terms of 
to what purpose? So we always want to make sure we are serving 
the good, the right purpose, because, as you have heard before, 
if you inundate a single web site with 120,000 studies, the 
usefulness of that may be diluted in terms of what your 
intention might be. So you really need to make sure you are 
aiming for the right purpose and ultimately for the right 
reason in terms of helping physicians to treat their patients 
appropriately.
    Mr. Bass. Anybody else? Yes.
    Ms. Clary. I would like to really second what Dr. Wheadon 
has said, which is that we all are committed to providing 
useful information which will improve prescribing and improve 
public health. I think, again, the concern--since a clinical 
study report with all the raw statistical analyses and data 
tables can really run thousands of pages, the concern is that 
flooding information out there may indeed cause confusion as 
opposed to really help inform people. But we are certainly at 
Pfizer committed to working to get the synopses, the rather 
lengthy synopses that have been described here that contain all 
the important primary and secondary efficacy and safety 
measures available.
    Mr. Bass. My time has expired. I would only conclude by 
saying that agreeing to make information available, not publish 
it, but agreeing to make it available if it were requested 
would not flood anybody with anything unless they asked for it. 
The gentleman from California, Mr. Waxman, is recognized for 10 
minutes.
    Mr. Waxman. Thank you, Mr. Chairman. I agree with your 
point, and I think that we ought to recognize that we are not 
flooding people with information. They are going to look at a 
specific drug, they are going to look at a specific disease and 
try to find out what studies there are in that area, not 
everything that has ever been done. In theory, the legislation 
that gave the manufacturers this pediatric exclusivity, which 
is a monopoly for an additional 6 months over their drugs, was 
supposed to remedy the problem of insufficient information on 
drug labels about how to prescribe for children. This was 
supposed to make sure that physicians finally had adequate 
information to know whether and how to use drugs in children. 
And in fact your companies gain literally billions of dollars 
from this extra monopoly, this pediatric exclusivity, for 
performing studies on Paxil, Zoloft, Effexor, Lovox and similar 
drugs. Can you tell us how much each of your companies spend on 
the pediatric trials on antidepressants that you submitted to 
the FBI--to the FDA? Wrong committee. Anyone have that 
information? Well, could we, Mr. Chairman, have the record open 
and I would like each of these witnesses to submit to us how 
much money they spent on those pediatric trials on 
antidepressants which they gave to the FDA.
    Mr. Bass. Without objection.
    Mr. Waxman. I am surprised that nobody here has that 
information. Do any of you know how much additional revenue 
your company gained as a result of the pediatric exclusivity? 
None of you seem to have a response to this, but, as I 
understand it, from Zoloft, it was over a billion dollars; for 
Paxil, which is Glaxo, there was over $800 million; for Forest, 
Celexa, it was a half a billion dollars; for Effexor, which is 
Wyeth, it was a half a billion dollars; and for Remeron, it was 
over $120 million, as I read it. But in other words, we are 
talking about huge sums of money. Somebody want to----
    Mr. Osinsky. Congressman?
    Mr. Waxman. Yes.
    Mr. Osinsky. Remeron did not get pediatric exclusivity. FDA 
denied it for us.
    Mr. Waxman. So you did not get pediatric exclusivity.
    Mr. Osinsky. We did not.
    Mr. Waxman. So you got no benefit for the studies you did.
    Mr. Osinsky. No.
    Mr. Waxman. Why is that? Why didn't you get exclusivity?
    Mr. Osinsky. There was some discussion with FDA about the 
scientific--if we completed all the requirements they wanted.
    Mr. Waxman. I see. Now, the other companies got pediatric 
exclusivity without completing their studies to get any 
conclusive result, except perhaps Prozac might be an exception, 
but your company didn't even do the studies sufficient.
    Mr. Osinsky. Well, we thought we did the studies FDA 
wanted, but at the end they said that we didn't complete them 
all the way they wanted them.
    Mr. Waxman. Well, I would like to have the record open for 
those of you who did get pediatric exclusivity to tell us how 
much money that was worth to you to get that additional 6-month 
monopoly. In exchange for the billions of dollars of profits 
that the manufacturers here today received for pediatric 
exclusivity on their antidepressants, did patients or 
physicians get any useful labeling information about how or how 
not to use antidepressants in children? Did any of you ask for 
label changes or get a label change? Yes, sir.
    Mr. Olanoff. We requested a labeling change. We were not 
able to get one.
    Mr. Waxman. You were not. What was the label change you 
requested?
    Mr. Olanoff. We asked that the studies or the positive 
study that we did in the U.S. be included in the labeling.
    Mr. Waxman. The positive study.
    Mr. Olanoff. That is correct. FDA considered--through our 
awareness, the FDA considered putting both the positive and the 
negative study in the labeling and then rejected that idea.
    Mr. Waxman. So rather than have the positive and the 
negative, you--rather than have the positive with the negative, 
you decided not to have either.
    Mr. Olanoff. No, no. We----
    Mr. Waxman. They decided.
    Mr. Olanoff. They decided.
    Mr. Waxman. Okay.
    Mr. Marcus. We also requested a labeling change.
    Mr. Waxman. And what was your request for?
    Mr. Marcus. Actually, we would indicate that both of our 
clinical studies were negative.
    Mr. Waxman. So you wanted a label change that would say 
your clinical studies were negative?
    Mr. Marcus. Well, we wanted it to reflect the information 
from the clinical trials, including pharmacokinetic information 
as well as some safety information.
    Mr. Waxman. This came up earlier with Dr. Woodcock. What 
was the reason FDA refused to give you that label change?
    Mr. Marcus. I am not clear but we can always provide you 
with the FDA correspondence.
    Mr. Waxman. Anybody else ask for a label change?
    Ms. Clary. Yes.
    Mr. Waxman. Go ahead.
    Ms. Clary. Pfizer did ask for a label change for Zoloft and 
indeed much valuable information was included in the label. As 
I had mentioned earlier in the hearing, we did do a pooled 
analysis of the studies. We asked for some efficacy labeling. 
We did not receive that. However, there was a significant 
amount of safety information that was included in the label, 
including adverse events, safety information about weight loss 
in children, and the label also clearly stated that efficacy 
had not been established in MDD in pediatric patients. So we do 
believe that even though there was not an efficacy statement, 
there was valuable information for prescribers that was 
included in the Zoloft label based on the studies that were 
performed.
    Mr. Waxman. Okay. And did someone else want to respond?
    Mr. Camardo. Yes, Mr. Waxman. Wyeth requested a label 
change to inform that in two studies efficacy was not 
demonstrated against placebo and to add some safety 
information.
    Mr. Waxman. And what reason did FDA not go along with that 
label change?
    Mr. Camardo. Well, we believe that one of the reasons is 
that the absence of the positive studies was not sufficiently 
definitive to declare the resulting labeling and----
    Mr. Waxman. Well, wait. You said the label you wanted was 
that it was not effective for pediatric use.
    Mr. Camardo. Yes.
    Mr. Waxman. What studies did you need for that?
    Mr. Camardo. What studies did we need----
    Mr. Waxman. I mean you said that the positive studies--what 
positive studies, to show that it was not effective?
    Mr. Camardo. Well, it is generally considered in depression 
studies that one or two negative studies may not be definitive 
proof that the product is not effective, and the FDA wanted to 
take a more balanced view of how to interpret those studies. 
And so they did not approve that request for us to put that 
information in the labeling. And I think partly, if I could 
just remind the committee what Dr. Wheadon said. Part of the 
reason I think was not to disseminate information that might 
actually have a negative effect on patients and parents who 
would seek treatment but rather to have that reviewed and 
advice taken from outside and then decide what would be best to 
put in labeling. But we had a specific request to add the 
results of the two studies and to add some safety information, 
and I believe that informed experts might disagree about what 
to do and the FDA had a review and we had a different point of 
view.
    Mr. Waxman. Do any of you disagree with the idea that the 
medical community deserves to have a complete and accurate 
picture of the data on a drug?
    Mr. Camardo. No. I would speak for everybody that none of 
us disagree with that.
    Mr. Waxman. As I understand it, the companies assembled 
here today published only what they regarded as the positive 
studies on their drugs and failed to publish a single negative 
study. Antidepressants are certainly not an isolated case of 
this. Medical journals have repeatedly reported that studies 
published by drug companies are far more likely to favor the 
company's drug than studies published by independent sources. 
Do you think that physicians and patients are well served when 
pharmaceutical companies publish only those results that are 
favorable to their products and withhold the remaining data 
from the public? Does anybody think that physicians and the 
patients are well served when they only get part of the story?
    Mr. Hayes. My answer to that, Mr. Waxman, is, no, I don't 
think they are well served, but I also wanted to point out that 
not only Lilly but the authors of studies about Prozac did in 
fact publish the one study in which efficacy was not 
demonstrated, and this was before there was any legislative 
pressure to do so.
    Mr. Waxman. Now, for drugs Zoloft and Paxil, something even 
more troubling occurred than simple suppression of negative 
data. Your companies took studies that the FDA had concluded 
did not show effectiveness and published reports claiming that 
the studies did show effectiveness. So your companies, in 
effect, tried to convince doctors to prescribe Zoloft and Paxil 
to kids on the basis of studies that FDA said had failed. The 
medical journal reports acknowledged that FDA had found the 
studies to be negative, and do you think it is appropriate to 
publish studies that you claim show effectiveness and withhold 
from doctors the crucial information that FDA disagreed with 
you? And if you are not responsible for telling the doctors 
this, should FDA do so? Anybody from those two companies?
    Mr. Wheadon. Congressman Waxman, with all due respect, I 
must correct one statement that you have made, and that is in 
the case of GlaxoSmithKline we have not submitted any of the 
pediatric depression studies in an attempt to get an 
indication. So the FDA did not give that sort of statement that 
the studies were not acceptable or what have you. Those studies 
we have never submitted for a pediatric indication for 
depression.
    However, I also want to point out that the study that was 
published, study----
    Mr. Waxman. There was an FDA review that said that the 
studies were not published, not effective.
    Mr. Wheadon. The FDA has looked at those studies in the 
context of other submissions. For example, we do have an 
outstanding submission for pediatric obsessive-compulsive 
disorder. The data from those studies were submitted as a part 
of the safety data base filed with that submission, but we have 
never submitted asking the FDA for approval for Paxil for 
pediatric depression.
    Mr. Waxman. Did you get pediatric exclusivity for that 
report, for that research?
    Mr. Wheadon. We have pediatric exclusivity for a host of 
studies that we have done, including depression, obsessive-
compulsive disorder, social anxiety disorder.
    Mr. Waxman. But not effectiveness. You never submitted 
studies for effectiveness to get----
    Mr. Wheadon. We have not submitted the depression studies 
for an indication for depression.
    Mr. Waxman. Dr. Clary, you testified that the letter you 
gave to physicians who ask about the use of Zoloft in kids 
contains a description of all published studies on Zoloft in 
kids, but we have heard today that companies routinely publish 
only positive studies and withhold negative data. So you have 
stacked the deck. A letter that lists all published studies 
will tend to promote your drug as safe and effective and will 
fail to give physicians a fair picture of the data on your 
drug. Is it your view that it is appropriate to withhold 
negative data from physicians in these letters you use to 
communicate to physicians?
    Ms. Clary. No, Mr. Waxman--Congressman Waxman, it is not, 
and, indeed, I wanted to sort of disagree with the 
characterization you had made before about Pfizer trying to 
convince doctors that Zoloft is effective for major depression. 
In the pooled analysis we performed, there was a small drug 
placebo difference, which is talked about in the article, put 
in context, and I also want us to sort of refocus on what Dr. 
Marcus, I think, alluded to.
    Mr. Waxman. Do you dispute the statement I just made, that 
you only published the studies that were positive and did not 
publish the studies that were negative and therefore----
    Ms. Clary. Yes, I do dispute that.
    Mr. Waxman. Okay.
    Ms. Clary. I do.
    Mr. Waxman. And how do you dispute it?
    Ms. Clary. I dispute it in the fact that we have published 
all the pediatric data on Zoloft with the exception of the one 
small uncontrolled trial conducted back in 1994 that I 
characterized in my oral testimony.
    Mr. Waxman. So it is not true that you pooled two negative 
studies and published them as positive.
    Ms. Clary. That is true, but that was a scientific decision 
that was made before we knew what the outcome could be. It 
could have gone against us. We didn't know. We didn't know 
whether Zoloft would be effective or not when we did this 
pooling.
    Mr. Walden [presiding]. All right. The gentleman's time has 
expired. Before I turn it over to the gentleman from New 
Jersey, I understand we have some votes in a few minutes. We 
would like this panel to stay with us for probably a second 
round. And in addition, Dr. Marcus, if possible, if you could 
provide the committee with Bristol-Myers correspondence with 
the FDA regarding the changed label issue, that would be most 
helpful to us. And, Dr. Camardo, if you could provide us as 
well with communication you had with FDA.
    Mr. Camardo. I think that may already be in documents we 
sent, but if it is not, we will be happy to.
    Mr. Walden. Thank you, sir.
    And now I recognize the gentleman from New Jersey, Mr. 
Ferguson.
    Mr. Ferguson. Thank you, Mr. Chairman. I had intended to 
ask Dr. Marcus some questions about the labeling issue as well, 
but I think Mr. Waxman has covered much of what I was going to 
ask about. So I will turn to Dr. Hayes. Thank you all for being 
here. I know many of the members have been in and out all day, 
but we have reviewed your testimony and appreciate the fact 
that you are here and appreciate some of the proactive steps 
that you are taking on some of these important issues.
    Dr. Hayes, I just have some questions specifically about 
the registry and the various steps that the companies are 
taking proactively, and Lilly has done a number of things, and 
I wanted to probe that a little bit. Your company has the only 
approved antidepressant drug for use in kids and has published 
all of its studies on Prozac on kids in peer review journals; 
is that correct?
    Mr. Hayes. That is correct.
    Mr. Ferguson. Would you turn on your microphone?
    Mr. Hayes. That is correct.
    Mr. Ferguson. That is correct. Is the reason that these 
studies have been published all over because the journals will 
easily accept positive studies?
    Mr. Hayes. As I stated before, one of them is a study which 
shows no separation from placebo, although both the placebo and 
the drug response were quite high, but that is still a failed 
study if you don't show a difference from placebo. I can't 
answer that. Of course it is possible that had we submitted 
negative studies the journals would not have accepted them.
    Mr. Ferguson. So they are not all positive studies.
    Mr. Hayes. No, they are not.
    Mr. Ferguson. Yet you have submitted and they have all been 
published.
    Mr. Hayes. Yes. Yes.
    Mr. Ferguson. That is important.
    Mr. Hayes. Yes, it is.
    Mr. Ferguson. Particularly in the context of what we are 
talking about today. Can you discuss--we are going to have 
several bells here. I will just be patient. Can you discuss 
some of the specifics surrounding Lilly's clinical trial 
registry, and, specifically, how does that differ from what 
PhRMA is suggesting and doing?
    Mr. Hayes. I think the major difference, as I understand 
the PhRMA proposal, probably lies in Lilly's intent to publish 
a list of all studies at their inception, the date that the 
study begins with a very brief descriptor. That list won't 
contain a lot of information, but it will say, ``This study 
that has this title has begun,'' and we will attach an 
identifier to that so that people, if they wish, can then track 
what happened to all those studies. If one ends, if it ends 
before it was expected to, if it takes longer than it was 
expected to, you can always go back to that and say what 
happened to this study? And when we get to the end----
    Mr. Ferguson. This is what you are doing.
    Mr. Hayes. This is what we are doing. And when we get to 
the end of that, we intend then to append the results of the 
study and the methodology, the primary and secondary outcomes 
to the identifier so that anyone who has had an interest of 
what became of that study will be able to see. So each study, I 
guess, will tell its own story. It will have a beginning, and 
it will have an end of some sort, whatever that is.
    Mr. Ferguson. How is that different from what PhRMA is 
doing?
    Mr. Hayes. I don't believe that the PhRMA proposal calls 
for listing the inception of each study.
    Mr. Ferguson. Why are you enhancing your internal standards 
when it comes to sharing information and creating this, I think 
you could accurately describe it as a more comprehensive trial 
registry? What has prompted the change at Lilly? What has 
encouraged you to go that route?
    Mr. Hayes. Well, we have been talking about this for some 
time and put together a task force that went across various 
levels and disciplines within the company, perhaps, I don't 
know, months ago to try to find a way to deal with transparency 
of our data and our results, and we believe that there is 
clearly, if you will, a societal crisis in terms of credibility 
for drug company results. We believe that we do a lot of good 
research, and we would like for people to have access to that 
in ways that they are comfortable with, which is why we have 
chosen to do the registry in the way that we have and also are 
choosing to have independent third party auditing of that, 
because I think we need to not only do that to be credible to 
you and everyone else who cares but also to assure our own 
compliance with our intent.
    Mr. Ferguson. Does your registry include summaries or is it 
more comprehensive data?
    Mr. Hayes. Well, I have been confused as to what various 
members of the committee have meant by entire studies. I think 
we are having a communication gap between the two sides of us 
here about that. I mean if you talk about a complete study, it 
is hard to describe what that means. And I am not trying to 
obfuscate; people have alluded to it. We recently had a new 
drug application that was 417,000 hard copy pages for a single 
indication. That is filled with lots of raw data, and if 
somebody wants to say, ``Gee, I need to have access to all the 
raw data, each data point,'' each patient comes for a visit 
they have perhaps 100 things, their blood pressure is measured, 
they are asked various questions. All of those things are in 
those summary reports.
    That is not what goes into a scientific article that is 
peer reviewed, which is usually considered enough information, 
which is what I meant when I answered Mr. Bass' question or 
perhaps it was Mr. Walden's question about do you mean the 
format in which a scientific article appears in a journal in 
which there should be an adequate explanation of the methods, 
including the statistical analysis plan, enough understanding 
of the results as well as the conclusions that someone reading 
the article can tell what you planned to do and how it came 
out. Now, that sort of summary in either the usual journal 
template fashion or some other fashion is I think probably what 
all of us intend, because I think anything much more than that 
in terms of posting it on our web site will not be of use 
either to doctors and certainly not to families.
    Mr. Ferguson. Is there any reason other than sheer volume 
of data not to share complete data? Is there any internal 
reason at the company that--is there some sort of competitive 
disadvantage?
    Mr. Hayes. Well, I think people are hesitant to put raw 
data pools in the public because that allows not only the kind 
of transparency we would like to have but all sorts of 
shenanigans, if you will, that you wouldn't like to have.
    Mr. Ferguson. Obviously, you would protect people's privacy 
and what not but----
    Mr. Hayes. Sure.
    Mr. Ferguson. [continuing] other than that.
    Mr. Hayes. No. Other than that, I don't see good reasons 
for that. It is the volume, and it is the possibility that raw 
data could be used in ways which would be unintended and not 
useful to anyone.
    Mr. Ferguson. Does Lilly plan to participate in PhRMA's 
registry----
    Mr. Hayes. Yes.
    Mr. Ferguson. [continuing] as well as your own?
    Mr. Hayes. Yes.
    Mr. Ferguson. Why?
    Mr. Hayes. As far as I know. Lilly people actually chaired 
the committee that came up with the principles that 
Congresswoman DeGette had a few minutes ago, as well as the 
questions and answers that were there. We have provided 
leadership, I think, within PhRMA to try and deal with this 
issue ever since about 2000. We will continue to cooperate with 
all of our colleagues in trying to deal with the issue, and 
also we will proceed with our web site that I think inculcates 
our own principles because we think it is important.
    Mr. Ferguson. I am just about out of time and I know we 
have a vote on, but I appreciate--I want to say again I 
appreciate the witnesses for being here to testify and to talk 
about some of these issues today.
    I will refer back to my opening statement when I said 
sharing of this information is crucial. Giving information to 
the decisionmakers, to the parents and by extension the kids of 
potential red flags, of potential problems that could be coming 
down the pike for them is absolutely crucial, and I would urge 
you to continue to take steps, as you are doing at Lilly and 
others in the industry and with PhRMA, to continue to make as 
much information as possible available to those who can use it 
and who can benefit from it and frankly whose lives can be 
saved by it. And as we have said, a lot of people have said 
here today, if that type of cooperation isn't forthcoming and 
if we don't see that kind of benefit, we are going to end up 
taking legislative or regulatory action, which should be a last 
result, but if it means the lives of our kids, that is 
something that is clearly going to happen. So I appreciate your 
cooperation and hope that cooperation will continue in an even 
more enthusiastic way. Thank you, Mr. Chairman.
    Mr. Walden. I want to thank the gentleman from New Jersey. 
We are going to recess now. We would like this panel to remain 
with us, but you will get about a 50-minute break it looks 
like. We have 5 votes and so probably 50 minutes to an hour. So 
a good time to catch your breath, and the committee will return 
as soon as the last vote is over.
    [Brief recess.]
    Mr. Walden. We're going to reconvene the committee. So if 
our panelists would return to their chairs. And I'll call the 
Subcommittee on Oversight and Investigations back to order. And 
I'll now recognize the ranking member, the gentleman from 
Florida for 10 minutes.
    Mr. Deutsch. Thank you, Mr. Chairman. Thank you, panelists 
for your indulgence.
    Dr. Wheadon, you have expressed considerable concern that 
patients and their physicians not be confused by whatever 
information is disclosed. This includes, as I understand it, 
concern that neither patients nor physicians be misled or 
overwhelmed by data. I find that to be a genuine concern, but 
I'm a bit confused about Glaxo's position on this matter.
    If you turn to page 9 of Tab 11, the complaint that New 
York State filed against GlaxoSmithKline, item 38, in part 
states and I'm quoting, ``in a cover memo that transmitted the 
published articles concerning Study 329 to all sales 
representatives selling Paxil, Zachary Hawkins, CSX, Paxil 
Product Management stated Paxil demonstrates remarkable 
efficacy and safety in the treatment of adolescent 
depression.''
    You notice in bold the word ``remarkable.'' First, would 
you please provide a copy of this entire memo to the committee 
to be included in the record. Second, would you have this 
committee believe that Paxil demonstrates remarkable safety and 
efficacy in the treatment of adolescent depression?
    Mr. Wheadon. Well, first of all, Congressman, we'd be happy 
to give you the entirety of that memo. Second of all, I think 
it's important that the committee be fully aware that this was 
