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

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PUBLICATION AND DISCLOSURE ISSUES IN ANTIDEPRESSANT

PEDIATRIC CLINICAL TRIALS

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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

2

COMMITTEE ON ENERGY AND COMMERCE

JOE BARTON, Texas, Chairman

W.J. ‘‘BILLY’’ TAUZIN, Louisiana

RALPH M. HALL, Texas

MICHAEL BILIRAKIS, Florida

FRED UPTON, Michigan

CLIFF STEARNS, Florida

PAUL E. GILLMOR, Ohio

JAMES C. GREENWOOD, Pennsylvania

CHRISTOPHER COX, California

NATHAN DEAL, Georgia

RICHARD BURR, North Carolina

ED WHITFIELD, Kentucky

CHARLIE NORWOOD, Georgia

BARBARA CUBIN, Wyoming

JOHN SHIMKUS, Illinois

HEATHER WILSON, New Mexico

JOHN B. SHADEGG, Arizona

CHARLES W. ‘‘CHIP’’ PICKERING,

Mississippi, Vice Chairman

VITO FOSSELLA, New York

STEVE BUYER, Indiana

GEORGE RADANOVICH, California

CHARLES F. BASS, New Hampshire

JOSEPH R. PITTS, Pennsylvania

MARY BONO, California

GREG WALDEN, Oregon

LEE TERRY, Nebraska

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

DARRELL E. ISSA, California

C.L. ‘‘BUTCH’’ OTTER, Idaho

JOHN SULLIVAN, Oklahoma

JOHN D. DINGELL, Michigan

Ranking Member

HENRY A. WAXMAN, California

EDWARD J. MARKEY, Massachusetts

RICK BOUCHER, Virginia

EDOLPHUS TOWNS, New York

FRANK PALLONE, Jr., New Jersey

SHERROD BROWN, Ohio

BART GORDON, Tennessee

PETER DEUTSCH, Florida

BOBBY L. RUSH, Illinois

ANNA G. ESHOO, California

BART STUPAK, Michigan

ELIOT L. ENGEL, New York

ALBERT R. WYNN, Maryland

GENE GREEN, Texas

KAREN MCCARTHY, Missouri

TED STRICKLAND, Ohio

DIANA DEGETTE, Colorado

LOIS CAPPS, California

MICHAEL F. DOYLE, Pennsylvania

CHRISTOPHER JOHN, Louisiana

TOM ALLEN, Maine

JIM DAVIS, Florida

JANICE D. SCHAKOWSKY, Illinois

HILDA L. SOLIS, California

CHARLES A. GONZALEZ, Texas

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

CLIFF STEARNS, Florida

RICHARD BURR, North Carolina

CHARLES F. BASS, New Hampshire

GREG WALDEN, Oregon

Vice Chairman

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

JOE BARTON, Texas,

(Ex Officio)

PETER DEUTSCH, Florida

Ranking Member

DIANA DEGETTE, Colorado

TOM ALLEN, Maine

JANICE D. SCHAKOWSKY, Illinois

HENRY A. WAXMAN, California

EDWARD J. MARKEY, Massachusetts

JOHN D. DINGELL, Michigan,

(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, BristolMyers 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)

(1)

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.

2

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.

3

[The e-mail follows:]

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 disVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00011 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
4

order, 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

5

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

6

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

7

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

8

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

9

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

10

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 studVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00018 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
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ies 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 beVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00019 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
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cause 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.

13

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

14

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-tohead 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 marVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00022 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
15

keting 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 efVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00023 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
16

fect 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

17

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

18

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

19

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 lifethreatening 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,

20

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.

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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

22

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

6s064lProzac.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 conVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00030 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
23

ditions. 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-IyasuAuditlreport.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.

24

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

25

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 nonresponsive. 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

26

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?

27

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——

28

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

29

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

30

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?

31

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

32

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.

33

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.

34

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.

35

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.

36

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

37

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.

38

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.

39

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.

40

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?

41

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.

42

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?

43

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?

44

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

45

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.

46

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.

47

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.

48

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 antidepressants? 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

49

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

50

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.

51

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

52

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.

53

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 ‘‘offlabel.’’ 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.

54

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 abVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00062 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
55

stracts 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

56

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

57

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,

58

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 ADOLES- CENTS

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 Lillysponsored 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 longterm 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.

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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

60

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 placebotreated children. For anxiety, one study showed a clear benefit of

61

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

62

1 ICH Harmonised Tripartite Guideline for Good Clinical Practice.

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.

