FDA’S ROLE IN PROTECTING THE PUBLIC HEALTH:

EXAMINING FDA’S REVIEW OF SAFETY AND

EFFICACY CONCERNS IN ANTI-DEPRESSANT USE

BY CHILDREN

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HOUSE OF REPRESENTATIVES

ONE HUNDRED EIGHTH CONGRESS

SECOND SESSION

SEPTEMBER 23, 2004

Serial No. 108–125

Printed for the use of the Committee on Energy and Commerce

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FDA’S ROLE IN PROTECTING THE PUBLIC HEALTH: EXAMINING FDA’S REVIEW OF

SAFETY AND EFFICACY CONCERNS IN ANTI-DEPRESSANT USE BY CHILDREN

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FDA’S ROLE IN PROTECTING THE PUBLIC HEALTH:

EXAMINING FDA’S REVIEW OF SAFETY AND

EFFICACY CONCERNS IN ANTI-DEPRESSANT USE

BY CHILDREN

HEARING

BEFORE THE

SUBCOMMITTEE ON

OVERSIGHT AND INVESTIGATIONS

OF THE

COMMITTEE ON ENERGY AND

COMMERCE

HOUSE OF REPRESENTATIVES

ONE HUNDRED EIGHTH CONGRESS

SECOND SESSION

SEPTEMBER 23, 2004

Serial No. 108–125

Printed for the use of the Committee on Energy and Commerce

(

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

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:

Knudsen, James, Food and Drug Administration; accompanied by Robert

Temple, Food and Drug Administration; Paul Seligman, Food and Drug

Administration; Thomas Laughren, Food and Drug Administration; and

Tarek Hammad, Food and Drug Administration ....................................... 64

Mosholder, Andrew D., Food and Drug Administration ................................ 21

(III)

(1)

FDA’S ROLE IN PROTECTING THE PUBLIC

HEALTH: EXAMINING FDA’S REVIEW OF

SAFETY AND EFFICACY CONCERNS IN ANTIDEPRESSANT USE BY CHILDREN

THURSDAY, SEPTEMBER 23, 2004

HOUSE OF REPRESENTATIVES,

SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS,

COMMITTEE ON ENERGY AND COMMERCE,

Washington, DC.

The subcommittee met, pursuant to notice, at 11:05 a.m., in room

2123, Rayburn House Office Building, Hon. Joe Barton (chairman)

presiding.

Members present: Representatives Bilirakis, Stearns, Bass, Walden, Ferguson, Rogers, Barton (ex officio), Deutsch, DeGette, Allen,

Schakowsky, and Waxman

Also present: Representative Stupak.

Staff present: Mark Paoletta, majority counsel; Alan Slobodin,

majority counsel; Kelli Andrews, majority counsel; Joby Fortson,

majority counsel; Billy Harvard, majority staff assistant; David

Nelson, minority investigator; and Jessica McNiece, minority research assistant.

Chairman BARTON. Today we are continuing a series of hearings

on FDA’s role in protecting the public health, examining the FDA’s

review of safety and efficacy concerns in anti-depressant use in

children.

As part of this committee’s jurisdiction over public health, the

subcommittee today will examine the FDA’s process in determining

the safety and public health concerns of anti-depressants in children.

The controversy over the use of anti-depressants in children is of

great public interest. Over 10 million children a year are prescribed

anti-depressants in the United States. The committee’s interest in

this issue began in January of this year in response to media reports about the concerns over the safety and efficacy of anti-depressants used by children.

One month earlier, in December 2003, British regulators contraindicted all anti-depressants for children except Prozac due to the

risk-benefit analysis of safety concerns related to suicidal behavior

coupled with a weak showing of efficacy. Despite the action taken

by British regulators in December 2003, at that time in the United

States there appeared to still be substantial support in the medical

community for the use of anti-depressants in children and for the

belief that these drugs saved children’s lives.

2

The U.S. psychiatric establishment had repeatedly assured the

public that the drugs are very safe. At around the same time that

the British regulators announced their decision, an internal FDA

analysis of the pediatric clinical trials of these drugs did show an

increased risk of suicide related events, and seemed to be at odds

with these assurances of safety.

This analysis was prepared by a medical review officer specializing in pediatric anti-depressants named Dr. Andrew Mosholder.

Dr. Mosholder was first requested in June 2003 by the

Neuropharm Division of FDA to perform this consult after

GlaxoSmithKline provided the FDA and other regulatory agencies

with an internal analysis showing an increase in suicidality during

their pediatric clinical trials of the anti-depressant Paxil.

The Neuropharm Division requested that Dr. Mosholder review

the Paxil data as well as the data from other pediatric clinical

trials to determine whether the signal was limited to Paxil or

whether other anti-depressants showed a similar association.

In September of this year—excuse me, in September 2003 Dr.

Mosholder informed the agency at an internal briefing of his preliminary conclusions. He concluded that the pediatric clinical data

showed an association between children taking the drug and suicide related behavior.

Dr. Mosholder completed a second consult in December 2003

which confirmed his preliminary findings reported in September.

Although initially scheduled to present his findings at a February

2004 Advisory Committee meeting, the purpose of which was to

publicly discuss how the agency should handle the safety issues

raised in pediatric anti-depressant trials, Dr. Mosholder was informed in early January of this year he would not be presenting

at the Advisory Committee.

It is my understanding that the individuals within the

Neuropharm Division, who incidentally were in charge of this February meeting, told Dr. Mosholder that they had, ‘‘reached a different conclusion’’ about the data. As a result of this disagreement,

he was prevented from presenting his analysis before the FDA Advisory Committee.

The first question that this raises is quite simple: Why? Isn’t an

Advisory Committee a panel of experts? Aren’t those people capable

of hearing different points of view and making decisions? What was

the harm in allowing Dr. Mosholder an opportunity to present his

data, his analysis, and his opinion to a group of experts?

I am looking forward to hearing from Dr. Mosholder and some

of the other FDA witnesses about these issues to get to the very

heart of this matter.

On September 13, 2004, which was just several weeks ago, the

FDA convened another meeting of the Advisory Committee to consider the question again, whether there was an increased risk of

suicide related behavior in children taking anti-depressants. This

time at this meeting, Dr. Mosholder did present his data.

As I understand it, the FDA also presented another analysis recently completed by Dr. Hammad. Both Dr. Hammad’s analysis

and Dr. Mosholder’s December 2003 analysis essentially reached

the same conclusions. There is an increase in suicide related behavior with children taking anti-depressants.

3

Let me repeat that. Their two analyses essentially reached the

same conclusions. There is an increase in suicide related behavior

with children taking anti-depressants. The agency now acknowledges this association.