an internal memo provided from the author of the memo to sales 
representatives with a clear instruction of ``for your 
information only'' and not to be used for any sort of 
promotional purpose.
    To go specifically to your question concerning the 
adjective, if you will of in terms of ``remarkable'', while I 
did not author this memo and I certainly would not have chosen 
to use the words that the author of the memo used, as you cite, 
I think it is important as we've discussed earlier in this 
particular panel, that we keep in mind that pediatric 
depression and the study of how one approaches in terms of 
treatment, pediatric depression, has been extraordinarily 
difficult.
    The literature is just littered with all sorts of studies 
where we've not been able to show that medications that we 
know, based on personal experience of clinicians to be 
effective, we've not been able to show it in a controlled way 
in terms of separation from placebo.
    So in the case of this particular study, Study 329, there 
were, while the primary efficacy parameters did not show the 
expected separation from placebo, there were findings within 
the study, most notable, for example, the Hamilton rating scale 
score, Hamilton is a rating scale for depression, looks at the 
many symptoms of depression. And one parameter was looking at 
the rating scale score of less than or equal to 8 which is 
usually and pretty traditionally in these types of studies 
viewed as response. And in that particular assessment, the 
response rate for Paxil was 63 percent versus 46 percent for 
placebo. That was to the minds of the individuals who were 
carrying out the study quite an important and interesting 
finding because it was one of the first times, particularly 
with Paxil, we've been able to see even a beginning of a hint 
of efficacy.
    So while I would not have used the terms used by the author 
of this memo, I would encourage that we do take a step back and 
look at the fact that we are trying to do the best. Everyone at 
this table, everyone involved in treating depression in 
children, are trying to do the best we can to discern exactly 
how these agents can be effective in a safe and appropriate 
way.
    Mr. Deutsch. Let me just follow up on two specific things 
you mentioned. I mean would your--I mean based on your the 
evidence you just cited, would you say that Paxil is effective 
in terms of treating adolescent depression? I mean is it an 
appropriate prescription?
    Mr. Wheadon. Well, first of all, I have to be, Congressman, 
certainly very quick to say that Paxil is not approved by the 
FDA as a treatment for adolescent or pediatric depression. I 
then have to add that based on personal experience, not my own 
personal, but personal experience of individuals that practice 
child and adolescent psychiatry, there are those situations 
that have been reported where the drug has been effective in 
treating children. However, due to the very difficult 
circumstances of studying this particular disease, we, in the 
case of Paxil have not been able to discern a significant 
effect versus placebo, based on the protocols that have been 
carried out. Fortunately, other companies and other agents have 
been able to do so and we're very pleased that at least that 
advance has occurred.
    Mr. Deutsch. Again, I understand what you're saying and 
your words are obviously well chosen. I mean wouldn't by 
inference what you just said, placebo would have the same 
effect?
    Mr. Wheadon. Quite honestly, Congressman, I think everyone 
at this table who has ever treated someone with depression 
would not begin to even think of using placebo as a treatment 
for depression because while you may see a 40 to 50 to 60 
percent placebo response rate, we know that that is short-
lived. We know that due to the inherent fluctuation of the 
symptoms of depression within an individual, that individual 
may on 1 day actually score relatively low on the Hamilton 
rating scale or the MADRAS, which is another rating scale and 
then the next day, the full force of the symptoms are back.
    So simply looking at placebo response is really not looking 
at the totality of the disease you're trying to study. You 
really do need to look at the whole host of parameters 
including the rating scales, the clinical global impression, 
activities of daily living. It's a very difficult study or area 
of study.
    Mr. Deutsch. You know, I mean just to follow up also, as 
well, in terms of what you're saying, I just find it and I hate 
to use this word ``remarkable'', but remarkable to say that in 
a memo about remarkable efficacy for your eyes only to sales 
reps and having some experience with pharmaceutical sales reps, 
that they're not going to mention that. I just think it is not 
credible that the sales reps are not going to use that 
information in terms of making sales.
    Mr. Wheadon. I certainly can tell you that that is not our 
corporate practice, that is not our standard operating 
procedure. Instructions are clearly, clearly delineated for the 
sales reps, that they are not to promote off-label which 
obviously this study would be off-label promotion.
    Mr. Deutsch. If you turn to Tab 13 which also is a Paxil 
adolescent depression issue, the positive piece on the phase 
three clinical studies, first please note that this is a 1998 
memo that's marked confidential for internal use only. If you 
turn to the last page of that document under proposals, the 
following statements are made and I'm quoting again: ``based on 
the current data from studies 377 and 329 and following 
consultation with SB country regulatory and marketing groups, 
no regulatory submissions will be made to obtain either 
efficacy or safety statements related to adolescent depression 
at this time. Regulatory agencies would not approve a statement 
indicating that there are no safety issues in adolescents, as 
this could be seen as promoting off-label use. And finally, it 
would be commercially unacceptable to include a statement that 
efficacy had not been demonstrated as this would undermine the 
profile of Paroxetine.''
    Again, there seems to be a considerable discrepancy with 
the impression your company would like to lead with the 
committee regarding the nonpromotion of Paxil for off-label use 
in treating adolescent depression.
    What exactly was Glaxo's position before Mr. Spitzer filed 
his suit and what does it now discourage or does it discourage 
off-label use of Paxil in adolescents at this point in time?
    Mr. Wheadon. First of all, let me be very clear that this 
particular memo that you're referring to is authored by an 
individual based in the United Kingdom, not in the U.S. Second 
of all, while the reference to the negative studies as you 
cited in the memo, are as you've cited, the negative study 377 
has indeed been published in abstract form by one of the 
investigators involved in that study, so that information was 
disseminated.
    In terms of promoting off-label, we do not promote off-
label. We do not allow our sales reps to promote off-label. We, 
however, cannot control the legal right of prescribing 
clinicians to prescribe a medication as they deem fit. We do 
not encourage it, we do not promote it, but also cannot control 
the legal right of that prescriber to prescribe a medication 
off-label.
    Mr. Deutsch. Just as one last follow-up question, do you 
ever audit your sales force to see about off-label 
prescriptions, just to get a feel for how much is, in fact, 
done off-label? I know that sometimes companies send audit 
personnel to physicians' offices to make sure sales forces are 
staying on message.
    Have you done that in the face of Paxil?
    Mr. Wheadon. We do that in the case of all of our 
medications. We have an internal auditing program that, as you 
say, will go out, ask physicians to relate back what they've 
heard from their sales reps and we are very keen to ensure that 
there is not--as best we can, off-label promotion because that 
is not per our procedures and obviously is not acceptable from 
the regulations standpoint.
    Mr. Deutsch. And in terms of Paxil, could you relate to us 
what your auditing has found out?
    Mr. Wheadon. I unfortunately don't have that information in 
front of me.
    Mr. Deutsch. Can you provide that to the committee?
    Mr. Wheadon. Okay.
    Mr. Deutsch. Thank you.
    Mr. Wheadon. Thank you.
    Mr. Walden. I thank the gentleman from Florida. The chair 
now recognizes the gentleman from Michigan, Mr. Stupak.
    Mr. Stupak. Thank you, Mr. Chairman. Dr. Clary, you 
mentioned adverse events. How many adverse events have been 
with your drug there, which one you have. You have Zoloft. How 
many adverse events have been reported to FDA with your drug?
    Ms. Clary. Congressman, all of the adverse events from the 
clinical trials, both in pediatric and adult, have been 
reported to the FDA. That's a routine matter.
    Mr. Stupak. I'm not asking about the clinical, I'm asking 
about the people who have been using your drug for some time 
here, Zoloft, you're the No. 1 seller. How many adverse events 
have been reported to the FDA?
    Ms. Clary. I think you may be asking me about spontaneous--
--
    Mr. Stupak. No, you got to do--yes, spontaneous adverse 
events. You're required as a manufacturer when it comes to your 
attention to report it to the FDA.
    Ms. Clary. Yes.
    Mr. Stupak. So how many do you have?
    Ms. Clary. I want to make sure that I'm answering the 
question correctly because----
    Mr. Stupak. I want to make sure you're not stalling.
    Ms. Clary. I'm really not. I'm wanting to clarify because 
there's adverse events in clinical trials and there's 
spontaneously reported adverse events which come from all 
different places, physicians, patients and they report these to 
Pfizer, to the pharmaceutical company or to the FDA MedWatch 
and we report them routinely to FDA. If they're serious, we 
report them to----
    Mr. Stupak. I'm asking for a number.
    Ms. Clary. I'm sorry, Congressman, I don't have the exact 
number.
    Mr. Stupak. Okay.
    Ms. Clary. We can get that to you, if you'd like.
    Mr. Stupak. Sure, I'd really like to know that. If Zoloft, 
in your testimony, has not been effective, no efficacy, and if 
there's some question about the safety, how is it you become 
the No. 1 seller of this drug?
    Ms. Clary. I'm not sure what you mean by the question about 
the safety. In adults, Zoloft is approved for six different 
indications, major depression----
    Mr. Stupak. I'm looking here for Zoloft, Pfizer, top sales 
was $258 billion.
    Ms. Clary. Yes.
    Mr. Stupak. And from the pediatric exclusivity, almost got 
another $1 billion. So if it's not effective, and actually may 
increase the danger of some people, especially pediatric 
patients, how is it you become the top seller in this area, I 
guess?
    Ms. Clary. Zoloft is approved in adults for six different 
indications and the vast majority of its use is in adults. A 
small portion of that is in children and adolescents and it's 
recognized by physicians. It's been recognized by the FDA as 
being efficacious, safe and well tolerated in multiple 
disorders in adults.
    Mr. Stupak. Okay, if you've got almost $1 billion, what do 
you sell Zoloft for say 30 tablets?
    Ms. Clary. I don't know the exact number, it's about $60 a 
month, that's the wholesale price, approximately.
    Mr. Stupak. Okay.
    Ms. Clary. I can get you that exact number, if you'd like 
it.
    Mr. Stupak. Sure, and I'd really like to know how much are 
sold to people under 18. Okay?
    Ms. Clary. Sure, we'd be happy to provide that.
    Mr. Stupak. You said that in response to an earlier 
question that all the stakeholders should come together. Would 
the public have a chance to come to your meetings on how we're 
going to do this reporting?
    Ms. Clary. We would welcome that. We would welcome 
organizations that deal with people who have depression and 
other mental health problems. They're certainly----
    Mr. Stupak. How about public citizen? Would you invite 
public citizen to the table?
    Ms. Clary. I certainly think they should have a voice and 
that they're a voice in this debate.
    Mr. Stupak. You know, there's this--Dr. Wheadon, when Mr. 
Deutsch, Congressman Deutsch was asking a question there on 
this remarkable efficacy and safety in the treatment of 
adolescent depression, that was in an article on your study 329 
to all sales representatives selling Paxil, by Zachary Hawkins 
the Paxil Products Management, right?
    Mr. Wheadon. That was in a memo from the Products 
Management Sales Reps----
    Mr. Stupak. Is he head of all your Paxil Product 
Management, United States and Great Britain?
    Mr. Wheadon. That is not correct, no.
    Mr. Stupak. Where is he?
    Mr. Wheadon. I quite honestly don't know where Mr. Hawkins 
is now.
    Mr. Stupak. I thought you said that was a Great Britain 
study or something.
    Mr. Wheadon. That was in reference to the second question 
from Congressman Deutsch which was, I think, tab 11, if I 
recall correctly.
    Mr. Stupak. If your company doesn't condone this, why would 
you even put this in writing to your sales representatives, 
that remarkable efficacy, when all the studies show it's not?
    Mr. Wheadon. Well, again, Congressman, I go back to the 
statement I made earlier in response to Congressman Deutsch, 
and that is I would not have used those particular words. But 
also, as I mentioned earlier, we need to keep in mind the 
context in which those results were becoming known. The context 
was----
    Mr. Stupak. But your study was, it's right here. It's 
negative results, except for the positive on most secondary 
endpoints. Why would you tell a sales team you have a 
remarkable efficacy, when you don't have a study that shows any 
efficacy for depression?
    Mr. Wheadon. Again, I would not use the word remarkable, 
however, the context is or was historically it was 
extraordinarily difficult to show effectiveness of these agents 
in pediatric patients. A number of the parameters, albeit not a 
priori defined primary parameters, but a number of the 
parameters did show some effect for drug----
    Mr. Stupak. Not for depression.
    Mr. Wheadon. For depression.
    Mr. Stupak. No, no, it's the secondary endpoints.
    Mr. Wheadon. Congressman, if I could finish?
    Mr. Stupak. Sure.
    Mr. Wheadon. As I mentioned, one of the parameters of 
response is looking at the score on the Hamilton rating scale 
for depression. It's called the HamD. It's the number of 
items----
    Mr. Stupak. I'm familiar with it.
    Mr. Wheadon. [continuing] that look at the degree of the 
symptoms. One of the analyses looked at what we call a 
responder analyses. That's HamD, total score less than or equal 
to 8. And in that analysis, 63 percent of patients on Paxil met 
that definition of response, i.e., they had----
    Mr. Stupak. But it's not enough to elevate to be an 
effective drug for depression by the FDA standards.
    Mr. Wheadon. Paxil showed the 63 response. Placebo showed a 
44 percent response. That was a significant finding. However--
--
    Mr. Stupak. My question is why would you use words like 
remarkable to your sales representatives, if you say they're 
not using it to help sell the drug. I think you just had about 
$2.13 billion in sales in 2002 of this drug?
    Mr. Wheadon. Again, I would not have used the term 
remarkable.
    Mr. Stupak. Right.
    Mr. Wheadon. However, we do think it is important that 
sales reps are familiar with studies that are being reported in 
the literature.
    Mr. Stupak. And I think they should get accurate 
information to sales reps.
    Mr. Wheadon. Absolutely, they should get accurate 
information and the accurate information would be in the actual 
article, not in the memo and the memo, unfortunately----
    Mr. Stupak. Do you give your sales reps the full study?
    Mr. Wheadon. If it's a published article, yes.
    Mr. Stupak. If it's not published, they don't get them.
    Doctor, I'm going to say your name wrong, I'm sorry, and I 
apologize. Camardo?
    Mr. Camardo. That's right.
    Mr. Stupak. You said in earlier testimony high risk 
patients. Could you describe what the high risk patients are in 
this group of people we're trying to treat here?
    Mr. Camardo. Actually, I would have to defer to practicing 
psychiatrists for more, really a more accurate definition of 
that, but in fact, we would leave it to the psychiatrists who 
identify children who might be--who might have demonstrated 
suicidal behavior in the past. That would be a high risk child. 
A child who might have had a reaction to a drug in the past, 
that might be a high risk child. Certainly, a child or an adult 
who had had a suicide attempt in the past. It really has to be 
up to the practicing physician to help identify some of the 
higher risk for possible suicide attempt when depression, anti-
depression therapy is initiated.
    In fact, the language in our label is pretty standard for 
psychiatric guidelines and for most of the antidepressants. 
It's been observed that occasionally initiating therapy can 
bring on a period where suicide might, suicide risk might 
increase.
    Mr. Stupak. A lot I've heard from this panel is a concern 
if we post these studies, we'd be flooding the marketplace with 
too much information. How about unless you can establish the 
effectiveness and safety and if you can't establish that, then 
how about if your company doesn't sell these drugs to anyone 
under the age of 18? Would you agree that's a good idea?
    Mr. Camardo. Let me answer--I think that we have in the 
United States taken the position in terms of regulation that 
unless there is a clear consensus for contraindication or a 
clear consensus of an unacceptable side effect we have given 
doctors the latitude to make practice related decisions.
    Mr. Stupak. Right, but you control the drug and you could 
very well, as you're all telling me these profits are from 
people, adults, so why don't you just sell your drug, until you 
can prove effectiveness and safety, you don't sell it to anyone 
under age 18. You can put that right on the packaging, inform 
the doctors, why don't you go that way?
    Mr. Camardo. Congressman Stupak, we actually do inform the 
doctors that it hasn't been approved----
    Mr. Stupak. No, no. How about if you accept the moral, 
legal and ethical responsibility, not to sell it if they're 
under 18 unless you can prove safety and effectiveness? Hell, 
you might as well give them placebo, right? That's just as 
effective as some of the studies I've seen up here.
    Mr. Camardo. That's not----
    Mr. Stupak. And it isn't really--these kids really are 
depressed and you're giving them a drug that's shown to be 
ineffective and they actually increase their suicide behavior. 
Don't you share the responsibility here to say, I'm giving this 
pill that's marketed to help you out, but we know it really 
doesn't, but you'll get better if you take this.
    Mr. Camardo. Our literature, our promotion, our practices, 
our training, which is all subject to very rigorous internal 
review, has never promoted or recommended effects are for 
children, but we have----
    Mr. Stupak. Well, how do these doctors know about your 
drugs if they're not promoted to that? Don't your sales reps 
promote them to the doctors?
    Mr. Camardo. They promote under very rigorous guidelines 
for adults.
    Mr. Stupak. Right, with remarkable efficiency?
    Mr. Camardo. Well, they promote with--under rigorous 
guidelines, very highly regulated to adults and in fact, we 
take very seriously precaution to make sure that they're aware 
that the product is not approved in children. But we have, in 
the United States, decided that the absence of data in a 
certain area would not restrict a practicing expert physician 
from using the product. I think that's a decision that was made 
somehow, but that's what we've accepted.
    Mr. Walden. The gentleman's time has expired. I recognize 
the gentleman from Maine.
    Mr. Allen. Thank you, Mr. Chairman. Dr. Marcus, FDA told 
Bristol-Myers that Serzone was not indicated for use in 
pediatric patients. But a Bristol-Myers sponsored study which 
is at tab 26 concludes that and I quote: ``in this study, 
Serzone was shown to be safe and effective in the acute 
treatment of adolescents with major depressive disorder.'' So 
the question is if your studies conclude that this drug is safe 
and effective for adolescents with MDD, why would the FDA not 
approve your drug for pediatric patients?
    And the second question is did the FDA disagree with the 
way your study was conducted or with your results?
    Mr. Marcus. Can I first ask you which tab was that?
    Mr. Allen. Twenty-six.
    Mr. Marcus. Twenty-six.
    Mr. Allen. And I'll repeat the question if it's helpful.
    Mr. Marcus. Twenty-six is a press release from Forest Labs. 
I'm sorry.
    Mr. Allen. Just 1 minute. Let me put that question aside. 
We'll try to find the right citation and let me go back to some 
other questions. I'll come back to that one.
    This is really for the whole panel and I guess Dr. Wheadon, 
we'll start with you. And just work down the row, if we can.
    The PhRMA guidelines on publishing clinical trial data 
states there should be a timely publication of meaningful trial 
results. So my question to all of you is how would each of your 
companies interpret compliance with these guidelines? What 
would be considered timely and what would be considered 
meaningful? That's partly a question about if you accept the 
PhRMA proposal, is that really a proposal that each individual 
company decides what's timely and what's meaningful, in 
addition to being a voluntary proposal?
    Let me ask the second part of the question too, and then 
you can deal with it one by one. Do you believe the voluntary 
nature of the proposal from PhRMA serves the public interest of 
having better access to clinical trial results both positive 
and negative? And the question I'm really interested in there 
is if you have a voluntary proposals, if individual companies, 
basically can choose whether or not to provide the clinical 
trial data, don't you have an unlevel playing field that 
essentially gives an advantage to those companies which don't 
perhaps provide the data? Wouldn't it be better to have a 
system, a regulatory system that treats all of the companies 
the same way?
    So there are the two questions. If you could talk about 
timely publication, meaningful trial results, how you interpret 
those and also react to the voluntary nature of the proposal as 
opposed to a mandatory proposal.
    Thank you.
    Mr. Wheadon. Going down in that order, Congressman, timely, 
obviously, can have a variety of definitions applied to it, 
particularly in the context of publishing in peer-reviewed 
journals or even in presenting at medical conferences. You may 
want to publish within a month after the completion of the 
study. But due to the process that I think is appropriate, peer 
review, editors often sending manuscripts back for changes for 
further analyses, for answering questions, what you and I may 
view as timely may actually take the better part of a year, 2 
years, actually actualize the appearance of the manuscript in a 
peer-reviewed journal, the acceptance of the poster or 
presentation for medical conference.
    So within as much control as we can garner, I think it is 
appropriate for us to publish or make public in a timely 
fashion. Hence, the evolution of the websites. The websites 
obviously are things that we control 100 percent. So we have 
ultimate ability to post those data on the website within 
virtual complete control of our individual companies.
    Mr. Allen. But is it your position that what is timely and 
what is meaningful should be decided by your company?
    Mr. Wheadon. Well, let me get to meaningful. Meaningful, 
obviously, can also be subject to a variety of definitions, 
depending on the disease entity you're discussing. So for 
example, and I think this is a point we've not had a chance to 
really put on the table, a negative study in depression, quite 
honestly, until the present discussion has not been something 
that the scientific arena would necessarily view as inordinate. 
In adults, it is not unusual for there to be upwards of 30 to 
40 percent placebo response rate and upwards of two or three 
studies that one needs to do for each, for one positive study 
because of the disease that we're studying.
    In pediatrics, it's even worse, if you will. The placebo 
response rate--the hurdle of trying to establish efficacy in 
terms of how we do these studies. So a negative study would not 
necessarily have raised an eyebrow because of that fact. A 
positive study, as you've heard today, was in the timeframe in 
which these studies were done, quite--I don't want to use the 
word remarkable--quite interesting, because of that extant 
literature, that extant experience in terms of studying 
depression.
    So meaningful can change. Now obviously, meaningful----
    Mr. Allen. I'm going to have to--in order to give anyone 
else on the panel a chance to speak.
    Mr. Wheadon. And then last voluntary. I think voluntary can 
work because we as a regulated industry, obviously, police 
ourselves and if GSK decides to voluntarily post a host of 
studies in a way that Forest may decide not to do and they're 
trying to take advance of that system, we obviously will self-
police and say well, hold on, this isn't a level playing field.
    Mr. Allen. I'd like to ask anyone on the panel who has a 
different opinion when Dr. Wheadon? A nuanced difference or----
    Mr. Hayes. Nuanced difference perhaps. At Lilly, we've 
defined meaningful as all of our phase one, two, three and four 
results and we've defined timely as phase one, two and three 
results at the time of approval of the indication for which 
they were done; and phase four, when we have a marketed product 
as soon as possible, but no longer than 1 year. We picked 1 