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.

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.

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 apVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00070 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
63

4 A copy of Wyeth’s August 2003 Dear Healthcare Provider Letter is Attachment C.

5 A copy of Wyeth’s response letter from August 2003 is Attachment D.

proved 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.

• 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

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 ColumbiaKiddie 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

64

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 CKIDDIE-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.

65

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.

66

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 extendedrelease 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 oralclearance 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.

67

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.

68

69

70

71

72

73

74

75

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 selfharm.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

76

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 openlabel 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 XRtreated 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 CKIDDIE-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 XRand 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%).

77

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 placebotreated 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, obsessivecompulsive 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 commuVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00085 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
78

nication 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.

79

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 disVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00087 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
80

ease. 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 suiciderelated 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

81

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 conVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00089 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
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firms 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:

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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

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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

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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 BristolMyers 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.

86

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 TIMI22 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:]

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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

Continued

PREPARED STATEMENT OF RONALD N. MARCUS, EXECUTIVE DIRECTOR, NEURO- SCIENCE 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 BristolMyers 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

88

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

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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 selfmutilation), during the screening phase, prior to dosing. There were no statistically

significant differences between nefazodone and placebo on the incidence of suicidalrelated adverse events.

3 COMMUNICATIONS WITH FDA

As discussed above, BMS conducted nefazodone pediatric studies in response to

a request from FDA. BMS submitted to FDA the Final Study Reports for CN104-

136 on August 21, 1997, and January 20, 1999. BMS submitted to FDA the Final

Study Reports for the Acute Phases and the Ongoing Study Reports of the Extension Phases for CN104-141 and CN104-187 on April 16, 2002. Based upon the results of these studies, FDA told BMS that nefazodone is not indicated for use in pediatric patients and the product label specifically notes that the safety and efficacy

in individuals below 18 years of age has not been established.

Thank you for the opportunity to testify on this important issue this morning.

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Mr. WALDEN. Thank you, Dr. Marcus.

Mr. Osinsky.

TESTIMONY OF PATRICK J. OSINSKY

Mr. OSINSKY. Good afternoon, Congressman Walden, Congresswoman DeGette and members of the subcommittee. I am Patrick

J. Osinsky, vice president and general counsel of Organon USA,

Inc., on whose behalf I appear before you today.

At the outset, Organon would like to thank the subcommittee for

inviting us to participate in today’s hearing. Organon shares the

subcommittee’s concern about the safety of antidepressants in children. In response to the subcommittee’s letter of March 24,

Organon compiled data and other information about clinical trials

involving the use of Organon’s Remeron, mirtazapine tablets, for

the treatment of major depressive order in children.

On April 14, Organon submitted this information to the subcommittee and updated it on July 16. The following is a brief summary of that information. Organon conducted two studies, both of

which were subsequently submitted to FDA on May 1, 2001 as part

of Organon’s supplemental new drug application for pediatric exclusivity of Remeron tablets. One of these two studies was a safety

and efficacy study of the use of Remeron for the treatment of depression in pediatric patients. In terms of safety, the conclusion

was that Remeron was well tolerated and safe. In terms of efficacy,

however, there was no statistically significant difference detected

between the placebo and treatment groups. That study was the

subject of two presentations, one made in September of 2001 in

Pittsburgh at a consortium entitled, ‘‘Pharmacological Update in

Children and Adolescents,’’ and one made at a symposium held at

American Academy of Child and Adolescent Psychiatry Conference

in October 2001.

The second study that Organon sponsored and submitted to FDA

as part of its supplemental NDA was a pharmacokinetic study. The

conclusion of that study was that Remeron was relatively well tolerated and safe. That study was the subject of a manuscript, portions of which were presented at a March 2002 annual meeting of

the American Society of Clinical Pharmacology and Therapeutics in

an abstract entitled, ‘‘Single Dose Pharmacokinetics and

Mirtazapine and Demethyl Metabolite in Depressed Children and

Adolescents,’’ which was published in a 2002 issue of Clinical Pharmacology Therapeutics. A summary of the PK study was also disseminated as part of a poster session at the October 2001 American

Academy of Child and Adolescent Psychiatry Conference and subsequently included in the compilation of conference materials.