Where do we go from here? The FDA has now looked at the issue

in depth and has indicated that they are just about ready to announce a final course of action. What that course of action is and

when it will be implemented are two questions this committee is

very interested in knowing.

Will we have a black box on these drugs? Will we have a new

and stronger warning label? Will we have a pamphlet, known as

a Med Guide, attached to the drug? Will we contra-indict the drug

like they did in Britain when they banned it from pediatric populations? Will we have an informed consent form signed by the patient, parent and physician? These are all questions that need to

be addressed at today’s hearing.

We look forward to getting answers to these questions and a better sense of direction about where the FDA is going.

One final issue that I want an answer today from the FDA:

When the FDA first become aware of the potential link between

anti-depressants and suicidality in children, and what did they do

to get to the bottom of it?

Throughout our investigation, we have learned that as far back

as 1996, 8 years ago, a medical review at FDA, Dr. James Knudsen, raised the question of an increase in suicidality in pediatric

clinical trials of a drug called Zoloft. There was also an analysis in

1997 of Luvox, another anti-depressant, where the review, the

same Dr. Mosholder, noted that there was an increase in hostility

in children versus adults. The issue is noted in the Luvox labeling

as a result.

The fact that children taking anti-depressants were experiencing

psychiatric adverse events at greater rates than adults was known

at the agency as far back as 1996 and 1997. This committee wants

to know what did the agency do to respond to these concerns? Did

they require that pediatric clinical trials conducted pursuant to the

Best Pharmaceuticals for Children Act be designed to capture these

types of safety issues? If not, why not? Did the agency alert their

medical reviewers to this potential issue, tell them to look closely

at that type of data that the companies were submitting in their

pediatric trials? If not, why not?

I hope that today we will be able to view the whole picture concerning anti-depressants and their effect on children as well as the

FDA approval process as a whole. The FDA’s task is quite commendable. It is not easy. They are entrusted with being the guardians of our safety. That is a very difficult trust to maintain.

As Members of Congress, it is our duty to ensure through the

oversight process that the FDA undertake this task in an earnest

and diligent and, I might also say, an open and transparent fashion. We must ensure that the FDA fulfills its public health role and

its public trust.

The FDA serves the American people. We are the client. The

mission of the FDA is not to protect the FDA’s internal workings,

but to promote and protect the public health by helping safe and

effective products reach the market by monitoring for safety, by

4

disclosing the accurate, science based information, and for providing this in a clear and concise and timely fashion to the American people.

Is the FDA accomplishing its mission with anti-depressants used

by children? I would have to say the record is open on that, and

I would say that, unless we get some very straight answers at today’s hearing, it is probably going to be answered that the FDA is

not fulfilling its mission in this particular issue.

At the September 9 hearing concerning the publication of antidepressant clinical trial data, I was upset with the FDA’s lack of

full cooperation with the documentation production process pursuant to this committee’s request. Since that hearing, I have met

with the Acting FDA Commissioner, Dr. Lester Crawford, about

the issue of FDA’s cooperation in this matter.

I would like to take note that, since that meeting, there has been

improvement in the FDA’s cooperation in document production,

and for that I want to thank Dr. Crawford publicly. I also want to

thank Dr. Crawford for his assistance with securing the appearances of some of the witnesses that will be speaking today.

Finally, I would like to thank the FDA in their diligence to responding to several member questions that were raised at the September 9 hearing.

Having said that, I must say that we continue to be somewhat

surprised when we questioning them about their policy of document retention at the FDA. The answer we got back was, in writing, that they had none—that they have no policy for document retention, which is something that we still need to address with

them.

I must say, though, that since the last hearing the FDA is cooperating much more cooperatively with this committee, and again

for that I want to thank all of our FDA representatives.

[The prepared statement of Hon. Joe Barton follows:]

PREPARED STATEMENT OF HON. JOE BARTON, CHAIRMAN, COMMITTEE ON ENERGY

AND COMMERCE

As part of the Committee’s jurisdiction over public health, the Subcommittee

today will examine the Food and Drug Administration’s (FDA’s) process in determining the safety and public health concerns of anti-depressants in children.

The controversy over the use of anti-depressants in children is of great public interest. Over 10 million children a year are prescribed anti-depressants in the United

States. The Committee’s interest in this issue began in January of this year in response to media reports about the concerns over the safety and efficacy of anti-depressants used by children. One month earlier, in December 2003, British regulators

contraindicated all anti-depressants for children, except Prozac, due to the risk-benefit analysis of safety concerns related to suicidal behavior coupled with a weak

showing of efficacy.

Despite the action taken by British regulators in December of 2003, at that time,

in the United States there appeared to still be substantial support in the medical

community for the use of antidepressants in children, and for the belief that these

drugs save children’s lives. The U.S. psychiatric establishment had repeatedly assured the public that the drugs are very safe. At around the same time that the

British regulators announced their decision, an internal FDA analysis of the pediatric clinical trials of these drugs showed an increased risk of suicide-related events

and seemed to be at odds with these assurances of safety. This analysis was prepared by a medical review officer specializing in pediatric anti-depressants named

Dr. Andrew Mosholder. Dr. Mosholder was first requested in June 2003, by the

Neuropharm division of FDA to perform this consult, after GlaxoSmithKline provided the FDA and other regulatory agencies, with an internal analysis showing an

increase in suicidality during their pediatric clinical trials of the anti-depressant

5

Paxil. The Neuropharm division requested that Dr. Mosholder review the Paxil

data, as well as the data from the other pediatric clinical trials, to determine whether the signal was limited to Paxil or whether other anti-depressants showed a similar association. In September 2003, Dr. Mosholder informed the agency at an internal briefing of his preliminary conclusions: the pediatric clinical data showed an association between children taking the drug and suicide-related behavior. Dr.

Mosholder completed a second consult in December 2003, which confirmed his preliminary findings reported in September. Although initially scheduled to present his

findings at a February 2004 Advisory Committee meeting-the purpose of which was

to publicly discuss how the agency should handle the safety issues raised in pediatric anti-depressant trials-Dr. Mosholder was informed in early January 2004, he

would not be presenting at the Advisory Committee meeting. It is my understanding

that individuals within the Neuropharm Division, who incidentally were in charge

of this February meeting, told Dr. Mosholder-they had ‘‘reached a different conclusion’’ about the data. As a result of this disagreement, he was prevented from presenting his analysis before the FDA Advisory Committee.