year because it may take 6 to 8 months to get all of the 
analyses done and be able to put something in an understandable 
format and rather than pick 6 or 8 months and perhaps make a 
promise that we might not keep once in a while, we chose 1 
year. But we addressed those things, meaningful and timely in 
that way and tried to provide concrete answers for them.
    As for voluntary, I think you have a point about the 
levelness of the playing field, but I think we're going to do 
this anyway, regardless of whether someone else chooses to play 
on a more favorable field.
    Mr. Allen. When you say ``we'', you mean your company?
    Mr. Hayes. I mean Lilly, yes.
    Mr. Allen. You mean your company?
    Mr. Hayes. Yes.
    Mr. Allen. But you don't speak for all of the other 
companies?
    Mr. Hayes. No, I don't.
    Mr. Allen. Dr. Hayes, could you--I'm sorry, Dr. Camardo or 
whoever it was had their hand up there?
    Mr. Olanoff. If I could just make a comment, I think I 
agree in large part with what's been said. I would just also 
include, I think meaningful from a standpoint of content, I 
think a publication on a clinical trial registry should be to 
the same level of what would appear in a peer review 
publication in terms of the content and the explanatory value, 
perhaps less interpretation, if that wasn't necessary, but at 
least get the results out there so someone could review them. I 
think that's critical.
    In our case, we have a binding agreement with the Attorney 
General's Office, so we will be putting out studies for some 
years ahead and it would be nice to have a level playing field.
    Mr. Allen. Other comments?
    Ms. Clary. I just wanted to reiterate that Pfizer has 
worked with PhRMA on the proposal and it does include timely 
the definition is at most 1 year after the completion of the 
study for marketed products and that we are committed to 
getting those meaningful results out of all phase three and 
four studies of marketed products.
    Mr. Allen. Are there any definitions of the word 
``meaningful'' in the PhRMA proposal?
    Ms. Clary. I'm not sure in the PhRMA proposal. There is an 
issue which you may have seen. And again, I think it's one of 
these issues that perhaps we can all discuss together which has 
to do with exploratory or hypothesis-generating studies. 
There's some very early studies that are done early in drug 
development before there's any notion of efficacy which really 
are just to generate a hypothesis about what the drug might be 
used for. And there is some earnest discussion, I think, about 
whether those trials are really useful to patients and to 
physicians.
    Mr. Allen. Any other comments? Mr. Chairman, if I might 
just ask for the record, if Dr. Marcus, if I could ask him to 
respond later to the question that I have, I have the correct 
tab number, it's tab 28. But if you could respond in writing 
afterwards to the question I asked you and we'll give it to you 
in writing, so it will be clear.
    My time has expired which is why I'm suggesting that 
procedure.
    Mr. Walden. We're going to do a second round here, very 
quick.
    Mr. Allen. Thank you. I'll come back with it.
    Mr. Walden. Thank you. I guess I want to make sure that 
people are clear on one thing when they leave here and correct 
me if I'm wrong, Dr. Wheadon to Dr. Clary, Glaxo did three 
studies on pediatric depression, MMD, MDD, sorry. And FDA said 
it showed no effectiveness, correct? Did your three studies 
show effectiveness as defined by the FDA for treatment of MDD 
in children and adolescents?
    Mr. Wheadon. To be clear, Congressman, when you say FDA 
said it showed no effectiveness, again, we have not submitted 
for the indication of pediatric depression. If you are 
referring to----
    Mr. Walden. Do your studies, do you believe your studies 
showed that your drug is effective or would pass the FDA 
effectiveness test for treating pediatric depression?
    Mr. Wheadon. Certainly, obviously, since we have chosen not 
to submit for pediatric depression, we recognize that the 
studies do not meet the requirements as outlined by Dr. 
Woodcock earlier today in terms of showing the effectiveness 
for approval.
    Mr. Walden. But in short, your studies were negative 
according to the FDA, right?
    Mr. Wheadon. Again, when you say according to the FDA, I'm 
trying to understand what you're referencing in terms of the 
FDA.
    Mr. Walden. Why didn't you submit your studies to the FDA 
to prove efficacy for your drug for treatment of pediatric 
depression?
    Mr. Wheadon. We internally knew that we did not meet the 
standard that the FDA would set for approval.
    Mr. Walden. Thank you. That's what I was trying to get at. 
Is you know your study showed that your drug would not pass an 
FDA test to show effectiveness for treatment of pediatric 
depression?
    Mr. Wheadon. For an approval for that indication, that is 
correct.
    Mr. Walden. Right, so it should not be marketed for that 
use.
    Mr. Wheadon. It is not marketed for that use.
    Mr. Walden. And would you encourage doctors not to 
prescribe it for that use?
    Mr. Wheadon. We obviously do not encourage doctors to 
prescribe it for that use.
    Mr. Walden. Would you encourage doctors not to prescribe it 
for that use which is different than not encouraging doctors to 
prescribe it? Because I'm learning a lot about language up here 
and how we prescribe off-label and how in journals or articles 
or posters when studies show these various drugs are not 
effective, according to the FDA, but yet you'll see words about 
effectiveness. And then I'm told that effectiveness is 
different than efficacy as defined by the FDA and that's a word 
choice I'm just getting confused about. So that's why I'm 
asking.
    Mr. Wheadon. We certainly have indicated that the drug has 
not been shown to be effective.
    Mr. Walden. Okay. So you would not encourage doctors--well, 
you can't encourage doctors to prescribe, that would be 
illegal?
    Mr. Wheadon. That's correct.
    Mr. Walden. All right, and on Pfizer, your two studies, if 
they were to be published, stand alone, those two studies 
individually would show that Zoloft is not effective as the FDA 
would say effective is, right, in treatment of----
    Ms. Clary. Each individual study, taken by itself----
    Mr. Walden. Taken by itself----
    Ms. Clary. Yes. But as you know, Pfizer made a 
determination that the most scientifically sound thing to do 
was to pull.
    Mr. Walden. To pull.
    Ms. Clary. I wanted to clarify a point because you were 
asking Dr. Wheadon about what the intention was when Pfizer 
filed and indeed, as I've said, we did file all these studies 
with the FDA. We, as you know, in 1997, received an approval 
for use in children, in adolescents with OCD. And this approval 
was based on one placebo-controlled trial, not two, but one.
    When we received the written request, it was clear in the 
written request that we were to perform two studies. What was 
not clear was that two studies needed to be positive in order 
to receive approval. It just wasn't clear, which is why we 
sought approval----
    Mr. Walden. Approval for pediatric depression?
    Ms. Clary. For use in pediatric depression--approval for 
use in pediatric depression.
    Mr. Walden. So the FDA letter to you didn't make it clear. 
You needed to replicate the study that showed that it was 
effective.
    Ms. Clary. Right, for efficacy approval. I don't want to 
sound like we're parsing words, but--based on our understanding 
of the OCD, we really didn't know whether we would need two 
positive studies, one positive study.
    Mr. Walden. Isn't that fairly standard though in scientific 
research to do a study and then you prove the results of that 
study?
    Ms. Clary. I think the nuance here is that because the drug 
was already approved for depression in adults and the tests, 
these two studies were in a sub-population which were children 
and adolescents, just as was the same with OCD, it wasn't 
clear.
    Mr. Walden. Can I refer you to tab 60 in the book? You'll 
see it's a sample written request from FDA, this is their 
sample letter which I assume they sent to you and it says on 
the second page, ``study design, pediatric efficacy and safety 
studies. For the controlled efficacy studies--''
    Ms. Clary. Tab 60?
    Mr. Walden. Tab 60. It starts out ``pediatric program 
summary statistics''.
    Ms. Clary. Yes, I have it.
    Mr. Walden. You have it, good. Go to the second page and 
actually under the pediatric depression, about three quarters 
of the way down you'll see the word ``consequently''?
    It says ``consequently, we believe that a pediatric 
depression claim for any anti-depressant already approved in 
adult depression would need to be supported by two independent, 
adequate and well-controlled clinical trials in pediatric 
depression.''
    So did they send you a letter different from this one then?
    Ms. Clary. I would have to check the exact letter, but I 
believe they did. My experience with other drugs is that the 
actual content of these letters has been changing and they've 
been becoming more specific.
    Mr. Walden. Can you supply us with that letter?
    Ms. Clary. Sure, I'd be happy to.
    Mr. Walden. This is what we've been given from the FDA as 
their sample which--you can understand why we----
    Ms. Clary. The letters have been changing and becoming more 
specific over time.
    Mr. Walden. Dr. Camardo, turn to tab 42, if you would. This 
is a document you prepared in response to inquiries, to any 
inquiries from anyone in the public about effects or bids or 
only doctor inquiries. Is this one tab 42, sir?
    Mr. Camardo. This is attachment D, use of vaccine in 
children or adolescents? Is that 42?
    Mr. Walden. I'll double check. I'm sorry, it should be Tab 
41.
    Mr. Camardo. Right. This is the so-called ``Dear Doctor'' 
letter.
    Mr. Walden. Okay, so this would go to doctors or to doctors 
or anyone who inquired?
    Mr. Camardo. No, this one went without inquiry. This was 
mailed to 450,000 doctors.
    Mr. Walden. So Wyeth was strengthening their warnings. Was 
this done at the request of the FDA or by the company itself?
    Mr. Camardo. This was the company's decision.
    Mr. Walden. At the time, Wyeth implemented these new 
warnings, did FDA raise any objections to Wyeth having that in 
its label?
    Mr. Camardo. The FDA allowed us to proceed with the letter 
and with the change in the label. I think they had a somewhat 
different view of what should be done, but they allowed us to 
proceed with this.
    Mr. Walden. Does the effect source still contain that 
warning?
    Mr. Camardo. No, this warning was eliminated in favor of 
the class label warning that was added in April. So I guess----
    Mr. Walden. Isn't it correct to say the FDA basically made 
you back off with more specific language?
    Mr. Camardo. Well, the FDA had a different view and they 
essentially asked everyone to adopt similar labeling that would 
be a little broader. I believe that would be----
    Mr. Walden. Didn't they make you take out the references to 
increased hostility?
    Mr. Camardo. They did want us to take out the references 
from the pediatric----
    Mr. Walden. Are you comfortable in doing that?
    Mr. Camardo. Well, we thought it was reasonable to keep it 
in the labeling, but when we compared what we were saying with 
what was in the class labeling about suicide warning, I thought 
at the time it would be a reasonable compromise and we also 
knew that there would be additional advisory committee 
discussion about what actually should be done here.
    Mr. Walden. Did you ask FDA to tell you to do that in 
writing?
    Mr. Camardo. I think that they--we have a record of 
telephone calls and teleconferences. I think we may have asked 
them to specifically request it in writing, but there is----
    Mr. Walden. You might want to turn to tab 40 in the book.
    Mr. Camardo. Okay.
    Mr. Walden. And you'll see this is from--to you from Dr. 
Katz.
    Mr. Camardo. Right, I see this.
    Mr. Walden. ``We note your agreement to our request to 
remove your proposed position of hostility and suicide-related 
adverse events from the precautions usage in children's 
section. As discussed during that April 28, 2004 meeting, we 
continue to feel it not would be helpful to include the 
language regarding reports of hostility and suicidality that 
you have proposed for the pediatric use section.''
    Why did you think it was important to include that 
language?
    Mr. Camardo. Actually, we were taking a pretty simplistic 
view which is we observed it in the trials. We couldn't explain 
it completely. We wanted to provide doctors with the 
information we had, even though it wasn't fully interpretable 
and that's why we thought----
    Mr. Walden. Basically, it's a directive and I assume you 
wanted to flag it as something physicians should watch for, if 
indeed, they were prescribing a drug that's not supposed to be 
prescribed to children?
    Mr. Camardo. I would say it's fair, a fair way to 
characterize what we wanted to do, yes, that we wanted them to 
be aware of it, yes.
    Mr. Walden. Thank you. My time has expired. The gentleman 
from Maine?
    Mr. Allen. Thank you, Mr. Chairman.
    Dr. Marcus, we'll come back to you. Let me restate the 
question, just so the record is clearer than it would be if 
people have to go back and look at it.
    FDA told Bristol-Myers that Serzone was not indicated for 
use in pediatric patients, but Bristol-Myers' sponsored study, 
tab 28, concludes that ``in this study, Serzone was shown to be 
safe and effective in the acute treatment of adolescents with 
major depressive disorder.''
    So the question was if your studies conclude that this drug 
is safe and effective for adolescents with MDD, why would the 
FDA not approve your drug for pediatric patients? Did the FDA 
disagree with the way your study was conducted or with its 
results?
    Mr. Marcus. It's really very simple and the primary outcome 
measure, if you go to the last slide on this tab, it gives the 
conclusions of the study and essentially on the primary 
efficacy measure which is sort of the one you have to be 
positive on for it to be, from a regulatory perspective, a 
positive study, we just missed statistical significance. We 
need .05 and we had .055. On every other measure in the study 
for efficacy, we were actually robustly positive.
    Mr. Allen. Did you go back and do another study or follow-
up studies on this particular----
    Mr. Marcus. We did a second study which essentially was 
absolutely no difference between Serzone and placebo. So we did 
a second study. That was--this was just in adolescents, but we 
did a study that was in both children and adolescents and that 
study was absolutely no difference between Serzone and placebo.
    Mr. Allen. So that's why you didn't pursue it any further, 
I take it?
    Mr. Marcus. That's correct.
    Mr. Allen. I would like to go through--I'd like to get the 
reaction of the panel to the AMA proposal. After you are 
finished, I understand that a representative from the AMA will 
testify about their support for a new Federal level 
comprehensive clinical trials registry.
    Two questions. Do you believe that the creation of this 
type of registry would benefit physicians and patients? And 
two, would your companies be willing to fully participate in 
the Federal clinical trials registry?
    Dr. Clary, why don't we start from your end this time?
    Ms. Clary. Yes, so the AMA proposal just has come out and 
we have looked at it. We haven't had time to fully digest it, 
but we are certainly open to considering it. We, as I've said 
repeatedly today, we really would like to convene a group to 
speak with multiple stakeholders to decide. But we're certainly 
very open to considering that.
    Mr. Allen. Mr. Osinsky?
    Mr. Osinsky. Organon is open to considering it. We don't 
know the details. We haven't studied it yet.
    Mr. Hayes. I'm going to provide pretty much the same 
answer. I have not spoken to people within senior management to 
have a sense of what their response to it is. I think we'll 
also consider it.
    Mr. Olanoff. As I indicated in my testimony, we are open to 
participating in centralized registries.
    Mr. Camardo. We're open to participating in centralized 
registries as well. I think it would help physicians if it 
could be managed appropriately, so that they can actually use 
it.
    Mr. Allen. Could you punch the button?
    Mr. Hayes. Same answer. We'd be open to it, but we'd have 
to see the details and discuss and I think take a position on 
whether it met the goals we've been speaking about today.
    Mr. Wheadon. We, as well, would be willing to consider it 
and further discuss it with the AMA.
    Mr. Allen. Thank you all. Dr. Wheadon, in a lawsuit brought 
against GlaxoSmithKline, Elliott Spitzer, the Attorney General 
of the State of New York, alleges that Glaxo misrepresented the 
full details of their studies regarding Paxil. The lawsuit 
alleges that an additional study, extensions to studies 329 and 
701 were misleading.
    First, can you please explain what an extension study is?
    Mr. Wheadon. Typically, studies have what we call an acute 
phase and an extension. The acute phase may run anywhere from 8 
weeks to 12 weeks. And an extension may go out through a year 
or longer.
    Typically, patients that are showing some level of response 
go into the extension, so it's a longer term treatment for 
those who are responding.
    The primary parameters for assessing efficacy are typically 
carried out in the acute phase, but then you do obviously some 
follow-on assessments to see how the efficacy or the response 
is maintained over the course of longer term treatment.
    Mr. Allen. Thank you. The lawsuit states that the extension 
of study 329 was not randomized and was designed to evaluate 
relapse rate and longer-term safety and not efficacy.
    Can you respond to that accusation, that charge?
    Mr. Wheadon. I wouldn't say it was necessarily an 
accusation or charge, as I mentioned, those patients that 
respond go into an extension and you then, in that frame of 
study, look at relapse rate. So what is the reoccurrence of the 
depressive symptoms, active drug versus placebo, so that's 
relapse.
    Mr. Allen. And that's why you would say it was not 
randomized, because it's a follow on for those people who are 
responding?
    Mr. Wheadon. Exactly.
    Mr. Allen. I understand that. The lawsuit further alleges 
that study 716 was not randomized, placebo-controlled or blind 
and included participants from completed studies of pediatric 
patients with MDD or OCD.
    Can you respond to that as well, same kind of answer?
    Mr. Wheadon. If I recall 716 was just sort of an ability 
for patients to have continued treatment, but it was no 
intended to test an a priori hypothesis per se.
    Mr. Allen. And finally, Dr. Wheadon, the lawsuit also 
asserts that Glaxo is allowed positive information about the 
pediatric use of Paxil to be disclosed publicly, but has 
withheld and concealed negative information concerning its 
safety and efficacy.
    Can you respond to those allegations about whether or not 
Glaxo has misrepresented information concerning the safety and 
efficacy of Paxil for treating major depressive disorder in 
children and adolescents?
    Mr. Wheadon. With all due respect to the New York State 
Attorney General, I think as we've disclosed to this committee, 
we have indeed published 329, 377 which is the negative 
studies, 701. So those studies have been published in various 
venues, be it peer-reviewed journals, abstracts, presentations.
    Mr. Allen. Thank you. Mr. Chairman, I yield back.
    Mr. Walden. Thank you. I just wanted to get a couple of 
things quickly here on the record, Dr. Wheadon. I note that 
this summer Glaxo posted all of its study reports for pediatric 
clinical antidepressant trials on its website for public access 
and this does go beyond simply post summaries. I also note that 
Glaxo posted study 511 which was a non-industry--I'm sorry, 
non-IND study on its website. Did Glaxo submit the 511 study to 
the FDA since it was a non-IND study? And is Glaxo required to 
do so?
    Mr. Wheadon. Well, the study, since it's non-IND, it's not 
required to be filed to the FDA, however, I think as we've 
discussed with the committee staff members before and as Dr. 
Woodcock pointed out, any data that's garnered in any studies 
that are on-going or included in annual reports in terms of 
safety information.
    Mr. Walden. And that's safety, not efficacy.
    Mr. Wheadon. That's safety, exactly.
    Mr. Walden. So if a non-IND study showed no efficacy, 
there's no requirement for the company to inform FDA of that 
result, correct?
    Mr. Wheadon. In the context of updating, you can, for 
example, report to FDA the outcome of the study or the progress 
of the study, but there's no regulatory requirement that that 
study report be filed to the FDA if it's not done an IND.
    Mr. Walden. So you do provide safety information in an 
annual report, but are not required to report efficacy results?
    Mr. Wheadon. That's correct.
    Mr. Walden. Is Glaxo going to post efficacy results of non-
IND studies on its clinical trial registry?
    Mr. Wheadon. We are doing that.
    Mr. Walden. So the Paxil registry has IND and non-IND 
studies posted to the website. Okay.
    One other question, just perhaps for all of you, do your 
companies engage in marketing studies or analysis for sales of 
products that are off-label? Do you look at that? Do you do 
marketing analysis out there to see who's prescribing what 
drugs that are off-label and to whom? Does anybody do that 
first of all?
    Mr. Hayes. I think the major way in which sales are 
analyzed is through national data bases of prescriptions. You 
can get a rough idea of the reasons why your products was 
prescribed over some certain period of time in the same way you 
can have some sense of how many units were sold in a particular 
period.
    Mr. Walden. Do you look at age groups?
    Mr. Hayes. I don't--age groups can be looked at. I am 
trying to think whether I've really seen that.
    Mr. Walden. I don't know about you specifically, but in the 
companies, are you doing market analysis?
    Mr. Hayes. Certainly to some extent.
    Mr. Walden. Obviously, this is big dollar stuff.
    Mr. Hayes. To some extent you could, but I think people 
are--again, I can't speak for other companies, but I think when 
we do a market analysis or a market research about something 
that's not on label, it's by way of exploring the possibility 
that patients and doctors need some indication and if we find 
such a need, we may well pursue the appropriate research and 
the appropriate interactions with the FDA to see if we can 
develop a drug for that indication.
    And I understand what you're getting at. I'm not aware of--
--
    Mr. Walden. I guess in the final analysis what I hear and 
what I've come to understand and correct me if I'm wrong, is 
that you do clinical trials that may not show efficacy and so 
some companies don't turn those trial results into the FDA 
because you don't pursue the label. I've heard that today. And 
yet, in some of the posters and in some of the publications, a 
novice like myself in reading the words would be left with the 
opinion that these drugs are indeed effective and we see those 
words used in treatment of young people for a very serious 
disease. Even when the FDA, and some of you know the FDA 
wouldn't certify these drugs for that use, and I think I've 
heard nobody is out there telling docs not to prescribe. You're 
not encouraging them to prescribe, but nobody is saying don't 
prescribe, other than maybe raising a flag or two about the 
hostility or suicide, being told by the FDA don't raise that 
flag the way you did it. And it's a big industry.
    Am I missing something here?
    Ms. Clary. If I could make one comment, and that is I would 
really like us not to forget the patients. I think you know 
that I practiced psychiatry for quite a long time.
    Mr. Walden. They are the ones who are most concerned about 
it.
    Ms. Clary. Yes, exactly. I think we all are. I know we 
share that and there are not a lot of treatments that have been 
proven effective for pediatric depression, but physicians are 
struggling to try to figure out the best way to treat this 
disease. They're faced with a patient in their office who has 
very significant symptoms. They can't prescribe the older 
drugs, the tricyclics because they were not shown to be helpful 
and they had safety problems, so it's really a dilemma, I 
think, for all of us.
    Mr. Walden. I appreciate the time you've taken to be here 
today and your comments and we may have, obviously, some 
questions. I think you've heard we'll submit for the record. 
We'll have another hearing on the 23rd. So thank you for your 
participation.
    We have a third panel that we'd like to--oh yes, you're 
dismissed, I guess I'm supposed to say. Excused, whichever.
    And our third panel is Dr. Ronald M. Davis, M.D., Member, 
AMA, Board of Trustees from the American Medical Association; 
Dr. Caroline Loew, Vice President of Scientific and Regulatory 
Affairs with PhRMA; and Dr. Richard Gorman, M.D., American 
Academy of Pediatrics.
    Okay, as you're aware the committee is hold an 
investigative hearing and when doing so it has had the practice 
of taking testimony under oath. Do you have any objection to 
your testimony being taken under oath? Let the record show they 
do not.
    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 any of you desire to be advised by 
counsel? The record shows they do not.
    In that case, I would rise, since you already are, raise 
your right hand and I will swear you in. Do you swear the 
testimony you're about to give is the truth, the whole truth 
and nothing but the truth?
    [Witnesses sworn.]
    Mr. Walden. They answered in the affirmative. Please be 
seated and we'll begin with the testimony of Dr. Davis.