Grants were provided for two additional studies conducted on the

use of Remeron in children. The first was an open label study that

was conducted in Finland to evaluate the antidepressant efficacy

and safety of Remeron in adolescents suffering from major depression. Based on the results of that study, it was concluded that

Remeron may be a safe and effective treatment for major depression adolescents. This study is the subject of an article entitled,

‘‘Mirtazapine in the Treatment of Adolescents with Major Depression,’’ in an open label multicenter pilot study, which is expected

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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 DSM4 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

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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 Psychopharmacology.

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.

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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 SepVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00123 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
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tember 2003 to include additional safety information derived from

these studies. And in addition, the label did state that efficacy had

not been established in children under the age of 18 in major depressive disorder. I do want to emphasize that Pfizer does not promote the use of Zoloft in pediatric MDD. In addition, the Zoloft

label has recently been updated to reflect the new warning.

In total, Pfizer has completed nine pediatric studies with Zoloft.

Every one has been submitted to the FDA. In addition, seven have

been published in peer review journals, including our pediatric

MDD data, which were published in JAMA. The eighth study has

been submitted to a peer review journal and is undergoing peer review. The only study that Pfizer has conducted with Zoloft in the

pediatric population not published in a peer review journal, although of course submitted to FDA, is an open label continuation

of a dose finding study, an early pharmacokinetic study. We, of

course, filed this with FDA. Given the current interest in transparency of all results of pediatric trials, we are now preparing this

study for submission to a peer review journal.

In addition, Pfizer is committed to working with PhRMA, with

AMA, journal editors and all interested stakeholders to determine

the optimal means for disseminating information from all of our

trials that will have an impact on prescribing decisions in public

health. Pfizer’s participation in the recently announced PhRMA

data base is a first step in that direction, and I understand you will

hear more about that this afternoon.

In conclusion, I want to emphasize my belief, as a physician and

vice president at Pfizer, that our company has been and continues

to be committed to generating and communicating meaningful information to physicians about the appropriate use of Zoloft in the

pediatric population. Thank you, and I will be happy to take any

questions.

[The prepared statement of Cathryn M. Clary follows:]

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Mr. WALDEN. Thank you very much, Dr. Clary. We appreciate all

of you being here today and testifying as we look at how all this

information is made public. Dr. Clary, your company performed two

pediatric studies with Zoloft in depressed children; is that correct?

Ms. CLARY. That is correct.

Mr. WALDEN. These study reports were submitted then to the

FDA in December 2001, right?

Ms. CLARY. Yes, that is correct.

Mr. WALDEN. And is it correct that neither study showed efficacy?

Ms. CLARY. It is correct that neither study showed a statistically

significant difference between Zoloft and placebo.

Mr. WALDEN. And, therefore, Zoloft is not approved, as you said,

for use in depressed kids, correct?

Ms. CLARY. Yes.

Mr. WALDEN. On the label.

Ms. CLARY. Yes.

Mr. WALDEN. Neither of these depression studies that you did in

children were published on a stand-alone basis, right?

Ms. CLARY. That is correct, because Pfizer had made a determination before the blinds were broken that the pooled analysis

was really what was needed in order to really have reliable results.

Mr. WALDEN. If you always sort of planned on pooling the studies, why is the Zoloft pooling article published 11⁄2 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

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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 AdminisVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00158 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
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tration. 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

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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 placebocontrolled studies until FDAMA was passed, which really did encourage controlled studies to be done, but a comprehensive search.

So every study is put into these letters, positive or negative, that

is in the literature.

Mr. WALDEN. I should have submitted this letter for the record,

and so I would like to do that without objection at this time.

[The information referred to follows:]

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Mr. WALDEN. One final question—I have blown past my time

limit here—do you have—what is the objection to publishing studies in full as stand-alone? Some of you, I think, your companies at

least have begun to do that. It would seem to me that it would be

in everyone’s best interest as we all try and get information to

make these studies published stand-alone, fully available to the

public without us having to mandate that legislatively. I noted

today that the various medical journals are now requiring additional standards in terms of what they are going to accept to be

published, I think, in part, because of these hearings, but can you

just quickly say if your company does support publication of standalone 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 standalone. 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

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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.

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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.

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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?

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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.

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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.

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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.

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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?

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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

171

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

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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

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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.

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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——

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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

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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?

177

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.

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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

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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

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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 representaVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00188 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
181

tives 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.

182

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?

183

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——

184

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 an- other $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

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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

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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?

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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.

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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.

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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.

190

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

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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?

192

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?