The first question this raises is simply: why? Isn’t an Advisory Committee a panel

of experts? Aren’t those people capable of hearing differing points of view and making decisions? What was the harm in allowing Dr. Mosholder an opportunity to

present his data, his analysis and his opinion to this group of experts? I am looking

forward to hearing from Dr. Mosholder and some of the other FDA witnesses about

these issues, to get to heart of this matter.

On September 13, 2004, the FDA convened another meeting of the Advisory Committee to consider the question again: whether there was an increased risk of suicide-related behavior in children taking anti-depressants. This time, at this September meeting, Dr. Mosholder did present his data. As I understand it, the FDA

also presented another analysis, recently completed by Dr. Hammad. Both Dr.

Hammad’s analysis and Dr. Mosholder’s December 2003 analysis essentially reached

the same conclusions-there is an increase in suicide-related behavior with children

taking anti-depressants. The agency now acknowledges this association.

Where do we go from here? The FDA has now looked at the issue in depth and

has indicated that they are just about ready to announce a final course of action.

What that course of action is, and when will it be implemented-are two questions

I am very interested to know. Will we have a ‘‘black-box’’ on the drugs? Will we have

a new and stronger warning label? Will we have a pamphlet, known as a ‘‘Med

Guide,’’ attached to the drug? Will we contraindicate the drug like they did in Britain when they banned it from the pediatric population? Will we have an informed

consent form signed by patient, parent and physician? I look forward to getting feedback on these questions and a better sense of that direction today.

One final issue that I want an answer from FDA today: When did the FDA first

become aware of a potential link between anti-depressants and suicidality in children and what did they do to get to the bottom of it? Through our investigation,

we have learned that as far back as 1996, a medical reviewer at FDA-a Dr. James

Knudsen—raised the question of an increase in suicidality in pediatric clinical trials

of Zoloft. There was also an analysis in 1997 of Luvox-another anti-depressantwhere the reviewer, the same Dr. Mosholder, noted that there was an increase in

hostility in children versus adults. This issue was noted in the Luvox labeling as

a result.

The fact that children taking anti-depressants were experiencing psychiatric adverse events-at greater rates than adults-was known at the agency as far back as

1996 and 1997. I want to know: What did the agency do to respond to these concerns? Did they require that pediatric clinical trials conducted pursuant to the Best

Pharmaceuticals for Children Act be designed to capture these types of safety

issues? If not-why not? Did the agency alert their medical reviewers to this potential

issue and tell them to look closely at that type of data the companies submitted in

pediatric trials? If not-why not?

I hope that after today we will be able to view the whole picture concerning

antidepressants and their effect on children, as well as the FDA approval process

as a whole.

The FDA’s task is quite commendable and not easy. They are entrusted with

being guardians of our safety. As Members of Congress, it is our duty is to ensure

through the oversight process that this vital agency undertake this task in an earnest and diligent manner. We must ensure that FDA fulfills its public health role.

The FDA serves the American people. We are the client. The mission of the FDA

is not to protect the FDA, but to promote and protect the public health by helping

safe and effective products reach the market, by monitoring for safety, and by disclosing accurate, science-based information. Is FDA accomplishing its mission with

anti-depressants used by children?

6

At the September 9th hearing concerning the publication of anti-depressant clinical trial data, I was upset with the FDA’s lack of full cooperation with the document production process pursuant to the Committee’s request. Since that hearing,

I have met with Acting FDA Commissioner Dr. Lester Crawford about the issue of

FDA’s cooperation in this matter, and I would like to note that since that meeting,

there has been some improvement, in FDA’s cooperation and document production.

I also want to thank Dr. Crawford for his assistance with securing the appearances

of some of witnesses that will be speaking today. Finally, I would like to thank the

FDA in their diligence in responding to several member questions that were raised

at the September 9th hearing.

However, if FDA does not continue this cooperation, I will be forced to address

this issue again just as I did at the September 9th hearing. Nevertheless, I am

hopeful that we can continue to move forward on improved document production

from the agency.

Once again, I would like to thank the witnesses for appearing today and the other

members present today, and I look forward to this hearing.

Chairman BARTON. I would now like to turn to our ranking member, Mr. Deutsch for any opening statement that he wishes to

make.

Mr. DEUTSCH. Thank you, Mr. Chairman, for holding this hearing and its counterpart earlier this month.

The September 9 hearing dealt with the fact that the FDA and

drug companies withheld from the public the important information that all but one of the pediatric trials of anti-depressants

failed to show efficacy in adolescents. Sadly, we got no good answers from the FDA witness at that time, Dr. Woodcock.

Today we deal with the critical question of the safety of these potent medications in children. Specifically, we need to understand if

the risk of suicidal behavior of teens taking SSRIs is greater than

the suicide risk associated with a failure to take these anti-depressants.

That is exactly the kind of straightforward, scientific question

that the Congress expects FDA to answer for the American people.

Unfortunately, the FDA has handled the decisions involving both

the safety and efficacy of these drugs in adolescents in such an unscrupulous manner that it is very hard for anyone to accept that

objective science is the basis of the agency’s conclusions.

Consider that the FDA extended the monopoly status of these

drugs for 6 months, costing American taxpayers and consumers

over $4 billion, and then decided that the public didn’t even need

to know that all but one of these drugs could not demonstrate efficacy.

The only labeling change was for Prozac, the only SSRI shown

to work at all in kids. Shockingly, the FDA made a deliberate decision to withhold information on the clinical failures from parents

as well as pediatricians and other prescribers. But it gets even

worse.

When Wyeth found evidence of elevated risk of suicidal ideation

and hostility among adolescents taking its drug and tried to change

its label to warn parents and providers about this increased danger, the FDA said no label change to reflect those warnings is permissible.

It is incredible that this agency charged with protecting the public health would stop a company from warning the public about

risks associated with the use of its products by children. But the

FDA was far from finished with its cover-up at that point.

7

As information flooded in from the industry and the British authorities who had banned the use of these drugs in kids, the FDA

began a review of the 15 studies that had been done on pediatric

use of SSRIs. They turned the project over to a scientist, Dr. Andrew Mosholder, a medical doctor, psychiatrist and epidemiologist

in the Office of Drug Safety.

Dr. Mosholder’s analysis of multiple studies concluded that there

was indeed an elevated risk of suicidal behavior discernible from

the pediatric studies. Dr. Mosholder was scheduled to present his

findings before the Advisory Committee charged with recommending action to the FDA on anti-depressant drugs in February.

Someone within the FDA did not want those conclusions to be

public and ripped his presentation from the program. Perhaps it

was the same people who thought Wyeth shouldn’t warn the public

either. The FDA excuse was that the underlying data needed to be

examined more critically before such a sensational conclusion could

be broached publicly.

