[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
____________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; (202) 512�091800
Fax: (202) 512�092250 Mail: Stop SSOP, Washington, DC 20402�090001
__________
COMMITTEE ON ENERGY AND COMMERCE
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.
[GRAPHIC] [TIFF OMITTED] T6094.002
[GRAPHIC] [TIFF OMITTED] T6094.003
[GRAPHIC] [TIFF OMITTED] T6094.004
[GRAPHIC] [TIFF OMITTED] T6094.005
[GRAPHIC] [TIFF OMITTED] T6094.006
[GRAPHIC] [TIFF OMITTED] T6094.007
[GRAPHIC] [TIFF OMITTED] T6094.008
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.
[GRAPHIC] [TIFF OMITTED] T6094.009
[GRAPHIC] [TIFF OMITTED] T6094.010
[GRAPHIC] [TIFF OMITTED] T6094.011
[GRAPHIC] [TIFF OMITTED] T6094.012
[GRAPHIC] [TIFF OMITTED] T6094.013
[GRAPHIC] [TIFF OMITTED] T6094.014
[GRAPHIC] [TIFF OMITTED] T6094.015
[GRAPHIC] [TIFF OMITTED] T6094.016
[GRAPHIC] [TIFF OMITTED] T6094.017
[GRAPHIC] [TIFF OMITTED] T6094.018
[GRAPHIC] [TIFF OMITTED] T6094.019
[GRAPHIC] [TIFF OMITTED] T6094.020
[GRAPHIC] [TIFF OMITTED] T6094.021
[GRAPHIC] [TIFF OMITTED] T6094.022
[GRAPHIC] [TIFF OMITTED] T6094.023
[GRAPHIC] [TIFF OMITTED] T6094.024
[GRAPHIC] [TIFF OMITTED] T6094.025
[GRAPHIC] [TIFF OMITTED] T6094.026
[GRAPHIC] [TIFF OMITTED] T6094.027
[GRAPHIC] [TIFF OMITTED] T6094.028
[GRAPHIC] [TIFF OMITTED] T6094.029
[GRAPHIC] [TIFF OMITTED] T6094.030
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:]
[GRAPHIC] [TIFF OMITTED] T6094.031
[GRAPHIC] [TIFF OMITTED] T6094.032
[GRAPHIC] [TIFF OMITTED] T6094.033
[GRAPHIC] [TIFF OMITTED] T6094.034
[GRAPHIC] [TIFF OMITTED] T6094.035
[GRAPHIC] [TIFF OMITTED] T6094.036
[GRAPHIC] [TIFF OMITTED] T6094.037
[GRAPHIC] [TIFF OMITTED] T6094.038
[GRAPHIC] [TIFF OMITTED] T6094.039
[GRAPHIC] [TIFF OMITTED] T6094.040
[GRAPHIC] [TIFF OMITTED] T6094.041
[GRAPHIC] [TIFF OMITTED] T6094.042
[GRAPHIC] [TIFF OMITTED] T6094.043
[GRAPHIC] [TIFF OMITTED] T6094.044
[GRAPHIC] [TIFF OMITTED] T6094.045
[GRAPHIC] [TIFF OMITTED] T6094.046
[GRAPHIC] [TIFF OMITTED] T6094.047
[GRAPHIC] [TIFF OMITTED] T6094.048
[GRAPHIC] [TIFF OMITTED] T6094.049
[GRAPHIC] [TIFF OMITTED] T6094.050
[GRAPHIC] [TIFF OMITTED] T6094.051
[GRAPHIC] [TIFF OMITTED] T6094.052
[GRAPHIC] [TIFF OMITTED] T6094.053
[GRAPHIC] [TIFF OMITTED] T6094.054
[GRAPHIC] [TIFF OMITTED] T6094.055
[GRAPHIC] [TIFF OMITTED] T6094.056
[GRAPHIC] [TIFF OMITTED] T6094.057
[GRAPHIC] [TIFF OMITTED] T6094.058
[GRAPHIC] [TIFF OMITTED] T6094.059
[GRAPHIC] [TIFF OMITTED] T6094.060
[GRAPHIC] [TIFF OMITTED] T6094.061
[GRAPHIC] [TIFF OMITTED] T6094.062
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:]
[GRAPHIC] [TIFF OMITTED] T6094.063
[GRAPHIC] [TIFF OMITTED] T6094.064
[GRAPHIC] [TIFF OMITTED] T6094.065
[GRAPHIC] [TIFF OMITTED] T6094.066
[GRAPHIC] [TIFF OMITTED] T6094.067
[GRAPHIC] [TIFF OMITTED] T6094.068
[GRAPHIC] [TIFF OMITTED] T6094.069
[GRAPHIC] [TIFF OMITTED] T6094.070
[GRAPHIC] [TIFF OMITTED] T6094.071
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.