 TESTIMONY OF RONALD M. DAVIS, MEMBER, AMA, BOARD OF TRUSTEES; 
   CAROLINE LOEW, VICE PRESIDENT, SCIENTIFIC AND REGULATORY 
    AFFAIRS, PhRMA; AND RICHARD GORMAN, AMERICAN ACADEMY OF 
                           PEDIATRICS

    Mr. Davis. Good evening. My name is Ron Davis. I'm a member 
of the American Medical Association's Board of Trustees and a 
preventive medicine physician in Detroit. On behalf of the AMA, 
thank you for the opportunity to share our views on the need 
for more clinical trial information pertaining to children and 
adolescents.
    The AMA has long supported congressional efforts on this 
front and we're pleased to be here today to offer a broader 
solution to further address this problem. Quite simply, 
physicians need complete and unbiased information about the 
safety and effectiveness of the treatments they prescribe for 
their patients. A centralized clinical trials registry would 
improve physician and researcher access to this information and 
would facilitate patient enrollment in clinical trials.
    The bottom line is that physicians and researchers who 
formulate treatment guidelines for patients must be able to 
trust the information they use. To this end, the AMA this past 
June called on the Department of Health and Human Services to 
establish a centralized registry for clinical trials conducted 
in the United States. How such a registry would be constructed 
and maintained requires further discussion with key 
stakeholders including Congress, HHS, the research community 
and the pharmaceutical manufacturers.
    As initial guidance, we recommend the following. The 
registry should include phase 2 and phase 3 clinical trials 
that evaluate a new drug, biologic or medical device, post-
marketing studies and other trials designed to test the 
therapeutic intervention. Identifying information should be 
included such as the name of the trial sponsor, sources of 
funding, a unique identifier and contact information for the 
persons responsible for the clinical trial.
    Details such as the trial purpose and objective, the 
methodology, the population and diseases being studied and the 
dates the trial began and ended should all be included in a 
simple, easy to understand format.
    To ensure that clinical trials are reported to the 
registry, Institutional Review Boards or IRBs should require 
registration as a condition for approval of the clinical trial. 
It is important to remember that the basic conduct and 
operation of IRBs are already federally regulated.
    And finally, clinical trial results should be made publicly 
available. Centralized clinical trial registry should offer 
links to published journal articles or clinical trial reports. 
And if a trial was terminated early, the reason for such 
termination should be explained.
    The AMA is encouraged by the individual efforts of a number 
of pharmaceutical companies, as well as the recent PhRMA 
proposals intended to promote voluntary disclosure of clinical 
trial information for currently marketed drugs.
    As we move forward, we hope to work closely with these 
organizations, as well as Congress, the Administration, and the 
research community to develop a centralized clinical trials 
registry that benefits physicians, researchers and especially 
our patients.
    Thank you.
    [The prepared statement of Ronald M. Davis follows:]