When the San Francisco Chronicle got wind of the story that the

FDA had squelched its own investigator’s report, the real cover-up

began. Both this subcommittee and the Senate Finance Committee

chaired by Senator Grassley began inquiries, but even as Congress

was gearing up, senior officials within the FDA decided to conduct

a witch hunt.

They sent criminal investigators to probe the source of the leak.

It is readily apparent that the probe was not about information

but, rather, about intimidation. It was a warning to Dr. Mosholder

and other dedicated epidemiologists at the Office of Drug Safety,

and the ostensible initiating officer was the Director of the Office

of Drug Safety.

When we authorized the Prescription Drug User Fee Act in the

last Congress, the clear tradeoff for the continuing rapid review

and approval of new drug applications was that the FDA would

place a renewed emphasis on post-marketing surveillance to detect

safety problems with drugs just as soon as they emerged.

The Mosholder investigation is a substantive demonstration that

drug safety remains a stepchild in the FDA-drug company partnership at the Center for Drug Evaluation and Research. But it gets

even worse.

To be clear, the events I am about to describe involve response

to requests from Senator Grassley, although I have no doubt that,

had this ploy succeeded, false documents would have been supplied

to this committee as well.

Andy Mosholder was forced to supply a statement to the Office

of Internal Affairs regarding the events surrounding the decision to

remove his analysis from the Advisory Committee’s agenda and the

leaking of that story to the Chronicle. This document was apparently in response to a request from Senator Grassley.

Apparently, officials in the FDA Office of Legislative Affairs and

the Office of Chief Counsel met to decide how to respond. They decided that not only should the Mosholder affidavit be redacted, but

that a new document needed to be created to hide the fact that an

investigation had even taken place.

Ultimately, Dr. Mosholder on advice of his personal counsel declined to sign the phony document suggested and drafted by an

8

FDA lawyer. Had Dr. Mosholder not acted to thwart the submission of an altered document to a bona fide Congressional investigation, a criminal act of obstruction of justice would have occurred.

As it was, the FDA and its lawyers are only guilty of attempting

to obstruct justice.

As you are well aware, Mr. Chairman, the FDA has stonewalled

lawful requests from this committee regarding documents in the

past. It has also slow-rolled and stonewalled our requests for interviews.

I applaud the determination that you have shown to get to the

bottom of this, despite the obstruction that has been employed by

FDA and its attorneys. As a result of this committee’s efforts, the

Advisory Committee did receive the Mosholder analysis last week,

as well as subsequent analysis done by Dr. Tarek Hammad. That

reached the same conclusion.

As we are all well aware, the Advisory Committee recommended

that a black box warning of increased suicide risk in children be

attached to the labels of these drugs, and that patients be informed

of the increased risk when each prescription is dispensed. They

also recommended that each drug that has failed its efficacy test

be so labeled.

I expect that the FDA will tell us at this hearing that it will

adopt the recommendations of its Advisory Committee. if so, this

may be an appropriate result. But for the investigations by Congress, specifically this committee, and the media, I doubt that we

would have reached the level of public knowledge and concern that

has prompted this result.

Mr. Chairman, I congratulate you on the witness panel you have

assembled before us today. I hope that the Secretary will provide

us with an accurate account of events that were exposed today.

There is something terribly rotten at the FDA. No agency

charged with protecting the public health should behave with such

indifference to the public safety as is evidenced in this case, and

no agency should ever treat Congress with the disrespect shown by

the FDA during the course of this investigation.

Again, Mr. Chairman, you are to be applauded for your determination and commitment to the public interest in pursuing this

difficult inquiry.

Chairman BARTON. Thank you, Mr. Deutsch, and let me say before I recognize our vice chairman: This has been a bipartisan effort. Mr. Deutsch has been applauding me, but it is actually the entire subcommittee and the staffs on both sides. We have worked together on this, and we are finally beginning to get the truth out

to the American people.

With that, I would like to recognize the distinguished vice chairman of the committee, Mr. Walden, Mr. Greg Walden, for an opening statement.

Mr. WALDEN. Thank you, Mr. Chairman. I thank you for holding

this second hearing on the safety and efficacy concerns of anti-depressants in children.

Giving parents and doctors as much information about the benefits or lack thereof and the risks associated with drugs that are

being prescribed for millions, tens of millions, of our Nation’s children should be at the forefront of FDA’s mission. I am troubled by

9

issues raised at the last hearing about what information is on the

label of these drugs and what information was publicly presented

to doctors and parents about these pediatric anti-depressant trials.

Testimony from certain pharmaceutical companies at the last

hearing raised two issues that I would like the agency to fully discuss today. The first question is about stronger warnings.

As I understand it, in August 2003, Wyeth Pharmaceuticals

issued a ‘‘Dear Health Care Provider’’ letter to more than 450,000

health care practitioners warning them of increased hostility in

children taking Efexir and recommending that it not be prescribed

to anyone under 18 years of age. Wyeth also added a stronger

warning to their label reflecting this safety issue.

Approximately 8 months later when the FDA finally decided to

change the warnings on all the labels of all anti-depressants, they

required Wyeth to remove—to remove this stronger labeling. What

this tells me is the regulatory agency charged with protecting the

public health is preventing a company from disseminating important safety information to parents, the public and physicians.

I want answers from the folks at the Neuropharm Division at

FDA that made this decision to explain their rationale for it.

The second question concerns efficacy. In testimony from various

pharmaceutical companies at the last hearing, it became clear that

many companies—in fact, most except Eli Lilly—conducted anti-depressant clinical trials in kids that showed no efficacy. That is why

none of the anti-depressants except Prozac is approved by the FDA

for use in treating depressed kids.

Yet the FDA also decided not to allow the companies’ product labeling to state that clinical trials conducted in kids did not demonstrate efficacy. The question is why? Why wouldn’t you put that

on the label? Why shouldn’t the label reflect that information?

I note that the Advisory Committee just recommended that this

labeling change take place, but the point is that the FDA knew

about the lack of efficacy in these trials several years ago, and

nothing has been done to change the label to inform doctors, patients and parents of this finding.

I am also interested to learn more about the FDA Advisory Committee process and the recommendations that the Advisory Committee made last week concerning how to notify the public that

clinical trial data indicate that there is an increased risk of suicide

related behavior in children that take anti-depressants.

I was struck by the press release that the FDA sent out on September 16, just a few days after their Advisory Committee meeting.

Now in that release, the FDA states, ‘‘that it generally supports’’—

generally supports—‘‘the recommendations of the Advisory Committee.’’ Generally supports? To me, that sounds like the FDA has

some doubts about the Advisory Committee’s recommendations.