[GRAPHIC] [TIFF OMITTED] T6094.072
[GRAPHIC] [TIFF OMITTED] T6094.073
[GRAPHIC] [TIFF OMITTED] T6094.074
[GRAPHIC] [TIFF OMITTED] T6094.075
[GRAPHIC] [TIFF OMITTED] T6094.076
[GRAPHIC] [TIFF OMITTED] T6094.077
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:]
[GRAPHIC] [TIFF OMITTED] T6094.078
[GRAPHIC] [TIFF OMITTED] T6094.079
[GRAPHIC] [TIFF OMITTED] T6094.080
[GRAPHIC] [TIFF OMITTED] T6094.081
[GRAPHIC] [TIFF OMITTED] T6094.082
[GRAPHIC] [TIFF OMITTED] T6094.083
[GRAPHIC] [TIFF OMITTED] T6094.084
[GRAPHIC] [TIFF OMITTED] T6094.085
[GRAPHIC] [TIFF OMITTED] T6094.086
[GRAPHIC] [TIFF OMITTED] T6094.087
[GRAPHIC] [TIFF OMITTED] T6094.088
[GRAPHIC] [TIFF OMITTED] T6094.089
[GRAPHIC] [TIFF OMITTED] T6094.090
[GRAPHIC] [TIFF OMITTED] T6094.091
[GRAPHIC] [TIFF OMITTED] T6094.092
[GRAPHIC] [TIFF OMITTED] T6094.093
[GRAPHIC] [TIFF OMITTED] T6094.094
[GRAPHIC] [TIFF OMITTED] T6094.095
[GRAPHIC] [TIFF OMITTED] T6094.096
[GRAPHIC] [TIFF OMITTED] T6094.097
[GRAPHIC] [TIFF OMITTED] T6094.098
[GRAPHIC] [TIFF OMITTED] T6094.099
[GRAPHIC] [TIFF OMITTED] T6094.100
[GRAPHIC] [TIFF OMITTED] T6094.101
[GRAPHIC] [TIFF OMITTED] T6094.102
[GRAPHIC] [TIFF OMITTED] T6094.103
[GRAPHIC] [TIFF OMITTED] T6094.104
[GRAPHIC] [TIFF OMITTED] T6094.105
[GRAPHIC] [TIFF OMITTED] T6094.106
[GRAPHIC] [TIFF OMITTED] T6094.107
[GRAPHIC] [TIFF OMITTED] T6094.108
[GRAPHIC] [TIFF OMITTED] T6094.109
[GRAPHIC] [TIFF OMITTED] T6094.110
[GRAPHIC] [TIFF OMITTED] T6094.111
[GRAPHIC] [TIFF OMITTED] T6094.112
[GRAPHIC] [TIFF OMITTED] T6094.113
[GRAPHIC] [TIFF OMITTED] T6094.114
[GRAPHIC] [TIFF OMITTED] T6094.115
[GRAPHIC] [TIFF OMITTED] T6094.116
[GRAPHIC] [TIFF OMITTED] T6094.117
[GRAPHIC] [TIFF OMITTED] T6094.118
[GRAPHIC] [TIFF OMITTED] T6094.119
[GRAPHIC] [TIFF OMITTED] T6094.120
[GRAPHIC] [TIFF OMITTED] T6094.121
[GRAPHIC] [TIFF OMITTED] T6094.122
[GRAPHIC] [TIFF OMITTED] T6094.123
[GRAPHIC] [TIFF OMITTED] T6094.124
[GRAPHIC] [TIFF OMITTED] T6094.125
[GRAPHIC] [TIFF OMITTED] T6094.126
[GRAPHIC] [TIFF OMITTED] T6094.127
[GRAPHIC] [TIFF OMITTED] T6094.128
[GRAPHIC] [TIFF OMITTED] T6094.129
[GRAPHIC] [TIFF OMITTED] T6094.130
[GRAPHIC] [TIFF OMITTED] T6094.131
[GRAPHIC] [TIFF OMITTED] T6094.132
[GRAPHIC] [TIFF OMITTED] T6094.133
[GRAPHIC] [TIFF OMITTED] T6094.134
[GRAPHIC] [TIFF OMITTED] T6094.135
[GRAPHIC] [TIFF OMITTED] T6094.136
[GRAPHIC] [TIFF OMITTED] T6094.137
[GRAPHIC] [TIFF OMITTED] T6094.138
[GRAPHIC] [TIFF OMITTED] T6094.139
[GRAPHIC] [TIFF OMITTED] T6094.140