    Prepared Statement of Ronald M. Davis, MD, Member, AMA Board of 
         Trustees on Behalf of the American Medical Association

    The American Medical Association (AMA) appreciates the opportunity 
to present its views on the need for broader public information about 
clinical trials. We commend the Chairman and members of this 
Subcommittee for holding this important hearing. In particular, the AMA 
shares your commitment to improving the value of clinical research for 
the pediatric population.
    The AMA has long-standing policy that supports the development and 
testing of drugs in the pediatric age groups in which they are used. 
Specifically, AMA policy states,
        Our AMA urges pharmaceutical manufacturers and the FDA to work 
        with the American Academy of Pediatrics and experts in 
        pediatric medicine to identify those investigational drugs that 
        would have pediatric indications and set up a mechanism to 
        ensure that necessary pediatric clinical studies are completed 
        prior to submission of [New Drug Applications] (NDAs) for 
        approval of these drug products.
    Fortunately, through the leadership of the American Academy of 
Pediatrics with support from the AMA, Congress has passed and we have 
seen legislation enacted to address this problem. The Better 
Pharmaceuticals for Children Act (P.L. 107-109), which re-authorized 
and improved upon Section 111 of the Food and Drug Administration (FDA) 
Modernization Act of 1997 (P.L. 105-115), provides additional patent 
exclusivity as an incentive to pharmaceutical manufacturers to do 
clinical trials of their drugs in the pediatric population. In 
addition, in 2003 Congress passed the Pediatric Research Equity Act 
(P.L. 108-155), which provides the FDA with the authority to require 
pharmaceutical companies to evaluate the clinical effectiveness and 
safety of their products in children when appropriate. Recent evidence 
suggests these laws are proving successful in increasing the number of 
clinical trials conducted in children and in improving the pediatric 
information in FDA-approved drug product labeling. The AMA supported 
passage of these laws and is hopeful that we will continue to see 
necessary pediatric clinical trials conducted so that children will no 
longer bear the label of ``therapeutic orphans.''
    Against this backdrop of concern for continued and enhanced 
pediatric clinical trials, in today's testimony, the AMA will focus on 
the broader issue of clinical trials registries. The issue, which is 
not limited to pediatrics, involves the lack of disclosure or 
publication of the results, either positive or negative, of clinical 
trials involving a therapeutic intervention, such as a drug product. 
Such information is invaluable to researchers, scientists and 
physicians, who conduct or evaluate clinical research, formulate 
treatment guidelines and provide advice on best practices which 
ultimately benefits patients, both young and old.
    Therefore, more needs to be done to address the issues that are 
keeping physicians and researchers from having access to information 
about what clinical research is currently being conducted, as well as 
the results of such research, regardless of whether the clinical trials 
are done on adult or pediatric populations.
    At the AMA's 2004 Annual Meeting, our House of Delegates adopted a 
report by the Council on Scientific Affairs (CSA) which recommended, 
among other things, that ``the Department of Health and Human Services 
establish a comprehensive registry for all clinical trials conducted in 
the United States.'' Additionally it recommended that ``every clinical 
trial should have a unique identifier,'' and that ``all results from 
registered clinical trials be made publicly available through either 
publication or an electronic data-repository.'' A longstanding concern 
about the impact of pharmaceutical industry sponsorship on publication 
bias in pharmaceutical research was a major factor in adopting this 
policy.
    Publication bias is the selective publication of studies based on 
the direction (positive), magnitude, and statistical significance of 
the treatment effect. When an investigator has a financial interest in 
or funding from a company with activities related to his or her 
research, the research is more likely to favor the sponsor's product, 
less likely is to be published, and more likely to have delayed 
publication. Publication bias is often attributed to decisions made by 
authors/investigators and journal editors, but in fact can intrude into 
the entire process of planning and conducting the clinical trial and 
publishing the results, leading to outcome bias.
    In its review, the CSA found, among other things, that industry-
funded studies with positive results were more likely to be published 
than studies with negative or neutral results. Factors that contribute 
to such bias include: trial designs that make favorable results more 
likely; clinical trial agreements that may restrict publication of some 
results; and even the simple human factor that researchers may be more 
excited by and interested in pursuing publication of positive results. 
In addition, journal editors and reviewers may give preference to 
publishing positive results because they are more likely to impact 
medical practice and, therefore, be of more immediate interest to their 
audience. The consequences of these shortcomings are obvious. The 
evidence-based practice of medicine depends on the analysis of current 
research, and medical practice guidelines are often based on systematic 
reviews or meta-analyses of available data. If negative and neutral 
trial results are not published or lost, for whatever reasons, the 
interpretation of this data is incomplete and faulty, inevitably 
skewed, and presents a more positive picture than may be warranted.
    There is general agreement that the two most powerful remedies to 
publication bias are to register all clinical trials, and to make 
results publicly available. Clinical trials should be registered when 
they are begun so that essential details are made public from a trial's 
inception, rather than from publication many years later. Openness 
about trials in progress reduces the impact of publication bias, 
prevents duplication of effort, promotes collaboration, and may improve 
evidence-based medical practice.
    Recently, the International Committee of Medical Journal Editors 
(ICMJE), of which the Journal of the American Medical Association 
(JAMA) is a member, announced that it is considering a proposal to 
require registration of a clinical trial as a prerequisite for 
publication. The AMA applauds ICMJE's proposal and believes that such 
an effort will significantly increase the number of clinical trials 
that are registered. However, there are currently not enough peer 
reviewed medical journals in existence to accommodate and publish the 
results of every clinical trial, even with the increasing number of 
online journals. Additionally, hundreds of clinical trial registries 
currently exist, ranging from individual hospitals or practice groups 
to meta-registries that attempt to collate information from disparate 
sources. Yet, information in these registries is not standardized and 
many contain only a subset of trials, often in high profile areas such 
as cancer or AIDS. Many are hard to use, none are comprehensive, and 
many trials are not registered anywhere. It is for this reason, as well 
as for the reasons mentioned above, that the AMA has recommended a 
comprehensive clinical trials registry at the Federal level.
    The infrastructure for such a registry is already in place. 
ClinicalTrials.gov, established by Section 113, ``Information Program 
on Clinical Trials for Serious or Life-Threatening Diseases,'' of the 
Food and Drug Administration Modernization Act of 1997 (P. L. 105-115), 
currently provides information about federally and privately supported 
clinical research involving drugs for ``serious or life-threatening 
diseases and conditions.'' This registry includes information about the 
purpose of a trial and a brief description, inclusion and exclusion 
criteria, locations, and phone numbers for additional information and 
is required to be ``integrated and coordinated with related activities 
of other agencies of the Department of Health and Human Services, and 
to the extent practicable, coordinated with other data banks containing 
similar information.'' Currently, this registry contains references to 
roughly 7885 NIH-sponsored trials, 2382 industry-sponsored trials, 4566 
university-sponsored trials, and 379 trials sponsored by other Federal 
agencies.
    ClinicalTrials.gov is not a comprehensive registry. For example, 
trials do not have to be registered if the sponsor has provided a 
detailed certification to the Secretary that disclosure of such 
information would substantially interfere with the timely enrollment of 
subjects in the investigation, and the Secretary agrees. Also, 
ClinicalTrials.gov does not require the results of clinical trials to 
be included although the law allows the registry to include information 
pertaining to the results of clinical trials, with the consent of the 
sponsor. Finally, a recent analysis by FDA staff showed that many 
industry-sponsored trials have not been submitted to the registry at 
all.
    While it is still too early in the process to say definitively what 
a comprehensive Federal clinical trial registry should include or 
precisely how it should be implemented, the AMA recommends that such a 
comprehensive clinical trials registry should meet the following 
criteria:

1. To the extent possible, the registry should be comprehensive. For 
        example, Phase 2, 3 and 4 clinical trials conducted in support 
        of new drug, biologic, or device applications, other randomized 
        controlled trials (e.g., investigator-initiated and federally-
        funded studies involving therapeutic interventions), and 
        pharmacoepidemiologic studies designed to test a hypothesis 
        should be included. At the same time, however, access to 
        information to more effectively translate clinical research 
        into medical practice must be balanced with the need to protect 
        pharmaceutical manufacturers' proprietary information in order 
        to preserve the incentive to conduct clinical trials that will 
        result in innovative new therapies. How to achieve this balance 
        requires further discussion among key stakeholders.

2. Identifying information should be included such as, the name of the 
        trial sponsor(s), protocol number and contact information for 
        the lead principal investigator or person with overall 
        responsibility for the trial. Additionally, a unique alpha-
        numeric identifier should be assigned by a database 
        administrator. For example, trials registered through 
        ClinicalTrials.gov are assigned a unique NLM identifier (e.g., 
        NCT00037952).

3. Sources of funding for the clinical trials should be revealed, 
        complete with reference numbers given to the trials by each 
        funding agency.

4. Trial details should be included while also ensuring that the 
        information is not overly burdensome for either patients or 
        researchers who wish to access the information. Such details 
        should include:
     Trial purpose and/or Objectives;
     Type of trial, for trials conducted as part of an NDA, the phase 
            of the trial;
     Methodology (Interventions and duration of treatment for trial 
            groups);
     Title of the trial and acronym (if relevant);
     Disease or condition;
     Participants (eligibility criteria);
     Trial locations and Principal Investigator(s);
     Recruitment status;
     Date trial started; and
     Date completed or terminated.

5. The results of all clinical trials should be publicly available. If 
        the trial was terminated, the reason for the termination should 
        be explained. Conceptually, the registry could include a link 
        to another site where the published results could be found 
        (i.e., PubMed citation), or for studies that were conducted in 
        support of a New Drug Application (NDA), a link to the Medical 
        Review of the NDA. We recognize that there are inherent risks 
        in publishing data that has not been validated or peer-reviewed 
        in one way or another. The question of what would comprise 
        validated results (other than the raw data) for studies that 
        have not been published in the peer-reviewed literature or as 
        part of an NDA needs broader discussion. The synopsis of the 
        guideline approved by the International Conference on 
        Harmonization for the structure and content of clinical study 
        reports may be a useful template for standardized reporting of 
        such results. This guideline and synopsis are available 
        electronically on the FDA website www.fda.gov/cder/guidance/
        iche3.pdf.

6. In order to create an efficient enforcement mechanism, approval of 
        clinical trial protocols by Institutional Review Boards (IRBs) 
        should include the additional criteria of clinical trial 
        registration and assignment of a unique alpha-numeric 
        identifier. The basic conduct and operation of IRBs is already 
        federally-regulated.
    The AMA recognizes that there are other proposals currently that 
attempt to address the issues of publication bias, and we applaud the 
independent efforts of organizations such as ICMJE and the 
Pharmaceutical Research and Manufacturers Association (PhRMA) who, on 
June 30, 2004, released an update of its voluntary guidance on 
``Principles for Conduct of Clinical Trials and Communication of 
Clinical Trial Results.'' PhRMA's ``principles'' cover (1) commitment 
to protecting research participants; (2) conduct of clinical trials; 
(3) ensuring objectivity in research; and (4) public disclosure of 
clinical trials results. While these principles do not necessarily 
address all of the AMA's concerns, particularly with regard to 
registration of clinical trials, they contain much we could support. It 
is the AMA's hope that as we move forward in our efforts to establish a 
comprehensive clinical trials registry, we are able to work closely 
with all interested parties, including both the Congress and the 
Department of Health and Human Services, to make sure that our nation's 
patients have access to complete information, either directly or 
through their physicians or other researchers, to allow them to make 
informed decisions about their health care treatment options.
    Once again, the AMA commends the committee for holding today's 
hearing, and we thank the chairman for the opportunity to present our 
views. We look forward to working together on this important issue.

    Mr. Walden. Thank you, Dr. Davis.
    Dr. Loew.

                   TESTIMONY OF CAROLINE LOEW

    Ms. Loew. Mr. Chairman and members of the subcommittee, 
thank you for the opportunity to testify today on issues 
surrounding the publication and disclosure of clinical trial 
information.
    My name is Dr. Caroline Loew and I'm the Vice President of 
Scientific and Regulatory Affairs at PhRMA, Pharmaceutical 
Research and Manufacturers of America. PhRMA shares the 
subcommittee's view that clinical trial information should be 
made available to physicians and patients and we have taken 
concrete steps to ensure that the clinical trial process is 
transparent and accessible.
    At the outset, it is important to distinguish between a 
clinical trial registry and a clinical study results data base. 
The two are often confused. A registry, such as 
clinicaltrials.gov, created by Section 113 of FDAMA, lists 
clinical trials into open and recruiting patients. A clinical 
study results data base, by contrast, has results of completed 
studies. PhRMA believes it is important to keep these concepts 
separate when discussing publication and disclosure issues to 
clinical trials.
    Regarding the clinical trials registry, PhRMA strongly 
supports the National Library of Medicine's clinical trial 
registry as an important resource for physicians and patients 
seeking information about on-going clinical trials.
    Following passage of FDAMA, it took several years to 
implement the registry. PhRMA worked closely with the National 
Library and the FDA to ensure that the registry was 
successfully implemented and that it educated its members about 
the registry and the statutory requirements.
    Further details on our efforts in these regards have been 
provided in our written testimony, but in short, we believe the 
registry is a critical resource for patients and physicians and 
PhRMA and its member companies are committed to ensuring that 
it is complete and effective.
    I would now like to turn to the disclosure of clinical 
study results. PhRMA's commitment to transparency in this area 
is not new. It was 2 years ago that the PhRMA Board approved a 
set of principles on the conduct of clinical trials and 
communication of clinical trial results. These principles 
expressed the commitment of PhRMA member companies to 
communicate the results of all hypothesis testing clinical 
trials, both positive and negative, for drugs that are on the 
market.
    Given the publication in a peer-reviewed journal, as we've 
heard today, is not always possible, other publication means 
are necessary. PhRMA has sought to address this problem and I 
am pleased to inform this subcommittee that the PhRMA Board 
recently approved the establishment of a clinical study results 
data base. This data base is a central, widely accessible, web-
based repository for clinical study results in a user-friendly, 
standardized format. This data base will make clinical study 
results more transparent and accessible and be a valuable 
resource for physicians and patients.
    The data base will contain results from all hypothesis 
testing clinical studies completed since the first of October 
2002 for drug products approved in the United States. It will 
have a bibliography of published articles, summaries of 
unpublished clinical studies, as well as a link or reference to 
the FDA approved drug label. Study summaries are in a standard, 
nonpromotional format, accepted by regulators in the United 
States, Europe and Japan.
    It is important that the information presented not be 
considered a substitute for the FDA-approved prescribing 
information. The website will thus include a notice stressing 
that the data base is being made available for informational 
purposes only and that the full prescribing information 
approved by the FDA should be the physicians primary source of 
information about the use of every medicine.
    We have consulted with several physician groups, including 
the American Medical Association, and the American Psychiatric 
Association. While we do not want to speak for any of these 
groups, we are optimistic that we're heading in the right 
direction. We realize it will be critical to obtain on-going 
feedback from physicians and patients once the site is up and 
running. There is a form on the site for this purpose and we 
look forward to receiving feedback over the coming months.
    Finally, PhRMA believes the data base will be most useful 
if it is administered in partnership with, or by, an 
independent third party. We plan to explore this possibility. 
However, as we are committed to establishing the data base as 
quickly as possible, we will be launching it initially as a 
PhRMA project. A data base will be operational and available 
for public use on the first of October of this year, with 
information being added on an on-going basis.
    In sum, PhRMA and its member companies are firmly committed 
to transparency of clinical trial information. We are excited 
about our data base initiative, and we will be pleased to keep 
the subcommittee updated.
    Thank you for the opportunity to inform the subcommittee 
about PhRMA's activities in this critical public health area.
    [The prepared statement of Caroline Loew follows:]

  Prepared Statement of Caroline Loew, Vice President, Scientific and 
   Regulatory Affairs, Pharmaceutical Research and Manufacturers of 
                                America

                              INTRODUCTION

    Mr. Chairman and members of the subcommittee, thank you for the 
opportunity to testify today on issues surrounding the publication and 
disclosure of clinical trial information. My name is Dr. Caroline Loew, 
and I am Vice President of Scientific and Regulatory Affairs at the 
Pharmaceutical Research and Manufacturers of America, also known as 
PhRMA. PhRMA represents the country's leading research-based 
pharmaceutical and biotechnology companies, which are devoted to 
inventing medicines that allow patients to lead longer, healthier and 
more productive lives. Our member companies invested more than $32 
billion last year in discovering and developing new medicines for 
American patients. It is thus no overstatement to say that PhRMA 
companies are leading the way in the search for cures.
    While I cannot provide any information specific to anti-depressant 
clinical trials conducted by our member companies, I can address 
generally PhRMA's efforts to facilitate the accessibility of 
information about clinical trials. PhRMA and its member companies are 
committed to ensuring that physicians and patients have access to all 
relevant information from the clinical studies our companies conduct--
consistent with applicable regulatory requirements--so that our 
products can be used in a manner that is as safe and effective as 
possible. This commitment is reflected in the PhRMA Principles on 
Conduct of Clinical Trials and Communication of Clinical Trials Results 
(the Principles), which I will discuss later in more detail, and in our 
strong support for Section 113 of the Food and Drug Administration 
Modernization Act (FDAMA). In short, PhRMA shares this subcommittee's 
view that clinical study information, including both positive and 
negative data, should be made available to physicians and patients, and 
we have taken concrete steps to ensure that the clinical trial process 
is transparent and accessible.
    Before discussing the steps we have taken to improve transparency, 
it is important to distinguish between two different concepts: the 
clinical trial registry and the clinical study results database. A 
clinical trial registry, of which there are many, is designed to inform 
patients and health care providers about clinical trials that are open 
and recruiting patients. An example of a clinical trial registry is the 
website clinicaltrials.gov created by Section 113 of FDAMA. A clinical 
study results database, by contrast, is designed to provide access to 
the results of clinical studies that have already been completed. These 
two concepts often are confused, but they are fundamentally different 
and are intended for different audiences. PhRMA thus believes it is 
important to keep these concepts separate when discussing publication 
and disclosure issues for clinical trials.