193

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, conVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00201 Fmt 6633 Sfmt 6602 96094.TXT HCOM1 PsN: HCOM1
194

cludes 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?

195

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 followon 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

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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 ongoing 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

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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.

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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.

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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 FDAapproved 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 invesVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00207 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
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tigator 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 metaregistries 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 LifeThreatening 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 impleVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00208 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
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mented, 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 physiVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00209 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
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cians 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

203

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 REGU- LATORY 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

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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

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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

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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 esVerDate 11-MAY-2000 12:01 Nov 18, 2004 Jkt 000000 PO 00000 Frm 00214 Fmt 6633 Sfmt 6621 96094.TXT HCOM1 PsN: HCOM1
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tablish 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

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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

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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.

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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 nonpharmacological 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

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care, legal pursuits, etc)? What might be the unintended consequences of well-intentioned policies?

A number of proposals have been raised. Each comes with potential benefits but

must be carefully examined within the context of potential issues. Proposals include:

Review of Clinical Trial Findings: There are considerable concerns that non-published studies which have not undergone peer review (or for that matter, any review) may be included in a database that will be easily accessible by the general

population and will contain insufficient information by which to judge a study’s validity. Examples include:

• Medications have the FDA for oversight, but there is little to prevent a company

or individual from posting ‘‘results’’ of their independent research that demonstrates the benefit of a completely non-efficacious or potentially harmful

intervention (with claims based on seriously flawed research). • Through the media and advertising industry there are many claims of product or

intervention efficacy that are likely based on research that would not be judged

as supported if subjected to the peer review process of professional journals

(e.g., dietary supplements, some non-evidence-based mental health interventions, non-pharmacological diet or pain ‘‘treatments’’ to name just a few). • Inclusion of a disclaimer that a study did not undergo ‘‘peer-review’’ will not likely

have sufficient impact, especially if the study is posted on a government website

along with the best of scientific studies. The general population may likely view

the study as having more credibility, irrespective of any disclaimers.

Clinical Trial Registries and Databases: A central clinical trial registry or database for clinical trial information would go a long way towards addressing concerns

about a lack of awareness outside the scientific community of the full nature, scope,

and results of clinical trials.

One of the most frequently-cited rationales for registries is that such a database

would lead to a decrease in reporting bias—the tendency of scientists to publish only

those studies yielding positive results. However, this may not necessarily be the

case. If all results, including negative ones, are available in a registry, then it is

quite possible that the prevalence of positive studies reported in peer-reviewed journals might actually increase, since the negative studies will have already been disclosed elsewhere (and possibly in a relatively cursory manner).

There are many other concerns that must be addressed on this issue of a registry,

including what entity will administer it and how compliance will be enforced, how

the raw data will be filtered and presented in a way to allow those outside the scientific community to interpret it, concerns of industry over the disclosure of proprietary information, etc.

Clearly it is imperative that any effort to establish or expand clinical trial registries be well considered and thoughtful, as well as taken at a reasonable pace.

Conclusion and Recommendations

It is not an issue of IF there is a need to provide health care professionals and

patients appropriate information about clinical trials findings. Rather it is a matter

of HOW the information is provided. It is no simple task to develop an appropriate

mechanism but there are existing models such as the pediatric clinical trials summaries within the Best Pharmaceuticals for Children Act that may help shape the

process.

The AAP and pediatric academic societies propose the following initial recommendations:

• We urge Congress to broaden their investigation to include all medications, rather

than simply anti-depressants. In addition, it is necessary to include all populations and ages in order to best improve patient care. • While concerns related to publication and disclosure of clinical trial findings are

not limited to medications, it may be necessary to begin with that therapy as

an incremental step. • Thoughtful and deliberative assessment of how data collection and registries are

developed is essential.— The role of peer-review of studies must be thoroughly

explored. The AAP urges the medical community, pharmaceutical manufacturers, scientific journals, policy makers, researchers and other stakeholders to

work together to identify the scope of the problems and develop appropriate solutions. We must work with deliberate speed but must also ensure that the solutions adequately address the problem and do not, in fact, cause even more

problems.

On behalf of the American Academy of Pediatrics and the pediatric academic societies, thank you for the opportunity to testify on this important issue. We offer our

assistance and expertise to the Congress and other stakeholders as this important

discussion continues.

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Mr. WALDEN. Thank you, Doctor, for your testimony. I’m going

to recess the committee at this point. We’ll go over and cast the two

votes that we have. We should be back here no later than 6:30.