[GRAPHIC] [TIFF OMITTED] T6094.141
[GRAPHIC] [TIFF OMITTED] T6094.142
[GRAPHIC] [TIFF OMITTED] T6094.143
[GRAPHIC] [TIFF OMITTED] T6094.144
[GRAPHIC] [TIFF OMITTED] T6094.145
[GRAPHIC] [TIFF OMITTED] T6094.146
[GRAPHIC] [TIFF OMITTED] T6094.147
[GRAPHIC] [TIFF OMITTED] T6094.148
[GRAPHIC] [TIFF OMITTED] T6094.149
[GRAPHIC] [TIFF OMITTED] T6094.150
[GRAPHIC] [TIFF OMITTED] T6094.151
[GRAPHIC] [TIFF OMITTED] T6094.152
[GRAPHIC] [TIFF OMITTED] T6094.153
[GRAPHIC] [TIFF OMITTED] T6094.154
[GRAPHIC] [TIFF OMITTED] T6094.155
[GRAPHIC] [TIFF OMITTED] T6094.156
[GRAPHIC] [TIFF OMITTED] T6094.157
[GRAPHIC] [TIFF OMITTED] T6094.158
[GRAPHIC] [TIFF OMITTED] T6094.159
[GRAPHIC] [TIFF OMITTED] T6094.160
[GRAPHIC] [TIFF OMITTED] T6094.161
[GRAPHIC] [TIFF OMITTED] T6094.162
[GRAPHIC] [TIFF OMITTED] T6094.163
[GRAPHIC] [TIFF OMITTED] T6094.164
[GRAPHIC] [TIFF OMITTED] T6094.165
[GRAPHIC] [TIFF OMITTED] T6094.166
[GRAPHIC] [TIFF OMITTED] T6094.167
[GRAPHIC] [TIFF OMITTED] T6094.168
[GRAPHIC] [TIFF OMITTED] T6094.169
[GRAPHIC] [TIFF OMITTED] T6094.170
[GRAPHIC] [TIFF OMITTED] T6094.171
[GRAPHIC] [TIFF OMITTED] T6094.172
[GRAPHIC] [TIFF OMITTED] T6094.173
[GRAPHIC] [TIFF OMITTED] T6094.174
[GRAPHIC] [TIFF OMITTED] T6094.175
[GRAPHIC] [TIFF OMITTED] T6094.176
[GRAPHIC] [TIFF OMITTED] T6094.177
[GRAPHIC] [TIFF OMITTED] T6094.178
[GRAPHIC] [TIFF OMITTED] T6094.179
[GRAPHIC] [TIFF OMITTED] T6094.180
[GRAPHIC] [TIFF OMITTED] T6094.181
[GRAPHIC] [TIFF OMITTED] T6094.182
[GRAPHIC] [TIFF OMITTED] T6094.183
[GRAPHIC] [TIFF OMITTED] T6094.184
[GRAPHIC] [TIFF OMITTED] T6094.185
[GRAPHIC] [TIFF OMITTED] T6094.186
[GRAPHIC] [TIFF OMITTED] T6094.187
[GRAPHIC] [TIFF OMITTED] T6094.188
[GRAPHIC] [TIFF OMITTED] T6094.189
[GRAPHIC] [TIFF OMITTED] T6094.190
[GRAPHIC] [TIFF OMITTED] T6094.191
[GRAPHIC] [TIFF OMITTED] T6094.192
[GRAPHIC] [TIFF OMITTED] T6094.193
[GRAPHIC] [TIFF OMITTED] T6094.194
[GRAPHIC] [TIFF OMITTED] T6094.195
[GRAPHIC] [TIFF OMITTED] T6094.196
[GRAPHIC] [TIFF OMITTED] T6094.197
[GRAPHIC] [TIFF OMITTED] T6094.198
[GRAPHIC] [TIFF OMITTED] T6094.199
[GRAPHIC] [TIFF OMITTED] T6094.200
[GRAPHIC] [TIFF OMITTED] T6094.201
[GRAPHIC] [TIFF OMITTED] T6094.202
[GRAPHIC] [TIFF OMITTED] T6094.203
[GRAPHIC] [TIFF OMITTED] T6094.204
[GRAPHIC] [TIFF OMITTED] T6094.205
[GRAPHIC] [TIFF OMITTED] T6094.206
[GRAPHIC] [TIFF OMITTED] T6094.207
[GRAPHIC] [TIFF OMITTED] T6094.208
[GRAPHIC] [TIFF OMITTED] T6094.209
[GRAPHIC] [TIFF OMITTED] T6094.210
[GRAPHIC] [TIFF OMITTED] T6094.211