So I would like to know if the FDA has reservations about these

recommendations; if so, what they are, and why. I would also like

to know more about FDA’s characterization of the Advisory Committee’s 15 to 8 vote as, ‘‘a split decision’’ on whether a black box

warning label should be on the labels of SSRIs.

Now it is my understanding that a black box warning will alert

doctors, patients and parents about the risks of taking these drugs

without preventing these drugs from being prescribed to depressed

10

children. Now here in the House, if you get a 15 to 8 vote, a 2 to

1 margin, that is a pretty significant vote, not generally described

as a split decision.

So it is my question as to how that is being described and why

in the FDA’s press release. Is the FDA going to follow the clear majority recommendation and implement this labeling change and, if

not, why? It is my understanding that Dr. Temple and Dr.

Laughren will be able to address these questions.

Finally, I hope to get some answers from the agency about the

timeline of events in terms of what they told the public about safety concerns raised within the agency about children taking these

drugs, and then when they told the public.

As we know, the British drug regulatory agency seemed to act

much swifter on this than the FDA with the same data. So I think

it is a fair question to ask this agency: Was the public health

served by a longer deliberative process in this case?

I also would like to know why the agency made the decision, as

you have heard from my colleagues, to prevent Dr. Mosholder from

presenting the findings from his extensive 6-month analysis of data

on SSRI clinical trials at the February 2004 Advisory Committee

meeting.

So I will be interested in hearing Dr. Mosholder’s perspective on

his consult, why he believed the safety signals were robust even in

December 2003, and how he believes his consult would have contributed to the February Advisory Committee’s deliberative process.

We have many witnesses from the FDA today, and I am hopeful

they will provide a more complete picture of this process and answer these questions that are on our minds and those of the people

we represent. I thank them for being here, and I thank you, Mr.

Chairman.

Chairman BARTON. We thank you, Congressman.

Now I will recognize the distinguished member from Colorado,

Congresswoman DeGette, for an opening statement.

Ms. DEGETTE. Thank you, Mr. Chairman. I would ask unanimous consent to put my full statement in the record.

Chairman BARTON. Without objection, so ordered.

Ms. DEGETTE. Thank you. I would just like to make a couple of

observations.

When I walked into our last hearing on September 9, I didn’t

know anything about this rampant off-label prescription of anti-depressants for kids, and I didn’t know about the risks about it, and

I don’t think most Americans did know about it.

Sometimes when I go out in my district, as I have the last few

weeks, my constituents say how can you stand doing the job that

you do; how can you stand it back there? What I have been saying

the last couple of weeks is, well, let me tell you a little story about

this hearing we had in Congress where we found out that anti-depressants, which have been approved by the FDA for adults, are

being prescribed for kids in rampant off-label use and, furthermore,

there was data that showed that, at best, those drugs did not work,

at worse and quite possibly, some of those drugs increase the risk

of suicide for kids.

11

So after we had that hearing, and with all the press associated

with that hearing and the witnesses, well, lo and behold, the FDA’s

Advisory Committee decided there was an increased risk of

suicidality, and they recommended a black box label.

So, Mr. Chairman, I guess every so often we do do some good in

Washington, but I think it is a damn shame that we have to have

Congressional hearings to make that happen.

Frankly, the public is desperate. Teen depression, in particular,

is on the rise. We only have one drug that has been approved by

the FDA for use in kids, and parents are desperate to find some

way to treat their kids. But they were unaware how the off-label

use of anti-depressants could really not only not help their kids but

could actually kill their kids.

Now I think that the FDA has to answer a lot of questions. They

need to answer questions about, for example, why there were

delays of presentation of data between the links of suicide and antidepressants. The FDA needs to answer what steps will be taken to

ensure that scientists at FDA are able to present their findings to

advisory committees. They have to answer as to what future actions the FDA is taking for pediatric and adult use of anti-depressants.

The American public and the U.S. Congress rely on the FDA to

ensure that all approved pharmaceuticals are safe. This is the responsibility that is at the very core of the FDA’s mission, and to

fulfill that mission the FDA must conduct objective studies with

rigorous scientific inquiry, and then they must present the results

to the public. They can’t simply just sweep this under the carpet

or put it in the back room because they are concerned about the

rise of teen depression and the lack of medications to deal with

this.

So I think—I am really glad we are having this series of hearings, but I think the FDA has a lot to answer for. I would also like

to add that at the last hearing, Mr. Chairman, you chastised the

FDA for its lack of cooperation with this committee, and rightly so.

But we are still having difficulty getting information from the FDA.

Some of the documents that we requested were not produced

until 36 hours before this hearing. The questions posed by the

Democrats at and after the last hearing, including myself, have

still not been answered, and the FDA did finally, I heard, respond

to some questions that Mr. Walden had last night.

We didn’t get Doctors Temple and Mosholder’s testimony until

after 7 o’clock last night, and I don’t know if Dr. Temple testimony

required OMB review, which is why the FDA usually says the testimony is tardy, but the delay is certainly a burden on the committee and our hard working staff. Some of us on this subcommittee were here until after 6 o’clock in a different hearing last

night, and it makes it very difficult to prepare for these hearings.

So in sum, Mr. Chairman—and I have an extension of remarks

I will put in the record—we have got to have cooperation in this

hearing by the FDA and by all the other Federal agencies. We are

elected as representatives of the American people to find the truth,

and I know. one of the things I love about this subcommittee, we

work on a bipartisan basis, as the chairman said.

12

We intend to get to the bottom of this, and I really want to thank

the chairman for not relenting, and I would hope these agencies

would realize they have got to cooperate.

I yield back the balance of my time.

Chairman BARTON. I thank the distinguished Congresswoman

from Colorado. You statement is the first I had heard that we

hadn’t had those questions answered. I wish I had known that yesterday, because I had a phone conversation with Dr. Crawford. But

what we might do is do another—maybe another meeting and get

you and Mr. Dingell and Mr. Deutsch involved, and we will get

your answers.

Ms. DEGETTE. Thank you, Mr. Chairman.

[The prepared statement of Hon. Diana Degette follows:]

PREPARED STATEMENT OF HON. DIANA DEGETTE, A REPRESENTATIVE IN CONGRESS

FROM THE STATE OF COLORADO

Today’s hearing is the second of this series on antidepressant use in pediatric populations. Parents, children and physicians seeking improved mental health carefully

weigh the risks and benefits of taking antidepressants. The Committee’s investigation has uncovered that the risks of taking antidepressants had not been fully

shared.