And we’ll reconvene for some questions and then we’ll wrap it up

for a really long day. Thank you. We’re in recess.

[Off the record.]

Mr. WALDEN. I’m going to call the subcommittee back to order.

Again, I want to thank our witnesses for putting in a pretty long

day.

There are several questions I’d like to ask for the record and Mr.

Allen who will not be able to rejoin us, apparently, did want to

make sure we kept the record open for written questions for committee members who obviously aren’t able to be with us any longer

tonight.

My first question really gets at an issue that has troubled me a

bit and maybe this is standard practice and I’m just learning about

it, but Dr. Davis, can you talk to me about doctors prescribing

drugs for children that have not been approved on the label for the

uses by the FDA? I mean the top four anti-depressant drugs given

to children all have not been approved for use as an anti-depressants. You can see tab 69, I’m at page 13.

And I figured that things weren’t prescribed that weren’t—didn’t

go through clinical trials and weren’t designed for that use and yet,

when you look at the data, I mean in some respects, poor old

Prozac is out there, the one that has gone through clinical trials

and been approved for this use and it’s not even one of the top,

what, two or three—it’s No. 4 in line. It’s No. 5 behind four drugs

and I’m not picking favorites here at all, but it just seems peculiar

to me that you have one that actually has been through clinical

trials and shows some effectiveness in anti-depressant treatment

for youth and yet, members of your profession or perhaps yours,

Dr. Gorman, are prescribing four others in greater quantities.

How does that happen? Is it a problem, something we need to be

concerned about?

Mr. DAVIS. This gets at the whole issue of off-label indications for

medications and our position at the American Medical Association

is that physicians should have the right to prescribe an FDA-approved drug or a medical device for an unlabeled indication when

such use is based on sound, scientific evidence and sound medical

opinion. In many cases, a physician is faced with a patient with a

serious or even life-threatening condition. Other treatments may

have already been tried and perhaps are no longer working, but

this physician may have reason to believe that this medication,

even though we’re talking about an off-label indication may help in

this patient who is in my office today. That reason may be based

on the mechanism of action of that drug. Maybe it is known to be

effective in a similar illness, but it has not get been proven to be

effective in this particular illness. Or maybe it works in one population group. We have not proven that it is effective in another population group.

So when you have to make the decision facing an individual patient with a dearth of information for reasons that we’ve discussed,

when no other treatments are available, that’s a situation when offlabel prescribing may be done.

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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-yearold 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.

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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

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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.

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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.

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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?

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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.

225

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.

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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?

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Ms. LOEW. I think in the earlier panel, this issue came up as

well, the definition of significant medical importance. That definition will vary by therapeutic area, but essentially where the result

of a clinical study provides information that it is believed to be important to practicing physicians, we believe that information should

be disclosed.

Chairman BARTON. Does it have anything to do with the number

of people?

Ms. LOEW. No.

Chairman BARTON. So it’s not——

Ms. LOEW. It’s independent of that.

Chairman BARTON. Okay. It’s the efficacy on people that need

that drug. Is that fair?

Ms. LOEW. That could be the reason, yes. But that could be one

of many reasons.

Chairman BARTON. What would be another one? I’m just trying

to get—I know it’s late. I’m not trying to be argumentative. I’m trying to understand this and I’m not a medical major.

Ms. LOEW. An example could be and I should also say I’m not

a physician either. An example could be that you are studying for

one disease condition and that’s the focus of your study, but you

find out during the study that the disease—sorry, the drug has a

significant impact in another disease area. That could be an example. You could, for instance, find a safety problem that you believe

should be communicated. There are a number of different reasons,

as I said.

Chairman BARTON. But it all revolves the result that occurs

when you take that specific drug?

Ms. LOEW. Correct.

Chairman BARTON. Thank you, Mr. Chairman, and again, I appreciate you chairing this hearing and I want to thank our last

panel again for being with us this late in the evening.

Mr. WALDEN. Thank you. Thank you, Mr. Chairman. And I, too,

want to thank our panel for your endurance and your participation.

The committee record will remain open for members who have

questions that we may want to ask and we would ask that all our

witnesses today be able to respond before our September 23 hearing which will take up this issue in further detail. We do appreciate your enlightenment on this subject and thank you for your

participation and you are excused. And we are adjourned.

[Whereupon, at 7:08 p.m., the hearing was concluded.]

[Additional material submitted for the record follows:]

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Æ