[GRAPHIC] [TIFF OMITTED] T6094.212
[GRAPHIC] [TIFF OMITTED] T6094.213
[GRAPHIC] [TIFF OMITTED] T6094.214
[GRAPHIC] [TIFF OMITTED] T6094.215
[GRAPHIC] [TIFF OMITTED] T6094.216
[GRAPHIC] [TIFF OMITTED] T6094.217
[GRAPHIC] [TIFF OMITTED] T6094.218
[GRAPHIC] [TIFF OMITTED] T6094.219
[GRAPHIC] [TIFF OMITTED] T6094.220
[GRAPHIC] [TIFF OMITTED] T6094.221
[GRAPHIC] [TIFF OMITTED] T6094.222
[GRAPHIC] [TIFF OMITTED] T6094.223
[GRAPHIC] [TIFF OMITTED] T6094.224
[GRAPHIC] [TIFF OMITTED] T6094.225
[GRAPHIC] [TIFF OMITTED] T6094.226
[GRAPHIC] [TIFF OMITTED] T6094.227
[GRAPHIC] [TIFF OMITTED] T6094.228
[GRAPHIC] [TIFF OMITTED] T6094.229
[GRAPHIC] [TIFF OMITTED] T6094.230
[GRAPHIC] [TIFF OMITTED] T6094.231
[GRAPHIC] [TIFF OMITTED] T6094.232
[GRAPHIC] [TIFF OMITTED] T6094.233
[GRAPHIC] [TIFF OMITTED] T6094.234
[GRAPHIC] [TIFF OMITTED] T6094.235
[GRAPHIC] [TIFF OMITTED] T6094.236
[GRAPHIC] [TIFF OMITTED] T6094.237
[GRAPHIC] [TIFF OMITTED] T6094.238
[GRAPHIC] [TIFF OMITTED] T6094.239
[GRAPHIC] [TIFF OMITTED] T6094.240
[GRAPHIC] [TIFF OMITTED] T6094.241
[GRAPHIC] [TIFF OMITTED] T6094.242
[GRAPHIC] [TIFF OMITTED] T6094.243
[GRAPHIC] [TIFF OMITTED] T6094.244
[GRAPHIC] [TIFF OMITTED] T6094.245
[GRAPHIC] [TIFF OMITTED] T6094.246
[GRAPHIC] [TIFF OMITTED] T6094.247
[GRAPHIC] [TIFF OMITTED] T6094.248
[GRAPHIC] [TIFF OMITTED] T6094.249
[GRAPHIC] [TIFF OMITTED] T6094.250
[GRAPHIC] [TIFF OMITTED] T6094.251
[GRAPHIC] [TIFF OMITTED] T6094.252
[GRAPHIC] [TIFF OMITTED] T6094.253
[GRAPHIC] [TIFF OMITTED] T6094.254
[GRAPHIC] [TIFF OMITTED] T6094.255
[GRAPHIC] [TIFF OMITTED] T6094.256
[GRAPHIC] [TIFF OMITTED] T6094.257
[GRAPHIC] [TIFF OMITTED] T6094.258
[GRAPHIC] [TIFF OMITTED] T6094.259
[GRAPHIC] [TIFF OMITTED] T6094.260
[GRAPHIC] [TIFF OMITTED] T6094.261
[GRAPHIC] [TIFF OMITTED] T6094.262
[GRAPHIC] [TIFF OMITTED] T6094.263
[GRAPHIC] [TIFF OMITTED] T6094.264
[GRAPHIC] [TIFF OMITTED] T6094.265
[GRAPHIC] [TIFF OMITTED] T6094.266
[GRAPHIC] [TIFF OMITTED] T6094.267
[GRAPHIC] [TIFF OMITTED] T6094.268
[GRAPHIC] [TIFF OMITTED] T6094.269
[GRAPHIC] [TIFF OMITTED] T6094.270
[GRAPHIC] [TIFF OMITTED] T6094.271
[GRAPHIC] [TIFF OMITTED] T6094.272
[GRAPHIC] [TIFF OMITTED] T6094.273
[GRAPHIC] [TIFF OMITTED] T6094.274
[GRAPHIC] [TIFF OMITTED] T6094.275
[GRAPHIC] [TIFF OMITTED] T6094.276
[GRAPHIC] [TIFF OMITTED] T6094.277
[GRAPHIC] [TIFF OMITTED] T6094.278
[GRAPHIC] [TIFF OMITTED] T6094.279
[GRAPHIC] [TIFF OMITTED] T6094.280
[GRAPHIC] [TIFF OMITTED] T6094.281
[GRAPHIC] [TIFF OMITTED] T6094.282