This hearing is more broadly about the Food and Drug Agency’s ability and efforts

to ensure that all approved pharmaceuticals are safe. This responsibility is at the

very core of the FDA’s mission. To fulfill that mission, FDA must conduct objective

studies with rigorous scientific inquiry. When risks are identified, it is essential that

they be communicated to the public.

The FDA staff here with us today must answer to this Committee and to the

American public. Why were there delays in the presentation of data on the link between suicides and antidepressants? What steps will be taken to ensure that scientists at FDA are able to present their findings to Advisory Committees? What future actions is FDA taking for pediatric and adult use of antidepressants?

This investigation on antidepressant use in pediatric populations has revealed

that transparency and availability of information may have been compromised. I

would once again like to remind the FDA of the importance of their role. It greatly

concerns me that the United Kingdom’s equivalent to FDA (the MHRA), contraindicated all anti-depressants for individuals less than 18 years of age in December

2003. That was almost one year ago. Why has the FDA not taken similar steps?

The FDA’s recent Advisory Committee meeting has determined that there is an

increased risk of suicidality in pediatric patients taking antidepressants. They have

recommended warning labels, but not contraindication. But the data has shown that

a risk of suicide does exist for two antidepressants (Effexor and Paxil). How can we

not provide that information to physicians and parents?

I, like many of my colleagues believe that we must balance safety concerns with

access to medication. I do not believe that this balance can exist when the risks are

hidden.

In addition to considerations about analysis of the data, this investigation has revealed that post-market surveillance of pharmaceuticals has not perhaps been as

strict as this Committee would like. I hope that the witnesses from the FDA will

provide some insight on how this monitoring process may be limited and what Congress can do to improve it.

I continue to be concerned about the inadequacy of our mental health research

and treatment system. While antidepressants have greatly improved treatment options, much more must be done. In addition to examining the FDA’s actions, this

hearing highlights the areas of improvement needed. While safety of medications is

of immediate importance, this Committee should not turn a blind eye to the more

significant shortcomings in our health system.

Chairman BARTON. The Chair would recognize Mr. Rogers for an

opening statement.

Mr. ROGERS. I will yield.

Chairman BARTON. Would Mr. Bilirakis like to make an opening

statement, distinguished subcommittee chairman?

13

Mr. BILIRAKIS. Well, thank you, Mr. Chairman, just very briefly.

Obviously, the recent reports of anti-depressant drugs possibly increasing the risk of suicidal thoughts and actions in children taking

these drugs are certainly extremely disturbing. While there are, as

I understand it, no actual suicides, it is important to recognize any

possible adverse effects that these drugs may have on adolescents

and children.

Mr. Chairman, I don’t disagree with any of the comments made

by you or any of the other members of the committee up here and

the fault on the part of the FDA and that sort of thing, but I guess,

as I understand it also, there have been some positive things that

have taken place.

I think we all can agree that the new FDA labeling requirements

are a step in the right direction. The FDA has been closely reviewing the results of anti-depressant studies in children since June

2003, and asked that the matter be investigated by the

Psychopharmacologic Drugs Advisory Committee, PDAC, and the

Pediatric Subcommittee of the Anti-Infective Drugs Advisory.

The Advisory Committee did recommend to the FDA that the labeling of these drugs be revised to advise the need to monitor patients closely when the anti-depressive therapy started and, based

on this recommendation, FDA did require changes to the labels for

anti-depressant drugs used for adolescents to include stronger cautions and warnings about the need to monitor patients for worsening of depression and the emergence of suicidality.

I don’t know that this will solve the problem, Mr. Chairman, and

certainly things like delays and not being apparently cooperative

and all that are concerns, but I suppose that this is a step in the

right direction. And thanks to you and Mr. Walden, the ranking

members in the committee, hopefully, this brings it out to the fore,

and these matters will be solved on an adequate basis, and I look

forward to hearing from all the witnesses.

Thank you, Mr. Chairman.

Chairman BARTON. Thank the distinguished subcommittee chairman. We now recognize Mr. Allen for an opening statement—Congressman Allen, I mean.

Mr. ALLEN. Thank you, Mr. Chairman, and thank you for calling

this second hearing to examine concerns surrounding the safety

and efficacy of anti-depressant use by children.

This committee must closely examine the FDA’s role in reviewing

clinical trial data indicating serious side effects associated with certain prescription drugs. The FDA’s mission is to protect public

health and, therefore, it has the responsibility to alert physicians

and the public to safety and efficacy concerns associated with various medical treatments.

I do find it very troubling that FDA officials appear to have attempted to suppress information indicating that SSRI anti-depressants may increase the risk of certain suicide related thoughts and/

or behaviors in children. I am disturbed that Dr. Mosholder’s full

report on this issue conducted at the behest of the FDA was not

allowed to be presented at FDA’s February Advisory Committee

meeting on this issue.

14

I look forward to hearing from Dr. Mosholder about the directive

under which he conducted his review on clinical trial data of SSRIs

and the conclusions of his report.

Clearly, there is debate among the scientific community about

whether episodes of attempted suicide while taking SSRIs are attributed to the underlying depression of an individual patient or to

the taking of SSRIs. However, disagreement about clinical trial

data does not mean that the studies and conclusions of specific researchers should be dismissed or suppressed. Rather, vigorous debate in the scientific community should be encouraged and conclusions challenged in order to arrive at the best determination of

what information should be disseminated to physicians and their

patients.

The increasing rate of clinical depression in children is a serious

public health issue. Children diagnosed with depression are clearly

at an increased risk for suicidal thoughts and behaviors. Each year,

more than 500,000 children and adolescents attempt suicide, and

approximately 2,000 young people die as a result of suicide.

I had the opportunity to discuss the link between SSRI use and

the possible increase in suicidal thoughts and behavior with a pediatric physiatrist in Maine. He said that there is a solid agreement

among physicians that they need better clinical data on the side effects of anti-depressants and not just studies financed by the drug

manufacturers.

He also stressed that physicians need to have a variety of drugs

available to them in order to make the best choice for their patients. Research indicates that between 30 and 40 percent of children and adolescents with depression will not respond to the first

medication. The debate surrounding this issue clearly indicates a

need for greater post-marketing studies on prescription drugs.

I am interested in learning from Dr. Temple about the recent

recommendations of the Psychopharmacologic Drugs and Pediatric

Advisory Committee, including the suggestion of requiring the

black box warning on all anti-depressant drugs, indicating an increased risk for suicidality in pediatric patients.

Certain drugs prescribed to children can be ineffective or dangerous. It is FDA’s responsibility to investigate the risks associated

with prescription drug use in order to protect the safety of our Nation’s children. FDA has a critical role in ensuring that doctors and

consumers receive balanced information.