                        CLINICAL TRIALS REGISTRY

    The first issue I would like to address today is PhRMA-member 
participation in the clinical trial registry established by Section 113 
of FDAMA. In particular, I would like to discuss the steps taken by 
PhRMA and its member companies to ensure compliance with the 
requirements of Section 113.
    PhRMA strongly supports the National Library of Medicine's Clinical 
Trials Registry as an important resource for physicians and patients 
seeking information about ongoing clinical trials for serious or life-
threatening diseases and conditions. While a clinical trial should not 
be viewed as a treatment option, such trials nevertheless can provide 
access to promising new therapies for seriously ill patients with few 
other options. Ultimately, a successful and robust clinical trial 
enterprise in the U.S. leads to new cures for all patients. PhRMA thus 
supports full participation in the Clinical Trials Registry by all 
sponsors of eligible clinical trials.
    Following passage of FDAMA, the National Library of Medicine and 
the Food and Drug Administration (FDA) took several years to establish 
and implement the registry. During that time, PhRMA worked closely with 
both government organizations to ensure that the registry was 
successfully implemented. For instance, PhRMA established a task force 
on Section 113 that provided significant comments and feedback to FDA 
and NLM during the implementation period on a number of issues 
associated with the registry, including technical issues regarding the 
web-based interface for posting clinical trial information. PhRMA's 
efforts have been directed at ensuring that the registry functions as 
seamlessly as possible so that patients and physicians have access to 
all relevant information about ongoing clinical trials.
    PhRMA also has made significant efforts to educate its members 
about the registry and the statutory requirement to submit information 
about ongoing clinical trials regarding serious or life-threatening 
diseases and conditions. On March 21, 2002, for instance, PhRMA 
notified its member companies (through its list of regulatory contacts) 
that as of March 18, 2002, the registry had begun accepting clinical 
trial information from industry sponsors and thus that the Section 113 
reporting requirement had finally been implemented. PhRMA specifically 
informed its members in that memorandum that ``there is an obligation 
on the part of all sponsors to submit descriptive information on the 
drug trial, recruitment information and trial location and contact 
information.'' Likewise, on November 7, 2003, PhRMA sent another 
memorandum reminding its members of the Section 113 reporting 
requirements and requesting that they ``review [their] ongoing trials 
to see if they meet the criteria [for submission] as outlined in the 
FDA guidance.''
    PhRMA and its member companies are strongly committed to full 
implementation of the Clinical Trials Registry. This issue, in fact, 
was discussed at a recent meeting of the PhRMA board of directors, 
during which we reiterated PhRMA's history of strong support for the 
registry and the need to ensure that all PhRMA members are and continue 
to be in full compliance with the reporting requirements. The 
commitment to transparency thus is being addressed at the highest 
levels of our member companies.
    Although there have been some reports of industry non-compliance, 
we are not aware of any reliable information demonstrating that the 
pharmaceutical industry is not meeting its commitment to comply with 
Section 113 with respect to clinical trials for serious and life-
threatening diseases. Information from the FDA appears based on 
submission rates for the first nine months of 2002. We do not believe 
these data should be construed as representative of the situation that 
exists today since the registry did not even begin accepting industry-
sponsored clinical trial information on a routine basis until March 
2002, three months into the evaluation period selected by the FDA.
    PhRMA understands that the FDA is undertaking a more comprehensive 
study of compliance with the requirements of Section 113 and looks 
forward to reviewing that study when it is completed. As such, we 
believe that conclusions about industry compliance should be deferred 
until the FDA's report has been completed and fully reviewed. If the 
FDA study identifies current problems with the system, we will work 
closely with the FDA and our member companies to identify the source of 
those problems and to make any necessary improvements as quickly as 
possible to ensure that there is full compliance with the statutory 
reporting requirements.
    The registry clinicaltrials.gov is a critical resource for patients 
and physicians, and PhRMA and its member companies are committed to 
ensuring that it is complete and effective.

                    CLINICAL STUDY RESULTS DATABASE

    I would now like to turn to the second issue before the 
subcommittee this morning: the communication and disclosure of clinical 
study (clinical trial) results. PhRMA member companies are firmly 
committed to communicating meaningful results of all controlled 
clinical trials of marketed drugs--regardless of outcome. This means 
that results will be communicated if they are positive, negative, or 
anywhere in between. While these disclosures of negative results may 
not make splashy headlines or conform to the current negative view of 
the pharmaceutical industry, they are made everyday by this industry. 
One recent example is the disclosure of the results of a multi-year 
head-to-head trial involving two well-known cholesterol-lowering 
agents, even though the results did not support the marketing position 
of the sponsor of the trial.
    And this commitment to transparency is not new. Two years ago, the 
PhRMA board of directors approved a set of voluntary Principles on 
Conduct of Clinical Trials and Communication of Clinical Trial Results 
(the Principles). These Principles, which have been in effect since 
October 1, 2002, express in straightforward language the commitment of 
PhRMA-member companies to communicate the results of clinical trials, 
both positive and negative:
        ``We commit to timely communication of meaningful results of 
        controlled clinical trials of marketed products or 
        investigational products that are approved for marketing, 
        regardless of outcome.'' (PhRMA Principles, Section 4(a)).
    To strengthen this commitment even further, the PhRMA executive 
committee approved at its June 2004 meeting additional ``Questions and 
Answers'' to clarify some of the concepts in the Principles. In 
particular, the Principles now state that PhRMA member companies commit 
to publish the results of ``all hypothesis-testing clinical trials 
[they] conduct, regardless of outcome, for marketed products or 
investigational products that are approved for marketing.'' (PhRMA 
Principles, page 30). Significantly, the Principles clearly state that 
results should be communicated regardless of whether they are positive 
or negative. Copies of the updated Principles have been provided to 
this subcommittee and staff.
    The Principles encourage sponsors to communicate clinical trial 
results by means of publication in a peer-reviewed medical journal, 
such as the New England Journal of Medicine, but recognize that 
manufacturers do not control which studies get published and that not 
all studies will merit publication in a peer-reviewed journal. The 
Principles thus provide for alternate methods of communication, such as 
through presentation at a public scientific meeting or posting the 
results on a website.
    One difficulty with these alternative methods of communication is 
they often only reach a limited audience, such as the physicians who 
attend a particular meeting. PhRMA believes an appropriately designed 
internet database could solve this problem. By providing a central, 
widely accessible repository for clinical study results and a 
standardized format for the reporting of such results, a clinical study 
results database could serve the valuable function of making clinical 
trial results more transparent and accessible. More importantly, in our 
opinion, this could be a valuable resource to support practicing 
physicians and their patients.
    Consequently, I am pleased to inform this subcommittee that the 
PhRMA board of directors recently approved the establishment of a 
Clinical Study Results Database. The database is a central, widely 
accessible, web-based repository for clinical study results in a user-
friendly, standardized format. This database will serve the valuable 
function of making clinical study results for U.S.-marketed 
pharmaceuticals more transparent.
    The database will contain the results from all ``hypothesis-
testing'' clinical studies completed since October 1, 2002--the 
implementation date of the PhRMA Principles--for drug products that are 
approved in the United States. This will include both positive and 
negative results by providing a bibliography of published articles and 
unpublished clinical study summaries. In short, the database will 
contain information that is consistent with the PhRMA Principles, i.e., 
the results of all hypothesis-testing clinical trials, regardless of 
outcome, for marketed drugs or investigational drugs that are approved 
for marketing.
    The information on the database will be presented in a standard 
format that is easily searchable and includes the sponsoring company's 
name, the proprietary and generic names of the drug, a link or 
reference to the FDA-approved drug label, the studied indication(s), a 
bibliography of published studies together with a link (where 
available) to the printed articles, and a summary of the results of 
clinical studies that have not been published.
    The summaries of unpublished results will be presented in a 
standard format accepted by regulators in the United States, Europe and 
Japan--the International Conference on Harmonization's (ICH) E-3 
guidance on the structure and content of clinical study reports. This 
will provide scientific information about the results of a study in a 
standard, non-promotional manner that doctors can understand. It will 
include basic information about the study and its results, such as the 
design of the trial, the number of patients studied, the dose and mode 
of administration, and a summary of conclusions and outcomes on the 
safety and efficacy of the drug.
    As we implement the database, we are addressing several important 
regulatory and policy issues. For example, while PhRMA supports both 
the free flow of scientific information and the practice of medicine, 
PhRMA wants to ensure that the information in the database is not 
considered a substitute for the FDA-approved prescribing information. 
Thus, while it is important that the information in a results database 
be comprehensive and presented in a manner that is useful to physicians 
seeking additional information about a drug product, we think it is 
equally important that users understand the limitations of the 
database. The website thus will include a notice stressing that the 
database is being made available for informational purposes only and 
that the full prescribing information approved by the FDA should be the 
physician's primary source of information about the use of every 
medicine. In addition, the database will provide a link to the drug's 
full prescribing information.
    We also want to ensure that the database is useful for practicing 
physicians. During the past few months, we have consulted with several 
physician groups, including the American Medical Association (AMA), the 
American Psychiatric Association, and others. While we do not want to 
speak for any of these groups, we are optimistic that we are heading in 
the right direction. We realize, however, that it will be critical to 
obtain ongoing feedback from these groups and from individual 
physicians and patients once the site is up and running. For that 
reason, the site will have a web-based form so users can comment on the 
utility of the database. We look forward to using this feedback to 
improve the site over the coming months.
    Finally, PhRMA believes a database will be most useful if it is 
administered in partnership with or by an independent third-party. We 
thus plan to explore the possibility of partnering with an independent 
group to actually administer the database. Because we are committed to 
establishing a database as quickly as possible, however, we do not 
intend to wait for a third party before initiating the program. On the 
contrary, we plan to establish the database, at least initially, as a 
PhRMA project to ensure it is up and running and available to 
practicing physicians in a timely manner. We will then seek to 
transition the program once an appropriate partner or independent third 
party has been identified.
    PhRMA also believes that the need for rapid deployment of a 
database counsels against government involvement at this time. For 
instance, the registry authorized by Section 113 of FDAMA was not fully 
implemented by the National Library of Medicine until nearly five years 
after passage of the authorizing legislation. We do not believe it is 
in anybody's interest to delay implementation of a results database in 
a similar fashion.
    PhRMA is taking a leadership role on this issue and plans to have 
its Clinical Study Results Database operational and available for 
public use on October 1, 2004. However, we realize that this is no 
small undertaking and expect that it may take up to a year before all 
relevant information is incorporated, especially clinical study 
information from complex multi-national phase IV studies.
    In sum, PhRMA and its member companies are firmly committed to the 
value of transparency of clinical trial information. We are excited 
about our initiative to establish the Clinical Study Results Database 
and anticipate rapid progress in the coming weeks. We would also be 
pleased to keep this subcommittee updated on its progress.
    Thank you for this opportunity to inform the subcommittee about 
PhRMA's activities in this critical public health area.

    Mr. Walden. Thank you, Dr. Loew.
    Dr. Gorman.
    While that buzzer is going off, what we're going to do is 
take your testimony, recess, and then we're going to go vote 
and come back for at least one round of questions before 
heading to the airports.
    Thank you.

                   TESTIMONY OF RICHARD GORMAN

    Mr. Gorman. Mr. Chairman, members of the committee, I am 
Richard Gorman, a practicing pediatrician for over 20 years. I 
am pleased to be here on behalf of the American Academy of 
Pediatrics which represents 60,000 pediatricians nationwide. My 
testimony has also been endorsed by several pediatric academic 
societies.
    I want to thank all the members of the Energy and Commerce 
Committee on behalf of the Academy and especially 
Representatives Jim Greenwood, Henry Waxman and Mike Bilirakis 
for their exceptional efforts, leadership and support of 
legislation that has advanced children's health.
    In my practice, I am able to better care for my young 
patients because of the passage of the Best Pharmaceuticals for 
Children Act and the Pediatric Research Equity Act.
    The American Academy of Pediatrics is pleased to testify 
today about the publication and disclosure of clinical trial 
findings. Over the last several years, the Academy has been a 
champion for disseminating information gained through pediatric 
clinical drug trials and has strongly supported these efforts 
as they relate to all medications, not just anti-depressants.
    This important issue is neither simple, nor easy to 
navigate and we want to thank you for beginning now to engage 
the medical community, pharmaceutical manufacturers, 
researchers, scientific journal editors, policymakers and other 
stakeholders in this open, thoughtful discussion with a goal of 
constructing constructive solutions.
    I'd like to focus my remarks on three major points. First, 
there are models for disseminating clinical trial information 
already in use. In 2002, the Best Pharmaceuticals for Children 
law established a mechanism to provide a public summary of 
clinical and medical information gathered through the clinical 
trial medications. An example of one of these summaries is 
attached to my written testimony.
    This information is intended to complement the label 
information by providing pediatricians and other health 
professionals with clinically significant findings from trials. 
This information is available for physicians to review, but is 
not necessarily included in the label. For an example, if 
Effexor is approved in adults for the treatment of major 
depressive disorders and generalized anxiety disorder, the 
pediatric section for Effexor reads simply that safety and 
effectiveness in individuals under 18 has not been established. 
Pediatric studies were conducted and the FDA clinical review of 
Effexor is available on the FDA website. The clinical summary 
states that Effexor failed to demonstrate effectiveness for the 
treatment of major depressive disorder and generalized anxiety 
disorder for 6 to 17-year-olds.
    Under the present legal and regulatory structure, the Food 
and Drug Administration recommended not including this 
demonstrated lack of pediatric efficacy in a positive way on 
the label, despite the accuracy of the label statement, not 
demonstrates safe and effective. The availability of important 
information for both clinicians and parents was not widely 
appreciated. The availability of this critical clinical 
information is a new phenomena which is only available in a 
limited way for clinical trials conducted under BPCA.
    These clinical summaries provided as a result of BPCA may 
be used as a model for the development of a dissemination tool 
for all clinical trial data that are determined to have 
important clinical findings.
    Second, we need to determine the scope of clinical trial 
reporting. While there presently seems to be compelling reasons 
to focus on medications related to the treatment of mental 
illness, there is limited scientific rationale as to why 
medications for this class of conditions should be highlighted 
over other medications in developing a national response to 
prevent subsequent miscommunication about clinical drug trial 
results.
    The need to publish and disclose findings from clinical 
trials is not limited to a particular drug, a particular age 
group or any specific medical therapy.
    Last, solutions require thoughtful and thorough review of 
both the needs and barriers to this dissemination. It is 
critical that we give careful consideration to the developments 
of a means to review and summarize in an impartial and accurate 
way, the extensive clinical trial data. We need to develop a 
system of dissemination of this information in a format that 
can be readily understood by the average U.S. citizen as well 
as the medical community.
    Let me conclude by saying it is not an issue of if there is 
a need to provide health care professionals and patients 
appropriate information about clinical findings. Rather, it is 
a matter of how and when this information is to be provided. 
Existing models such as pediatric clinical trial summaries 
within the Best Pharmaceuticals for Children Act may help shape 
this process. The AAP and pediatric societies stand ready too 
and expect to be called upon to provide their expertise and to 
participate in this process.
    Thank you, Mr. Chairman.
    [The prepared statement of Richard Gorman follows:]

   Prepared Statement of Richard Gorman for the American Academy of 
                               Pediatrics

    Mr. Chairman, members of the Committee, I am Richard Gorman, MD, 
FAAP, a practicing pediatrician who has taken care of infants, children 
and adolescents for over 26 years. I am pleased to be here on behalf of 
the American Academy of Pediatrics (AAP), which represents 60,000 
pediatricians nationwide.
    Though I am a Clinical Associate Professor of Pediatrics at the 
University of Maryland School of Medicine, and chair of the AAP 
Committee on Drugs, it is in my practice, Pediatric Partners in 
Ellicott City, Maryland, that I see first-hand the need for 
appropriately studied and approved medicines for children. I can also 
say with a sense of pride that through the efforts of the Congress, the 
Administration, and the Academy and pediatric societies, I am able to 
provide better care to my young patients because of the passage of 
important pediatric-focused legislation such as the Best 
Pharmaceuticals for Children Act (BPCA-Pub. Law 105-155) and most 
recently the Pediatric Research Equity Act (PREA-Pub. Law 108-155). 
With over 80,000 pediatric visits annually in the five clinical sites 
in four counties in Maryland, my partners and I can attest to the 
importance of having information available regarding safe and effective 
pediatric drug dosing.
    This testimony is also endorsed by the pediatric academic research 
community that includes the Ambulatory Pediatric Association, American 
Pediatric Society, Association of Medical School Pediatric Department 
Chairs and the Society for Pediatric Research also supports and 
endorses the Academy's testimony. These societies comprise academic 
general pediatricians, pediatric researchers, and full time academic 
and clinical faculty responsible for the delivery of health care 
services to children, the education and training of pediatricians, and 
the leadership of medical school pediatric departments.
    Before I begin my formal testimony, I want to thank the Energy and 
Commerce Committee on behalf of the American Academy of Pediatrics and 
the pediatric academic societies for its leadership and support of 
legislation that advances children's health--particularly pediatric 
therapeutic issues. This hearing is yet another example of the 
Committee's strong desire to ensure that infants, children and 
adolescents are not an afterthought when it comes to clinical studies 
that may affect the health and wellbeing of our citizens. I would be 
remiss if I didn't also thank Representatives Jim Greenwood, Henry 
Waxman, Mike Bilirakis and the other members of the Subcommittee for 
their efforts on behalf of children.
    The issue of today's hearing ``Publication and Disclosure Issues in 
Anti-Depressant Pediatric Clinical Trials,'' is both timely and 
complex. Over the last several years, the AAP has been a champion for 
disseminating information gained through pediatric clinical drug trials 
and has strongly supported these efforts as they relate to all 
medications, not only anti-depressants.
    The recent media attention regarding allegedly suppressed negative 
study results related to antidepressant use in children is just the 
latest volley on the issue of pediatric use of psychotropic 
medications. While the New York Attorney General's lawsuit against 
GlaxoSmithKline, the makers of Paxil, may be an appropriate trigger to 
action, the AAP and pediatric societies urge that the response by 
policymakers, whether in the public or private sectors, not be simply 
reactive but rather thoughtful and comprehensive.
    This committee should be commended for their efforts to explore the 
publication and disclosure of pediatric clinical trial findings. 
However, the AAP and pediatric societies respectfully caution that this 
important issue is neither simple nor easy to navigate. Acknowledging 
the degree of difficulty must not be interpreted as a desire to avoid 
or delay addressing this issue. Rather, it is a plea that efforts begin 
NOW to engage the medical community, pharmaceutical manufacturers, 
researchers, scientific journals, policymakers and other stakeholders 
in an open, thoughtful, thorough discussion with the goal of developing 
constructive solutions to this vexing problem.
    Let me propose an analogy: publication and disclosure of anti-
depressant pediatric clinical trails is a small tip of an iceberg 
visible above the water line, giving warning to great danger lurking 
nearby--if we responded by simply addressing drug trials of 
antidepressants it would be comparable to removing only the tip of the 
iceberg--thereby obscuring the rest of the iceberg and increasing the 
overall danger.
    I would like to address several issues during my testimony.