[GRAPHIC] [TIFF OMITTED] T6094.283
[GRAPHIC] [TIFF OMITTED] T6094.284
[GRAPHIC] [TIFF OMITTED] T6094.285
[GRAPHIC] [TIFF OMITTED] T6094.286
[GRAPHIC] [TIFF OMITTED] T6094.287
[GRAPHIC] [TIFF OMITTED] T6094.288
[GRAPHIC] [TIFF OMITTED] T6094.289
[GRAPHIC] [TIFF OMITTED] T6094.290
[GRAPHIC] [TIFF OMITTED] T6094.291
[GRAPHIC] [TIFF OMITTED] T6094.292
[GRAPHIC] [TIFF OMITTED] T6094.293
[GRAPHIC] [TIFF OMITTED] T6094.294
[GRAPHIC] [TIFF OMITTED] T6094.295
[GRAPHIC] [TIFF OMITTED] T6094.296
[GRAPHIC] [TIFF OMITTED] T6094.297
[GRAPHIC] [TIFF OMITTED] T6094.298
[GRAPHIC] [TIFF OMITTED] T6094.299
[GRAPHIC] [TIFF OMITTED] T6094.300
[GRAPHIC] [TIFF OMITTED] T6094.301
[GRAPHIC] [TIFF OMITTED] T6094.302
[GRAPHIC] [TIFF OMITTED] T6094.303
[GRAPHIC] [TIFF OMITTED] T6094.304
[GRAPHIC] [TIFF OMITTED] T6094.305
[GRAPHIC] [TIFF OMITTED] T6094.306
[GRAPHIC] [TIFF OMITTED] T6094.307
[GRAPHIC] [TIFF OMITTED] T6094.308
[GRAPHIC] [TIFF OMITTED] T6094.309
[GRAPHIC] [TIFF OMITTED] T6094.310
[GRAPHIC] [TIFF OMITTED] T6094.311
[GRAPHIC] [TIFF OMITTED] T6094.312
[GRAPHIC] [TIFF OMITTED] T6094.313
[GRAPHIC] [TIFF OMITTED] T6094.314
[GRAPHIC] [TIFF OMITTED] T6094.315
[GRAPHIC] [TIFF OMITTED] T6094.316
[GRAPHIC] [TIFF OMITTED] T6094.317
[GRAPHIC] [TIFF OMITTED] T6094.318
[GRAPHIC] [TIFF OMITTED] T6094.319
[GRAPHIC] [TIFF OMITTED] T6094.320
[GRAPHIC] [TIFF OMITTED] T6094.321
[GRAPHIC] [TIFF OMITTED] T6094.322
[GRAPHIC] [TIFF OMITTED] T6094.323
[GRAPHIC] [TIFF OMITTED] T6094.324
[GRAPHIC] [TIFF OMITTED] T6094.325
[GRAPHIC] [TIFF OMITTED] T6094.326
[GRAPHIC] [TIFF OMITTED] T6094.327
[GRAPHIC] [TIFF OMITTED] T6094.328
[GRAPHIC] [TIFF OMITTED] T6094.329
[GRAPHIC] [TIFF OMITTED] T6094.330
[GRAPHIC] [TIFF OMITTED] T6094.331
[GRAPHIC] [TIFF OMITTED] T6094.332
[GRAPHIC] [TIFF OMITTED] T6094.333
[GRAPHIC] [TIFF OMITTED] T6094.334
[GRAPHIC] [TIFF OMITTED] T6094.335
[GRAPHIC] [TIFF OMITTED] T6094.336
[GRAPHIC] [TIFF OMITTED] T6094.337
[GRAPHIC] [TIFF OMITTED] T6094.338
[GRAPHIC] [TIFF OMITTED] T6094.339
[GRAPHIC] [TIFF OMITTED] T6094.340
[GRAPHIC] [TIFF OMITTED] T6094.341
[GRAPHIC] [TIFF OMITTED] T6094.342
[GRAPHIC] [TIFF OMITTED] T6094.343
[GRAPHIC] [TIFF OMITTED] T6094.344
[GRAPHIC] [TIFF OMITTED] T6094.345
[GRAPHIC] [TIFF OMITTED] T6094.346
[GRAPHIC] [TIFF OMITTED] T6094.347
[GRAPHIC] [TIFF OMITTED] T6094.348
[GRAPHIC] [TIFF OMITTED] T6094.349
[GRAPHIC] [TIFF OMITTED] T6094.350
[GRAPHIC] [TIFF OMITTED] T6094.351
[GRAPHIC] [TIFF OMITTED] T6094.352
[GRAPHIC] [TIFF OMITTED] T6094.353