I look forward to hearing the testimony of all of you on this very

important topic. Mr. Chairman, I yield back the balance of my

time.

Chairman BARTON. Thank the distinguished member for that

statement.

Does the gentleman from New Hampshire wish to—Okay. Does

the gentleman from California, Congressman Waxman, wish to

make an opening statement? Mr. Stupak is not a member of the

subcommittee.

Mr. WAXMAN. Thank you very much, Mr. Chairman. I want to

commend you for holding this hearing. I am pleased with the bipartisan way the committee has operated, and this is an important

issue, the question of anti-depressant use in children.

15

The issue has a lot of different implications. Certainly, we ought

to learn how FDA oversees the safety and effectiveness of drugs,

both in the approval process and after the approval process when

drugs are used for an off-label use, and especially when we are

talking about children.

The issue also has implications for how the pharmaceutical industry shares data on its products with the public, and especially

the medical community.

The subcommittee’s investigations have revealed that all too

often the drug industry has concealed data from physicians and patients. In the case of anti-depressants, the data that was concealed

would have shown that the drugs failed to work in children.

Concealing these negative results had very serious consequences.

It now appears that many children taking these potentially ineffective drugs were put at an unnecessary risk, because the drugs they

were given may have actually increased the likelihood that they

might commit suicide.

Today the FDA is going to respond to allegations that the agency

failed to act quickly enough when the risk of suicide as first

brought to light. I am very interested in hearing what they have

to say, and hearing their responses.

In the weeks and months to come, I hope that the subcommittee

will continue to examine the broader issue of how information

about pharmaceuticals is made in general, so that we can better

protect patients from serious drug risks in the future. I think FDA

has a lot to answer to today, and I am pleased that we have them

here and under oath, so that the questions may be asked of them

and that we can pursue the matter fully.

I am disturbed to hear that perhaps they had not given the committee all the information that has been requested. I have very little patience, and I know the chairman feels this way as well, that

when we request information from any government agency in order

to do our job of oversight—and it is an important constitutional

function to do that job—we need to given all the information that

is requested so that we can make a better evaluation of the matter

before us.

So I commend you, Mr. Chairman, again for holding these hearings, and I look forward to the testimony today and working with

the members of this committee to figure out what actions we need

to take thereafter.

[The prepared statement of Hon. Henry Waxman follows:]

PREPARED STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN CONGRESS

FROM THE STATE OF CALIFORNIA

I’d like to thank the Subcommittee for holding this series of hearings on anti-depressant use in children. This is an extremely important issue, which has implications for how the FDA oversees the safety and effectiveness of drugs. The issue also

has implications for how the pharmaceutical industry shares data on its products

with the public.

The Subcommittee’s investigations have revealed that all too often the drug industry has concealed data from physicians and patients. In the case of anti-depressants,

the data that was concealed would have shown that the drugs failed to work in children. Concealing these negative results had very serious consequences. It now appears that many children taking these potentially ineffective drugs were put at unnecessary risk, because the drugs that they were given may have actually increased

the likelihood that they might commit suicide.

16

Today, the FDA will respond to allegations that the agency failed to act quickly

enough when the risk of suicide was first brought to light.

I am very interested in learning the response of the FDA to these allegations.

In the weeks and months to come, I hope that the Subcommittee will continue

to examine the broader issue of how information about pharmaceuticals is made

public in general, so that we can better protect patients from serious drug risks in

the future.

Chairman BARTON. We thank the gentleman from California.

The gentleman from New Jersey, Congressman Ferguson, is recognized for an opening statement.

Mr. FERGUSON. Thank you, Mr. Chairman. I thank you for holding this important hearing, continuing the committee’s investigation of adverse effects of anti-depressants in children.

Two weeks ago, we discussed how vital it is that doctors receive

all the latest relevant study data and results so they can make the

most informed decisions possible on the safety of the drugs that

they are prescribing. The drug makers discussed steps that they

are taking to make their trials available to doctors so they can

have all the information they need to confidently prescribe medicines to patients.

I commend the work of the committee and, most importantly, the

parents of children who have suffered unspeakable pain because of

the adverse reactions to some of these anti-depressants.

In the last hearing 2 weeks ago, I spoke about a constituent and

friend of mine, Lisa Van Sickel. Lisa is here with us again today.

I spoke about Lisa and her daughter, Michelle, as well as other

constituents of mine who have suffered in this way. Lisa, as I say,

is with us again here today.

I am told that Michelle, who is away at college, will be watching

via the committee’s webcast today. If that is the case, hello,

Michelle.

Since our last hearing, there have been developments from the

FDA regarding their recommendations for doctors prescribing antidepressants to children. Last week the FDA’s Psychopharmacological Drugs and Pediatric Advisory Committees met

and made their recommendations on the prescribing of anti-depressants to children.

I am interested to hear today what the panel has to say about

the recommendations and whether or not the FDA plans on fully

implementing the Advisory Committee’s recommendations, but also

of particular interest is the path that the FDA took to come to the

conclusions that they have decided upon.

I look forward to hearing the testimony of Dr. Mosholder today,

and then the testimony of the second panel about how we have arrived at the point that we are at now.

Question: Why was Dr. Mosholder’s work not presented to the

FDA’s February 2004 advisory committee, and when did the

Neuropharm Division first become aware of an increase in psychiatric adverse events occurring in pediatric randomized controlled trials of anti-depressants as compared with the adult population?

My constituents and I and members of this panel are looking forward to hearing the answers to these and a number of other questions from today’s panels of witnesses.

17

Thank you again, Mr. Chairman, for holding this hearing, and I

yield back.

Chairman BARTON. Thank the gentleman from New Jersey. The

gentlelady from Illinois, Ms. Schakowsky, is recognized for an opening statement.

Ms. SCHAKOWSKY. Thank you, Chairman Barton, for recognizing

me for the purpose of making an opening statement and for agreeing to hear the opening statement of a Member of Congress not on

this subcommittee, Mr. Stupak. I hope that the tradition of opening

statements will continue going forward.

I look forward to hearing the testimony of the members of the

panel who took part in reviewing the safety of anti-depressants in

children over the past 11⁄2 years. We need to get some straightforward answers as to why specific concerns regarding the safety

of those medications were kept not just from the public and from

the medical community, but from the Advisory Committee whose

job it is to advise the FDA on these issues.

The process of reviewing the safety and efficacy of medications

is complex. What is not complex is that the findings of someone

who is charged at taxpayers’ expense with the review should not

be hidden from sight. This is a particular concern when we talk

about the health and safety of our children.