 The need to disseminate pediatric findings of information is one of 
        great importance to the pediatric community. Some progress has 
        begun through the dissemination of information provision within 
        the Best Pharmaceuticals for Children Act, but more is needed;
 The need to publish and disclose findings from clinical trials is not 
        limited to a particular class of drugs or to just infants, 
        children and adolescents. In fact, it is not limited to drugs, 
        as the same concerns apply to clinical trials focused on other 
        non-pharmacological therapies--but for practical reasons the 
        AAP suggests that the initial efforts to create a clinical 
        trial registry center on medication trials;
 The issues surrounding the need to publish and disclose all sentinel 
        clinical trial findings are compelling and complex. Solutions 
        require thoughtful and thorough review of the needs and 
        barriers. It is critical that we give careful thought to the 
        development of the means to summarize and review with accuracy 
        the extensive trial data and results, and develop a system for 
        dissemination of this information in a format that can be 
        readily understood by the average U.S. citizen as well as the 
        medical community.

Disseminating Pediatric Clinical Trial Information:
    There currently exists a mechanism to provide a public summary of 
clinical and medical information gathered through pediatric clinical 
trials of medications--the ``Dissemination of Information'' provision 
within the Best Pharmaceuticals for Children law (Pub Law 105-115). The 
AAP was a catalyst for inclusion of this provision in BPCA.
    Congress acknowledged that timely dissemination of information to 
pediatricians, health care practitioners, and the public about findings 
in the pediatric studies is critical to ensuring that infants, 
children, adolescents and their caregivers have appropriate information 
about the medications available for their use. Dissemination of 
information is intended to not only complement the label information by 
providing pediatricians and other health professionals with significant 
clinical findings that are necessary for pediatricians and physicians 
to review but which may not be included in the label.
    The intention of the law is to make important information available 
to pediatricians and other health professionals within 6 months of 
submission of a report on a pediatric study, while ensuring that 
confidential and commercial trade secrets are not revealed through the 
summary process. These clinical and medical summaries are available on 
the pediatric page of the Food and Drug Administration web site. As an 
attachment to my testimony, I have included a copy of the pediatric 
Clinical Review of Effexor (venlafaxine) used for major depressive 
disorders (MDD) to illustrate the concise and useful information 
included in the summaries.
    These pediatric clinical summaries are an important starting point. 
They currently focus on a narrow but important segment of pediatric 
clinical studies and may be used as a model for the development of a 
dissemination tool for all clinical trial data that is determined to 
have important clinical findings.

Determining the Scope of Clinical Trial Reporting:
    Science must drive the process to define clinical trial reporting. 
Media attention, legal filings or isolated incidents should not dictate 
the availability or dissemination of the results of clinical trials. 
While there are compelling reasons to focus on medications related to 
the treatment of mental illness at this particular moment, given recent 
events, there is limited scientific rationale as to why medications for 
this class of conditions
    should be highlighted over other medications in developing a 
national response to prevent subsequent miscommunication about clinical 
drug trial results. Unfortunately, limited access to clinical drug 
trial data has long had an impact on the choice and use of all classes 
of drugs--antidepressant use in children is only one recent example. We 
therefore strongly encourage the inclusion of ALL classes of 
medications within any registry or monitoring system that is developed 
as a result of this effort.
    In addition, there is a need to define the kind of clinical trials 
that will be considered. Thus far, the discussions have focused on 
drug/medication trials; however, clinical trials include a great deal 
more than just drug/medication trials. Including all clinical trials 
(e.g., research related to human subjects; surgical, pharmacological, 
and non-pharmacological interventions; devices, etc.) may prove to be 
unwieldy to track in one database.
    We anticipate that the effort required to develop a safe and 
effective clinical drug trial registry will be extensive and therefore 
recommend that the focus, at least initially, be on clinical drug 
trials. Clinical drug approvals are already overseen by one federal 
agency--the Food and Drug Administration (FDA)--and this may help 
facilitate the development of a single, centralized drug trial 
registry. The success (and challenges) of this registry can inform the 
later development of comparable efforts to promote broader access to 
clinical trials of non-pharmacological interventions.
Publication and Disclosure of Clinical Trial Data: Understanding the 
        Challenges/Identifying Possible Solutions:
    There is a need to define the scope of the challenges related to 
publishing and disclosing clinical trial data in order to best address 
them. A series of questions helps illustrate the information necessary 
in order to determine the best course of action: How are clinical 
trials being defined (e.g., just for medications or for non-
pharmacological interventions as well)? Will the information released 
be peer reviewed (if not, who will review the data and at what time 
during the clinical trial)? How will the information be distilled and 
updated (e.g., summaries, full release of unfiltered trial results, 
etc.)? How are ``negative studies'' being defined? Who is the audience 
for these trial results (e.g., physicians, patients, researchers, 
etc.)? What is the intended outcome for releasing the clinical trials 
data (e.g., improved patient care, legal pursuits, etc)? What might be 
the unintended consequences of well-intentioned policies?
    A number of proposals have been raised. Each comes with potential 
benefits but must be carefully examined within the context of potential 
issues. Proposals include:
    Review of Clinical Trial Findings: There are considerable concerns 
that non-published studies which have not undergone peer review (or for 
that matter, any review) may be included in a database that will be 
easily accessible by the general population and will contain 
insufficient information by which to judge a study's validity. Examples 
include:

 Medications have the FDA for oversight, but there is little to 
        prevent a company or individual from posting ``results'' of 
        their independent research that demonstrates the benefit of a 
        completely non-efficacious or potentially harmful intervention 
        (with claims based on seriously flawed research).
 Through the media and advertising industry there are many claims of 
        product or intervention efficacy that are likely based on 
        research that would not be judged as supported if subjected to 
        the peer review process of professional journals (e.g., dietary 
        supplements, some non-evidence-based mental health 
        interventions, non-pharmacological diet or pain ``treatments'' 
        to name just a few).
 Inclusion of a disclaimer that a study did not undergo ``peer-
        review'' will not likely have sufficient impact, especially if 
        the study is posted on a government website along with the best 
        of scientific studies. The general population may likely view 
        the study as having more credibility, irrespective of any 
        disclaimers.
    Clinical Trial Registries and Databases: A central clinical trial 
registry or database for clinical trial information would go a long way 
towards addressing concerns about a lack of awareness outside the 
scientific community of the full nature, scope, and results of clinical 
trials.
    One of the most frequently-cited rationales for registries is that 
such a database would lead to a decrease in reporting bias--the 
tendency of scientists to publish only those studies yielding positive 
results. However, this may not necessarily be the case. If all results, 
including negative ones, are available in a registry, then it is quite 
possible that the prevalence of positive studies reported in peer-
reviewed journals might actually increase, since the negative studies 
will have already been disclosed elsewhere (and possibly in a 
relatively cursory manner).
    There are many other concerns that must be addressed on this issue 
of a registry, including what entity will administer it and how 
compliance will be enforced, how the raw data will be filtered and 
presented in a way to allow those outside the scientific community to 
interpret it, concerns of industry over the disclosure of proprietary 
information, etc.
    Clearly it is imperative that any effort to establish or expand 
clinical trial registries be well considered and thoughtful, as well as 
taken at a reasonable pace.

Conclusion and Recommendations
    It is not an issue of IF there is a need to provide health care 
professionals and patients appropriate information about clinical 
trials findings. Rather it is a matter of HOW the information is 
provided. It is no simple task to develop an appropriate mechanism but 
there are existing models such as the pediatric clinical trials 
summaries within the Best Pharmaceuticals for Children Act that may 
help shape the process.
    The AAP and pediatric academic societies propose the following 
initial recommendations:

 We urge Congress to broaden their investigation to include all 
        medications, rather than simply anti-depressants. In addition, 
        it is necessary to include all populations and ages in order to 
        best improve patient care.
 While concerns related to publication and disclosure of clinical 
        trial findings are not limited to medications, it may be 
        necessary to begin with that therapy as an incremental step.
 Thoughtful and deliberative assessment of how data collection and 
        registries are developed is essential.-- The role of peer-
        review of studies must be thoroughly explored. The AAP urges 
        the medical community, pharmaceutical manufacturers, scientific 
        journals, policy makers, researchers and other stakeholders to 
        work together to identify the scope of the problems and develop 
        appropriate solutions. We must work with deliberate speed but 
        must also ensure that the solutions adequately address the 
        problem and do not, in fact, cause even more problems.
    On behalf of the American Academy of Pediatrics and the pediatric 
academic societies, thank you for the opportunity to testify on this 
important issue. We offer our assistance and expertise to the Congress 
and other stakeholders as this important discussion continues.