[GRAPHIC] [TIFF OMITTED] T6094.354
[GRAPHIC] [TIFF OMITTED] T6094.355
[GRAPHIC] [TIFF OMITTED] T6094.356
[GRAPHIC] [TIFF OMITTED] T6094.357
[GRAPHIC] [TIFF OMITTED] T6094.358
[GRAPHIC] [TIFF OMITTED] T6094.359
[GRAPHIC] [TIFF OMITTED] T6094.360
[GRAPHIC] [TIFF OMITTED] T6094.361
[GRAPHIC] [TIFF OMITTED] T6094.362
[GRAPHIC] [TIFF OMITTED] T6094.363
[GRAPHIC] [TIFF OMITTED] T6094.364
[GRAPHIC] [TIFF OMITTED] T6094.365
[GRAPHIC] [TIFF OMITTED] T6094.366
[GRAPHIC] [TIFF OMITTED] T6094.367
[GRAPHIC] [TIFF OMITTED] T6094.368
[GRAPHIC] [TIFF OMITTED] T6094.369
[GRAPHIC] [TIFF OMITTED] T6094.370
[GRAPHIC] [TIFF OMITTED] T6094.371
[GRAPHIC] [TIFF OMITTED] T6094.372
[GRAPHIC] [TIFF OMITTED] T6094.373
[GRAPHIC] [TIFF OMITTED] T6094.374
[GRAPHIC] [TIFF OMITTED] T6094.375
[GRAPHIC] [TIFF OMITTED] T6094.376
[GRAPHIC] [TIFF OMITTED] T6094.377
[GRAPHIC] [TIFF OMITTED] T6094.378
[GRAPHIC] [TIFF OMITTED] T6094.379
[GRAPHIC] [TIFF OMITTED] T6094.380
[GRAPHIC] [TIFF OMITTED] T6094.381
[GRAPHIC] [TIFF OMITTED] T6094.382
[GRAPHIC] [TIFF OMITTED] T6094.383
[GRAPHIC] [TIFF OMITTED] T6094.384
[GRAPHIC] [TIFF OMITTED] T6094.385
[GRAPHIC] [TIFF OMITTED] T6094.386
[GRAPHIC] [TIFF OMITTED] T6094.387
[GRAPHIC] [TIFF OMITTED] T6094.388
[GRAPHIC] [TIFF OMITTED] T6094.389
[GRAPHIC] [TIFF OMITTED] T6094.390
[GRAPHIC] [TIFF OMITTED] T6094.391
[GRAPHIC] [TIFF OMITTED] T6094.392
[GRAPHIC] [TIFF OMITTED] T6094.393
[GRAPHIC] [TIFF OMITTED] T6094.394
[GRAPHIC] [TIFF OMITTED] T6094.395
[GRAPHIC] [TIFF OMITTED] T6094.396
[GRAPHIC] [TIFF OMITTED] T6094.397
[GRAPHIC] [TIFF OMITTED] T6094.398
[GRAPHIC] [TIFF OMITTED] T6094.399
[GRAPHIC] [TIFF OMITTED] T6094.400
[GRAPHIC] [TIFF OMITTED] T6094.401
[GRAPHIC] [TIFF OMITTED] T6094.402
[GRAPHIC] [TIFF OMITTED] T6094.403
[GRAPHIC] [TIFF OMITTED] T6094.404
[GRAPHIC] [TIFF OMITTED] T6094.405
[GRAPHIC] [TIFF OMITTED] T6094.406
[GRAPHIC] [TIFF OMITTED] T6094.407
[GRAPHIC] [TIFF OMITTED] T6094.408
[GRAPHIC] [TIFF OMITTED] T6094.409
[GRAPHIC] [TIFF OMITTED] T6094.410
[GRAPHIC] [TIFF OMITTED] T6094.411
[GRAPHIC] [TIFF OMITTED] T6094.412
[GRAPHIC] [TIFF OMITTED] T6094.413
[GRAPHIC] [TIFF OMITTED] T6094.414
[GRAPHIC] [TIFF OMITTED] T6094.415
[GRAPHIC] [TIFF OMITTED] T6094.416
[GRAPHIC] [TIFF OMITTED] T6094.417
[GRAPHIC] [TIFF OMITTED] T6094.418
[GRAPHIC] [TIFF OMITTED] T6094.419
[GRAPHIC] [TIFF OMITTED] T6094.420
[GRAPHIC] [TIFF OMITTED] T6094.421
[GRAPHIC] [TIFF OMITTED] T6094.422
[GRAPHIC] [TIFF OMITTED] T6094.423
[GRAPHIC] [TIFF OMITTED] T6094.424
[GRAPHIC] [TIFF OMITTED] T6094.425
[GRAPHIC] [TIFF OMITTED] T6094.426
[GRAPHIC] [TIFF OMITTED] T6094.427
[GRAPHIC] [TIFF OMITTED] T6094.428
[GRAPHIC] [TIFF OMITTED] T6094.429
[GRAPHIC] [TIFF OMITTED] T6094.430
[GRAPHIC] [TIFF OMITTED] T6094.431
[GRAPHIC] [TIFF OMITTED] T6094.432
[GRAPHIC] [TIFF OMITTED] T6094.433
[GRAPHIC] [TIFF OMITTED] T6094.434
[GRAPHIC] [TIFF OMITTED] T6094.435
[GRAPHIC] [TIFF OMITTED] T6094.436
[GRAPHIC] [TIFF OMITTED] T6094.437
[GRAPHIC] [TIFF OMITTED] T6094.438
[GRAPHIC] [TIFF OMITTED] T6094.439
[GRAPHIC] [TIFF OMITTED] T6094.440
[GRAPHIC] [TIFF OMITTED] T6094.441
[GRAPHIC] [TIFF OMITTED] T6094.442
[GRAPHIC] [TIFF OMITTED] T6094.443
[GRAPHIC] [TIFF OMITTED] T6094.444
[GRAPHIC] [TIFF OMITTED] T6094.445
[GRAPHIC] [TIFF OMITTED] T6094.446
[GRAPHIC] [TIFF OMITTED] T6094.447
[GRAPHIC] [TIFF OMITTED] T6094.448
[GRAPHIC] [TIFF OMITTED] T6094.449
[GRAPHIC] [TIFF OMITTED] T6094.450
[GRAPHIC] [TIFF OMITTED] T6094.451
[GRAPHIC] [TIFF OMITTED] T6094.452
[GRAPHIC] [TIFF OMITTED] T6094.453
[GRAPHIC] [TIFF OMITTED] T6094.454
[GRAPHIC] [TIFF OMITTED] T6094.455
[GRAPHIC] [TIFF OMITTED] T6094.456
[GRAPHIC] [TIFF OMITTED] T6094.457
[GRAPHIC] [TIFF OMITTED] T6094.458
[GRAPHIC] [TIFF OMITTED] T6094.459
[GRAPHIC] [TIFF OMITTED] T6094.460
[GRAPHIC] [TIFF OMITTED] T6094.461
[GRAPHIC] [TIFF OMITTED] T6094.462
[GRAPHIC] [TIFF OMITTED] T6094.463
[GRAPHIC] [TIFF OMITTED] T6094.464
[GRAPHIC] [TIFF OMITTED] T6094.465
[GRAPHIC] [TIFF OMITTED] T6094.466
[GRAPHIC] [TIFF OMITTED] T6094.467
[GRAPHIC] [TIFF OMITTED] T6094.566
[GRAPHIC] [TIFF OMITTED] T6094.468
[GRAPHIC] [TIFF OMITTED] T6094.469
[GRAPHIC] [TIFF OMITTED] T6094.470
[GRAPHIC] [TIFF OMITTED] T6094.471
[GRAPHIC] [TIFF OMITTED] T6094.472
[GRAPHIC] [TIFF OMITTED] T6094.473
[GRAPHIC] [TIFF OMITTED] T6094.474
[GRAPHIC] [TIFF OMITTED] T6094.475
[GRAPHIC] [TIFF OMITTED] T6094.476
[GRAPHIC] [TIFF OMITTED] T6094.477
[GRAPHIC] [TIFF OMITTED] T6094.478
[GRAPHIC] [TIFF OMITTED] T6094.479
[GRAPHIC] [TIFF OMITTED] T6094.480
[GRAPHIC] [TIFF OMITTED] T6094.481
[GRAPHIC] [TIFF OMITTED] T6094.482
[GRAPHIC] [TIFF OMITTED] T6094.483
[GRAPHIC] [TIFF OMITTED] T6094.484
[GRAPHIC] [TIFF OMITTED] T6094.485
[GRAPHIC] [TIFF OMITTED] T6094.486
[GRAPHIC] [TIFF OMITTED] T6094.487
[GRAPHIC] [TIFF OMITTED] T6094.488
[GRAPHIC] [TIFF OMITTED] T6094.489
[GRAPHIC] [TIFF OMITTED] T6094.490
[GRAPHIC] [TIFF OMITTED] T6094.491
[GRAPHIC] [TIFF OMITTED] T6094.492
[GRAPHIC] [TIFF OMITTED] T6094.493
[GRAPHIC] [TIFF OMITTED] T6094.494