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    Mr. Walden. Thank you, Doctor, for your testimony. I'm 
going to recess the committee at this point. We'll go over and 
cast the two votes that we have. We should be back here no 
later than 6:30. And we'll reconvene for some questions and 
then we'll wrap it up for a really long day. Thank you. We're 
in recess.
    [Off the record.]
    Mr. Walden. I'm going to call the subcommittee back to 
order. Again, I want to thank our witnesses for putting in a 
pretty long day.
    There are several questions I'd like to ask for the record 
and Mr. Allen who will not be able to rejoin us, apparently, 
did want to make sure we kept the record open for written 
questions for committee members who obviously aren't able to be 
with us any longer tonight.
    My first question really gets at an issue that has troubled 
me a bit and maybe this is standard practice and I'm just 
learning about it, but Dr. Davis, can you talk to me about 
doctors prescribing drugs for children that have not been 
approved on the label for the uses by the FDA? I mean the top 
four anti-depressant drugs given to children all have not been 
approved for use as an anti-depressants. You can see tab 69, 
I'm at page 13.
    And I figured that things weren't prescribed that weren't--
didn't go through clinical trials and weren't designed for that 
use and yet, when you look at the data, I mean in some 
respects, poor old Prozac is out there, the one that has gone 
through clinical trials and been approved for this use and it's 
not even one of the top, what, two or three--it's No. 4 in 
line. It's No. 5 behind four drugs and I'm not picking 
favorites here at all, but it just seems peculiar to me that 
you have one that actually has been through clinical trials and 
shows some effectiveness in anti-depressant treatment for youth 
and yet, members of your profession or perhaps yours, Dr. 
Gorman, are prescribing four others in greater quantities.
    How does that happen? Is it a problem, something we need to 
be concerned about?
    Mr. Davis. This gets at the whole issue of off-label 
indications for medications and our position at the American 
Medical Association is that physicians should have the right to 
prescribe an FDA-approved drug or a medical device for an 
unlabeled indication when such use is based on sound, 
scientific evidence and sound medical opinion. In many cases, a 
physician is faced with a patient with a serious or even life-
threatening condition. Other treatments may have already been 
tried and perhaps are no longer working, but this physician may 
have reason to believe that this medication, even though we're 
talking about an off-label indication may help in this patient 
who is in my office today. That reason may be based on the 
mechanism of action of that drug. Maybe it is known to be 
effective in a similar illness, but it has not get been proven 
to be effective in this particular illness. Or maybe it works 
in one population group. We have not proven that it is 
effective in another population group.
    So when you have to make the decision facing an individual 
patient with a dearth of information for reasons that we've 
discussed, when no other treatments are available, that's a 
situation when off-label prescribing may be done.
    Mr. Walden. So let's go to this issue a bit more because 
when you talk about, when it's backed up by sound science and 
yet the sound scientific evidence that may be out there isn't 
necessarily required to be out there or you can--professionals 
can access it. We found that out. Some of that sound, 
scientific evidence that has been done shows sugar pills may be 
almost as effective or more so. And most troubling, I think, is 
apparent, is when you look at the data put together by Dr. 
Mosholder, backed up by Columbia University just in this 
specific category of drugs, anti-depressants used to treat 
pediatric depression. There may be a fairly significant 
increase in suicidal tendencies or thought or ideas. All that 
science is out there and yet we're seeing fairly substantial 
rise in pediatric prescriptions for anti-depressants, SSRIs. 
Show me the evidence that says (a) it's effective; (b) it's not 
dangerous.
    Mr. Davis. Dr. Gorman may want to speak to this in a 
minute, but we were talking about this during the recess, but 
let me just make this point. You might ask why is a physician 
prescribing Zoloft for depression in a teenager instead of 
Prozac. And it may be that a patient was prescribed Prozac and 
the depression is getting worse and so the physician wants to 
try another medication and there is no other labeled medication 
for that usage. Or it may be, and Dr. Gorman may speak to this, 
it may be that a physician, say a family physician who treats 
depression in adults and children is used to prescribing 
Zoloft, is familiar with that medication, treats many adults 
with that medication and then he sees a 17-year-old with 
depression and he's asking himself is there any reason why this 
medication should be good for an 18-year-old and not good for a 
17-year-old? Is depression different in a 17-year-old versus an 
18-year-old?
    Mr. Walden. But the drug interaction may be different, 
right, according to the clinical trials?
    Mr. Davis. That's possible, although you could have a 
patient who is not on another medication. I'm just saying as a 
hypothetical.
    Mr. Walden. No, I know, but when you get into it that's 
possible. In fact, the data we have before us shows that is 
indeed the case. The FDA has said these aren't clinically----
    Mr. Davis. But just a hypothetical situation might be an 
18-year-old with no other medication, a 17-year-old, no other 
medication. Biologically, if it works for an 18-year-old, it 
should work for a 17-year-old.
    Mr. Walden. Right. Dr. Gorman?
    Mr. Gorman. If I can follow up on that just a little, 
pediatricians are trained to use drugs off-label because that's 
the situation we've been in since the beginning of pediatrics.
    Until recently, and including today, 75 percent of all 
drugs that come through the Food and Drug Administration, are 
not studied in or approved for use in children.
    Mr. Walden. What percentage?
    Mr. Gorman. Seventy-five percent.
    Mr. Walden. Wow.
    Mr. Gorman. Now, so in our training we're told to look at 
mechanisms of action and whether or not we believe that the 
pathophysiology of the disease, the cause of the disease is the 
same in adults and children and then we're asked to 
extrapolate.
    Mr. Walden. So I guess for both of you then, it seems 
pretty obvious to me, but do you think your members would want 
more information on anti-depressants beyond what's on the 
label?
    Mr. Gorman. Now only do we want more information, we're 
thankful that this group and the American Congress has enacted 
legislation recently that makes the data that we're discussing 
today available not only to the pediatricians, the 
practitioners, but also to the American public.
    Mr. Walden. You know, as we've kind of looked into this, it 
appears there are publications that describe clinical trial 
results in ways that are perhaps more flattering than the FDA 
would. There are references on posters at your conventions that 
describe some of these drugs in more flattering ways than 
perhaps the clinical trials on close peer review might describe 
them. Do you find that or am I missing something here?
    Mr. Gorman. Everyone gets excited about positive results 
because it gives you a possible way to treat people you have 
very few options for. There's an old saying in medicine, that 
you should always use the miracle drugs before they become less 
miraculous. So----
    Mr. Walden. I thought it was ``first do no harm.''
    Mr. Gorman. Well, no, that's part of the oath we take.
    Mr. Walden. Oh, okay.
    Mr. Gorman. But what happens is is that positive results 
are spread more rapidly by the pharmaceutical companies and 
they're more interesting to clinicians to listen to than 
negative results.
    Mr. Walden. And I guess, at least me, I won't speak for the 
committee, but what I'm trying to get at is to make sure that 
the information you get is both sides and if there is 
information out there that shows there may be no effect, that 
people aren't being asked to waste their money on drugs that 
show no effect or if there's potentially a downside in the 
sense of some of these disturbing studies that would indicate 
that perhaps additional suicidal thoughts or actions, that your 
folks are made aware of that rapidly.
    Mr. Gorman. The research that was performed because of the 
Best Pharmaceuticals for Children Act resulted in exclusivity 
for these, gave us the information that there's perhaps no 
efficacy and perhaps a strong safety signal that these drugs 
are dangerous to use in children. This is exactly the 
information that we wanted to be made available.
    Mr. Walden. But yet, I want to go back because I'm trying 
to remember which company it was that had the label, is that 
Glaxo? Wyeth. Wyeth tried to put on additional information 
saying watch for hostility in kids and potential suicide 
issues. I assume you were here for that testimony as well.
    Does that bother you that they were basically told by the 
FDA to back off that direct comment?
    Mr. Davis. I agree with your question a few moments ago, do 
physicians want more information about possible side effects 
and I would say absolutely yes.
    Mr. Walden. I would think so. It's your nature.
    Mr. Davis. We have long-standing policy at the AMA, this is 
again, getting into the issue of off-label use of drugs. We 
have a long-standing policy pointing out the important need for 
physicians to have access to accurate and unbiased information 
about unlabeled uses of drugs and devices, while ensuring that 
manufacturer-sponsored promotions remain under FDA regulation.
    So physicians want and need this information and this gets 
to our proposal that we've been testifying on today, the need 
for a single comprehensive registry where information on all 
clinical trials would be tracked from the very beginning, even 
before patients would be enrolled in these studies so that we 
would know which clinical trials have been done. We're talking 
phase 2 and phase 3 trials, track them all in a publicly 
accessible data base from before patients were even enrolled, 
follow up and add the results and then we would have the 
information we need.
    Mr. Walden. And that goes beyond what PhRMA is proposing?
    Mr. Davis. That's right. We're talking about not waiting 
until results are available, but registering the clinical 
trials before they begin, before patients are even enrolled and 
our proposal has an enforcement mechanism saying if you want 
your IRB approval to start the trial, to enroll patients, you 
need to be registered in a publicly accessible data base with a 
unique identifier. That would do three things. It would get 
around this problem of distorting the scientific literature 
because we'd know about all the studies that are out there. It 
would let patients know early on what trials are out there, so 
that they could get enrolled in one, if they would like, if 
they have that disease and three, it would allow researchers to 
know what studies are being done now or are about to be 
launched so that they could collaborate and avoid duplicating 
what somebody else might be doing.
    Mr. Walden. Dr. Gorman, does your organization support that 
same set of protocols?
    Mr. Gorman. The organization supports them in principle in 
the sense that that is the goal to which we hope to get to.
    Mr. Walden. Okay. I guess the question is if the 
prescribing community is seeking that level of protocols and 
evaluation of data and availability of data to Dr. Loew then, 
do you think your proposal at PhRMA goes far enough?
    Ms. Loew. A lot of the discussion that we've heard today, 
in fact, I would say it would be the majority of the discussion 
that we've heard has focused on access to information on 
completed clinical studies for products that are marketed in 
the United States.
    Mr. Walden. Although they both said before the completion 
of the studies, right?
    Mr. Davis. Before the initiation of the studies, before the 
enrollment of patients.
    Mr. Walden. Okay.
    Ms. Loew. What we have established is a data base for 
companies to post information on completed clinical studies for 
products that are marketed. Many of the points that have been 
raised today focus around a lack of centralized access to this 
information. The fact that it's extremely difficult to publish 
negative clinical studies, that they often are disclosed at 
medical meetings, these types of venues which aren't widely 
open to practicing physicians. Recognizing this problem, this 
is why we have taken the unprecedented step of establishing 
this data base.
    There are companies that will be posting three different 
types of information about their products that are on the 
market in the U.S. The first is they will be publishing a full 
bibliography of all peer-reviewed clinical studies. So it's a 
centralized point where physicians can access this information. 
The second thing is we mustn't lose sight of this. It will 
provide access to the FDA-approved drug label which should be 
the primary source of information for prescribing physicians. 
The third piece of information it will provide is a summary of 
unpublished clinical study results, something that's been a 
central point of concern----
    Mr. Walden. What would you say the objections are to going 
to the level, Dr. Davis, and I don't want to speak for you, Dr. 
Gorman, but similarly, I think, agrees. Why wouldn't you go to 
that level? What's the reason?
    Ms. Loew. In assessment of the situation, we were trying to 
primarily address, to establish a data base that we thought 
would be useful to practicing physicians and it would give them 
access on products that they can, sorry, to give them 
information to products that they are in a position to 
prescribe. So we have focused on information on products that 
are marketed in the United States. As I said in my testimony, 
the issue of information on on-going clinical trials is a 
separate problem that I think should be addressed, distinct 
from this issue. And in fact, there are a large, there are a 
number of resources already available publicly for information 
on on-going clinical studies. There are a number of commercial 
data bases and there is, of course, clinicaltrials.gov and we 
already know that there are some companies that publish more 
than the legislated requirement for posting serious and life-
threatening trials.
    Mr. Walden. I'm sorry, Lilly, that's Lilly that goes 
beyond?
    Ms. Loew. Lilly, I believe there are other companies as 
well that are posting more than the----
    Mr. Walden. What about this issue of publishing the stand-
alone studies? Is that something PhRMA can support?
    Ms. Loew. I think there's been a lot of confusion around 
today is what does the study mean, what do the results mean.
    Mr. Walden. Right.
    Ms. Loew. When we present data to FDA as part of a new drug 
application, the full study information is presented to the 
agency. On a study-by-study basis, that amounts to many 
thousands of pages----
    Mr. Walden. But that's when you're trying to get a new drug 
approved, right?
    Ms. Loew. Correct, but any study that is completed, that is 
written up, will amount to many thousands of pages of data.
    Mr. Walden. Right, but we can do the Congressional Record 
overnight and put it on line.
    Ms. Loew. The question is utility though. It's about----
    Mr. Walden. Well, the Congressional Record, that's a 
question, can we share this?
    Ms. Loew. I don't know anything about the Congressional 
Record, but I would like to--what I would like to say is that 
we have tried to provide an information resource that is of use 
to busy, practicing physicians.
    Mr. Walden. Sure, but there would be nothing that would 
stop you from publishing the summary data that you do now or 
want to or seek to, but it would seem to me for a researcher or 
a scientist or a physician who really wants to dig into it, 
what's the harm in allowing them access to more of the data, if 
they so choose? I mean you don't have to have one report that's 
so complicated and nobody understands it. You're going to have 
a summary of the findings, especially if they're good. It's 
going to get down to like one word, you know, well two, buy it.
    It works. You know what I'm saying.
    Ms. Loew. Exactly.
    Mr. Walden. I come from the belief that in a free and open, 
I think it's John Stuart Mill, in a free and open marketplace, 
the truth will win out and what you need is that information 
out there, so that these gentlemen to each side of you and 
others can, and parents, can know everything that's out there 
and make more important decisions.
    Ms. Loew. Understood. And what we have focused on in our 
data bases is a summary, as you rightly point out, something 
that we believe gives a brief, accessible amount of information 
that a physician can review relatively quickly. There's nothing 
to stop a practicing physician who is interested in gaining 
more information from approaching the particular company, 
asking them for more information, but that's not something that 
we have discussed as a policy within PhRMA. We took the 
position that we wanted to make this data base as useful as 
possible for practicing physicians and went for a summary 
format.
    Mr. Walden. Okay, I long overshot my time and in fact, I'm 
going to defer to the chairman now of the full committee who I 
know has very strong opinions on this issue.
    Chairman Barton. Thank you, Mr. Chairman. I want to commend 
you and console you for having to chair most of this hearing. 
It started at 11 this morning. If we were a casino, you know 
when you go out to Las Vegas and you play poker or black jack, 
after so many hours, you get a meal voucher.
    Mr. Walden. Well, Mr. Chairman, if I may----
    Chairman Barton. Not only would you get a meal voucher, the 
audience would get a meal voucher and probably a free room for 
the night.
    Mr. Walden. Some time after midnight I think I'm in Las 
Vegas tonight because I get to Portland, Oregon at 2 a.m.
    Chairman Barton. Oh wow.
    Mr. Walden. I'll look for that meal voucher.
    Chairman Barton. I want to thank this panel for persevering 
and being willing to still answer questions coherently at 7 in 
the evening and the audience that stayed with us.
    I don't have too many questions. I've got one generic 
question that's probably been asked about a thousand times 
today, but I'm going to try to ask it one more time because 
this is our medical panel.
    Why would the medical community prescribe off-label for 
children as young as six or seven drugs that to the extent the 
clinical trials have been made public, seem to indicate that 
there's no efficacy in the treatment? Why would a doctor do 
that?
    And I'm sure you all have been asked that in some way, but 
I mean that's kind of the heart of this debate.
    Mr. Gorman. And we've tried to answer that, so we'll try 
again. The pediatricians as a group have been in that position 
since the inception of pediatrics. Seventy-five percent of all 
approved medicines in the United States are not approved for 
children. So any time we treat your children, your step 
children and your grandchildren, we are using----
    Chairman Barton. You listened. You listened to me. 
Children, stepchildren and grandchildren.
    Mr. Gorman. And remember, 75 percent of the time we're 
doing things off-label. This information dissemination that 
came through Best Pharmaceuticals for Children Act is new to 
the medical community and has not been widely disseminated that 
this information about drugs that have been tested and shown 
not to be effective, this is new stuff for us. We've heard from 
PhRMA that the data base will be for drugs that are approved. 
The information we've been discussing today is information 
about drugs that have been studied and not approved. This is 
the first time these kinds of information are widely available 
to physicians and the public. And it's due to the Best 
Pharmaceuticals for Children Act.
    Chairman Barton. So when some of my friends on the Democrat 
side, Mr. Markey, Mr. Waxman and others, talk about a registry 
where everything is put up as soon as possible on these 
websites and open for public display, that's something that the 
pediatric community would be very supportive of?
    Mr. Gorman. We'd be supportive of that as a goal, yes.
    Chairman Barton. What about our AMA rep and our PhRMA rep? 
Would you all support that?
    Mr. Davis. Well, that's actually the crux of the American 
Medical Association's proposal. We want all phase 2 and phase 3 
clinical trials to be registered, ideally in one central data 
base. We also have proposed an enforcement mechanism to make 
that happen which would involve IRBs, Institutional Review 
Boards, requiring a clinical trial to be registered in a 
publicly accessible data base in order for the IRB to approve 
that clinical trial.
    So we believe that's the mechanism to allow physicians, 
other clinicians, researchers, policymakers and the public to 
know about all these phase 2 and phase 3 clinical trials that 
are underway or those that have been completed.
    Chairman Barton. Dr. Loew, do you want to comment?
    Ms. Loew. Just to--particularly to Dr. Gorman's point, but 
also a recurring theme today. The data base that we have 
established and that will be live from the first of October 
will contain both summaries of the positive and negative 
studies for products that are marketed in the United States. So 
to Dr. Gorman's point, if a product is marketed and approved 
for an adult population, what studies in the pediatric 
population did not result in an indication, that study, if it 
was a hypothesis testing clinical study will be published on 
the site. I think this is an unprecedented and major step 
forward for the industry. We're very committed to disclosing 
this information. We'll have this data base available in less 
than a month and physicians, practicing physicians will be able 
to start accessing this information.
    Chairman Barton. I have one more generic question and then 
I'm going to ask a staff question. And this again is to Dr. 
Gorman. Is there universal consensus on treating young 
children, like six and seven, with anti-depressant medications? 
Is that universally accepted, that that's acceptable practice? 
I mean I would think it might be hard to determine somebody 
that young whether they're actually clinically depressed or 
not.
    Mr. Gorman. I think that there is a growing belief and data 
to support that that children as young as six can be depressed. 
The treatment for any mental health condition is not just 
medication, but also the support of cognitive therapy and 
behavioral therapy as well. So I would hope that pharmaceutical 
intervention would be last on the list for potential 
interventions.
    Talking about off-label use, these drugs are probably also 
being used for other conditions besides depression in children 
six and younger.
    Chairman Barton. Okay, well, I don't want to be facetious, 
but about that age when I felt like I was depressed, my father 
just paddled my bottom five or six times and gave me something 
to do and somehow I became undepressed, you know. But I don't 
want to be--I know this is a very serious issue, so my staff 
question is to Dr. Loew. And this was in your testimony, the 
PhRMA testimony referred to timely communication of meaningful 
study results. Exactly what is a timely communication?
    Ms. Loew. The data base that we announced earlier this week 
defines timely communication for marketed products of 
publication of the clinical study results within 1 year of 
completion of the clinical study. The 1 year timeframe comes 
from the FDA regulations for annual reporting of clinical study 
results and the definition of completion of a study is defined 
as lost patient, lost visit. It's very clearly defined.
    We do have to exhibit some flexibility around that 
timeframe to allow for peer review publication of clinical 
studies. The peer review process can often take longer than 1 
year and so we have a mechanism whereby companies can designate 
on the website that they have competed the clinical study, but 
it is undergoing peer review, so there will be no data 
published there. As soon as the study is either published, the 
bibliography, the bibliographic reference will be posted on the 
site or if it's rejected for publication, the company does not 
believe it can be published, they will put a summary of that 
study on the site. We have very clearly defined that and have 
also allowed for the slightly extended peer-review process.
    Chairman Barton. The timely is basically within a year?
    Ms. Loew. Correct.
    Chairman Barton. What about meaningful study results?
    Ms. Loew. Meaningful is something that we have defined in 
the Q&A that we published in June of this year, our principles. 
It's basically defined as hypothesis testing clinical trials. 
Hypothesis testing is again something that's defined in 
regulation.
    Chairman Barton. Try to talk in Texas.
    Ms. Loew. Being British, I'm not sure whether I could 
attain that, but I will do my best. I wouldn't even try to 
cross the Atlantic, but broadly hypothesis testing clinical 
trial is one that's defined to statistically answer a pre-
defined question or set of questions. There's typically phase 3 
clinical studies and phase 4 clinical studies, but there can 
sometimes be phase 1 and phase 2 studies, but it's principally 
phase 3 and phase 4. These are the studies that are basically 
designed to inform how a physician could prescribe a product, 
if it were approved and in the marketplace.
    Chairman Barton. Does that mean it has to help 10 percent 
of the study group, 15 percent, 20 percent, to help somebody 
that's in dire straits?
    Ms. Loew. FDA has specific statistical criteria that they 
apply to efficacy standards. I don't have that information at 
my fingertips, but we can certainly get that to you in writing.
    Chairman Barton. Well, I listened carefully and I still 
don't understand meaningful study results. I mean I heard phase 
3 and phase 4, but I didn't--what's the difference between a 
meaningful study result and an unmeaningful study result?
    Ms. Loew. We defined meaningful as hypothesis testing. 
Hypothesis testing is principally phase 3 and phase 4.
    Chairman Barton. I don't understand that. I'm not being 
dense. I have no clue what that means. Give me an example.
    Ms. Loew. Clinical development, up to new drug approval, 
occurs in three distinct stages. Phase 1 is done in a very 
small study population using healthy volunteers and it's simply 
to assess the safety of the drug. It's basically to tell 
whether something very significant and bad happens when this 
drug is put in humans.
    When that study phase is completed, the drug moves to phase 
2 which is principally aimed at, it's typically done using 
people who have the disease condition that the drug is being 
studied for. And it's in an effort to understand what dose the 
drug should be prescribed at. That's the principle aim of phase 
2 clinical studies. Sometimes a little bit of extra data comes 
from it, but that's the main aim. .
    In phase 3, you're using many, many more people who have 
the disease, to try and assess whether the drug is actually 
effective in treating that disease. So to take an example, if 
you have asthma, whether the drug improves your asthma, whether 
it gets your asthma under control. You would aim at the end of 
that study to have an answer to that question, yes, it does 
improve my asthma; no, it doesn't improve my asthma.
    Chairman Barton. But doesn't the FDA to be approved have a 
requirement that between the control group and the group that 
gets the new drug, that there be a significant, like a certain 
percentage it has to help at least a certain percentage?
    Ms. Loew. Correct. There are statistical criteria that they 
apply. As I said, I don't have that----
    Chairman Barton. Is that what meaningful means, that it----
    Ms. Loew. Correct.
    Chairman Barton. At that stage, it actually has to help 
some minimal percentage?
    Ms. Loew. Yes, you have to be able to show demonstrated 
efficacy and safety, that the drug is safe and that it treats 
what you're trying to indicate it for.
    Chairman Barton. Now I have one more question and I 
hesitate to ask it, but it wants me to ask you to define 
significant medical importance. Do you want to take a crack at 
that?
    Ms. Loew. I think in the earlier panel, this issue came up 
as well, the definition of significant medical importance. That 
definition will vary by therapeutic area, but essentially where 
the result of a clinical study provides information that it is 
believed to be important to practicing physicians, we believe 
that information should be disclosed.
    Chairman Barton. Does it have anything to do with the 
number of people?
    Ms. Loew. No.
    Chairman Barton. So it's not----
    Ms. Loew. It's independent of that.
    Chairman Barton. Okay. It's the efficacy on people that 
need that drug. Is that fair?
    Ms. Loew. That could be the reason, yes. But that could be 
one of many reasons.
    Chairman Barton. What would be another one? I'm just trying 
to get--I know it's late. I'm not trying to be argumentative. 
I'm trying to understand this and I'm not a medical major.
    Ms. Loew. An example could be and I should also say I'm not 
a physician either. An example could be that you are studying 
for one disease condition and that's the focus of your study, 
but you find out during the study that the disease--sorry, the 
drug has a significant impact in another disease area. That 
could be an example. You could, for instance, find a safety 
problem that you believe should be communicated. There are a 
number of different reasons, as I said.
    Chairman Barton. But it all revolves the result that occurs 
when you take that specific drug?
    Ms. Loew. Correct.
    Chairman Barton. Thank you, Mr. Chairman, and again, I 
appreciate you chairing this hearing and I want to thank our 
last panel again for being with us this late in the evening.
    Mr. Walden. Thank you. Thank you, Mr. Chairman. And I, too, 
want to thank our panel for your endurance and your 
participation.
    The committee record will remain open for members who have 
questions that we may want to ask and we would ask that all our 
witnesses today be able to respond before our September 23 
hearing which will take up this issue in further detail. We do 
appreciate your enlightenment on this subject and thank you for 
your participation and you are excused. And we are adjourned.
    [Whereupon, at 7:08 p.m., the hearing was concluded.]
    [Additional material submitted for the record follows:]

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