[GRAPHIC] [TIFF OMITTED] T6094.495
[GRAPHIC] [TIFF OMITTED] T6094.496
[GRAPHIC] [TIFF OMITTED] T6094.497
[GRAPHIC] [TIFF OMITTED] T6094.498
[GRAPHIC] [TIFF OMITTED] T6094.499
[GRAPHIC] [TIFF OMITTED] T6094.500
[GRAPHIC] [TIFF OMITTED] T6094.501
[GRAPHIC] [TIFF OMITTED] T6094.502
[GRAPHIC] [TIFF OMITTED] T6094.503
[GRAPHIC] [TIFF OMITTED] T6094.504
[GRAPHIC] [TIFF OMITTED] T6094.505
[GRAPHIC] [TIFF OMITTED] T6094.506
[GRAPHIC] [TIFF OMITTED] T6094.507
[GRAPHIC] [TIFF OMITTED] T6094.508
[GRAPHIC] [TIFF OMITTED] T6094.509
[GRAPHIC] [TIFF OMITTED] T6094.510
[GRAPHIC] [TIFF OMITTED] T6094.511
[GRAPHIC] [TIFF OMITTED] T6094.512
[GRAPHIC] [TIFF OMITTED] T6094.513
[GRAPHIC] [TIFF OMITTED] T6094.514
[GRAPHIC] [TIFF OMITTED] T6094.515
[GRAPHIC] [TIFF OMITTED] T6094.516
[GRAPHIC] [TIFF OMITTED] T6094.517
[GRAPHIC] [TIFF OMITTED] T6094.518
[GRAPHIC] [TIFF OMITTED] T6094.519
[GRAPHIC] [TIFF OMITTED] T6094.520
[GRAPHIC] [TIFF OMITTED] T6094.521
[GRAPHIC] [TIFF OMITTED] T6094.522
[GRAPHIC] [TIFF OMITTED] T6094.523
[GRAPHIC] [TIFF OMITTED] T6094.524
[GRAPHIC] [TIFF OMITTED] T6094.525
[GRAPHIC] [TIFF OMITTED] T6094.526
[GRAPHIC] [TIFF OMITTED] T6094.527
[GRAPHIC] [TIFF OMITTED] T6094.528
[GRAPHIC] [TIFF OMITTED] T6094.529
[GRAPHIC] [TIFF OMITTED] T6094.530
[GRAPHIC] [TIFF OMITTED] T6094.531
[GRAPHIC] [TIFF OMITTED] T6094.532
[GRAPHIC] [TIFF OMITTED] T6094.533
[GRAPHIC] [TIFF OMITTED] T6094.534
[GRAPHIC] [TIFF OMITTED] T6094.535
[GRAPHIC] [TIFF OMITTED] T6094.536
[GRAPHIC] [TIFF OMITTED] T6094.537
[GRAPHIC] [TIFF OMITTED] T6094.538
[GRAPHIC] [TIFF OMITTED] T6094.539
[GRAPHIC] [TIFF OMITTED] T6094.540
[GRAPHIC] [TIFF OMITTED] T6094.541
[GRAPHIC] [TIFF OMITTED] T6094.542
[GRAPHIC] [TIFF OMITTED] T6094.543
[GRAPHIC] [TIFF OMITTED] T6094.544
[GRAPHIC] [TIFF OMITTED] T6094.545
[GRAPHIC] [TIFF OMITTED] T6094.546
[GRAPHIC] [TIFF OMITTED] T6094.547
[GRAPHIC] [TIFF OMITTED] T6094.548
[GRAPHIC] [TIFF OMITTED] T6094.549
[GRAPHIC] [TIFF OMITTED] T6094.550
[GRAPHIC] [TIFF OMITTED] T6094.551
[GRAPHIC] [TIFF OMITTED] T6094.552
[GRAPHIC] [TIFF OMITTED] T6094.553
[GRAPHIC] [TIFF OMITTED] T6094.554
[GRAPHIC] [TIFF OMITTED] T6094.555
[GRAPHIC] [TIFF OMITTED] T6094.556
[GRAPHIC] [TIFF OMITTED] T6094.557
[GRAPHIC] [TIFF OMITTED] T6094.558
[GRAPHIC] [TIFF OMITTED] T6094.559
[GRAPHIC] [TIFF OMITTED] T6094.560
[GRAPHIC] [TIFF OMITTED] T6094.561
[GRAPHIC] [TIFF OMITTED] T6094.562
[GRAPHIC] [TIFF OMITTED] T6094.563
[GRAPHIC] [TIFF OMITTED] T6094.564
[GRAPHIC] [TIFF OMITTED] T6094.565