I would like to hear an explanation today as to why, after spending months examining the connection between anti-depressant use

in children and increased suicidal ideation at the request of his superiors, an FDA medical examiner would be prevented by those

same superiors from presenting his conclusions to the FDA’s Advisory Committee.

I find this apparent suppression of information appalling, particularly when it serves to hide information that could have a significant impact on how medications are used by children.

In order for an advisory committee to come up with well-informed and accurate recommendations, it is absolutely crucial that

they are provided with the most comprehensive, up-to-date and accurate information available. When this does not happen and the

committee is prevented from hearing the conclusions of those who

actually conducted the reviews, the recommendations of the committee inevitably will fail to reflect the best interests of children

and their families. This not only leads to continued misuse of medications by misinformed parents and physicians, it results in a serious breach of trust of the FDA in its role of protecting the public

from unsafe foods and medications.

There already exists a great deal of misunderstanding and mistrust within our society regarding the diagnosis and treatment of

mental health disorders. Incidents such as these only serve to add

fuel to the fire and increase the anger and frustration on all sides.

Over the past weeks, we have heard from many mental health

professionals and parents who are convinced that these medications can be effective in the treatment of major depression in their

children if they are used in an appropriate manner and under the

right circumstances. Many parents are also very concerned about

the possible negative impact of these drugs on their children. All

of them, however, deserve to know that the decisions about these

18

drugs are based on a full, fair and independent analysis, and that

critical information has not been denied them. Thank you.

Chairman BARTON. The Chair would now recognize the distinguished member of the full committee, Congressman Stupak of

Michigan, for an opening statement.

Mr. STUPAK. Thank you, Mr. Chairman, and thank you once

again for allowing me to take part in this series of hearings concerning the safety and effectiveness of anti-depressants used by

children.

Two weeks ago, this committee heard the FDA repeatedly claim

the jury was still out about the safety of anti-depressants. Just 4

days later before an advisory committee in Bethesda, the FDA finally admitted what they had known for a year: There is an increased risk of suicidal thoughts and behavior in children who take

anti-depressants.

I am appalled but, frankly, not surprised by the systematic efforts of the FDA to suppress information that could have prevented

the senseless deaths of too many children.

I believe these anti-depressants should be banned until the jury

comes back with proof that they are safe and that they work. They

are not effective to treat depression. Increased risk, no matter how

large or small, is still an increased risk for suicidal behavior.

The American people have a right to demand the FDA to look out

for their interests and not the interests of the drug companies.

When safety is questioned, FDA should err on the side of caution.

The tragedies experienced by the families in the audience today

may have been prevented. The jury is no longer out. Congress at

a minimum should demand that the FDA to immediately and completely implement all the Advisory Committee recommendations

made last week. Those recommendations included warnings on all

anti-depressants, black box labeling, and easy to understand warnings on the packaging where parents and patients can see it.

What many here may not realize is the FDA is under no obligation to implement those recommendations. There are many instances when the FDA has ignored or scaled back Advisory Committee recommendations, caving to drug company pressure.

I know from my own experience that the FDA has repeatedly ignored for the past 4 years advisory committee recommendations

concerning the acne drug, Accutane. I am particularly concerned

the FDA might back away from the recommendation of package labeling that parents and patients can see and understand. The FDA

should require that information about the safety and efficacy of

these drugs be dispensed with every prescription and on the package labeling.

The FDA should also require parents to sign an informed consent

before treatment can begin. The FDA cannot ignore these recommendations like they ignored Dr. Mosholder’s analysis. They

can’t drag their feet on implementing the recommendations as they

dragged their feet on posting these studies on their website.

Congress and the American people have had enough of the

stonewalling and excuse making. It is time to take action. Let’s be

clear. Package labeling is the least the drug companies can do.

In 1997 Congress passed a law beginning a system where the

drug companies get patent extensions worth billions of dollars to

19

study these drugs in children. Children, the most vulnerable members of our society, are the only group that we grant patent extensions to drug companies in exchange for studies.

We don’t grant patent extensions to drug companies to study the

effect of drugs in women. We just demand it, and the drug companies do it. We don’t grant patent extensions worth billions of dollars to drug companies to study drugs in minorities. We just demand it, and drug companies do it.

Patents are extended once pediatric studies are turned in to the

FDA. There is no requirement that the studies were actually well

done or actually show whether the drug worked or was safe, and

there is no requirement that the packaging label on these drugs

are actually changed before the patent extension is granted.

At the very least, parents should get the facts in exchange for

these billions in profits. It is clear today that they are not.

Mr. Chairman, thank you again for calling these hearings and

for your leadership on this issue. This hearing illustrates a larger

problem at the FDA where too often drug companies trump parents

where medical evidence is suppressed and where expert opinion is

silenced, and it illustrates that our system to study the effects of

drugs on children is broken.

It is a system that gives billions of dollars to drug companies and

asks little in return. The FDA is failing to live up to its responsibility to the American people.

I yield back the balance of my time.

Chairman BARTON. We thank the distinguished gentleman from

Michigan.

The Chair would now recognize the gentleman from Florida for

an opening statement, Mr. Stearns.

Mr. STEARNS. And good morning and thank you, Mr. Chairman,

for holding this hearing.

I think, as Mr. Stupak and others who are parents of children

are very much interested in this, 2 weeks ago we explored the

measures to make the results of clinical drug trials more accessible

to doctors and parents, and I think that goes without saying.

You know, in our society today there seems to be a pill for everything that ails you and, of course, this is especially true for depression where millions of American children are being prescribed antidepressants. It is probably unquestionable that anti-depressants

have improved the quality of life for many children and their families, and may have even saved some lives. But for years now, we

have heard anecdotal evidence that some of these same anti-depressants increase suicidal behavior in some children.

Lately, the evidence has become less anecdotal and more and

more compelling. In March 2004 the FDA issued a warning that 10

popular anti-depressants can cause deeper depression, agitation,

and other forms of violent behavior, including suicide.

A month later, it was reported that the number of American children being treated with anti-depressants has soared over the past

decades—it has been in all the press—even though the vast majority of clinical trials have failed to prove that the medicines even

help—even help children at all.

Now we have also heard that the agency’s own drug safety analyst found a link between some anti-depressants and suicidal beVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00027 Fmt 6633 Sfmt 6602 96099.TXT HCOM1 PsN: HCOM1
20

havior in children. Yet, my colleagues, these findings were suppressed, and his analysis deemed unreliable.

Finally, a recent FDA commission study by Columbia University

researchers have confirmed the adverse results, and we are forced

to admit finally the truth that there is indeed an increase in suicide and suicidal thoughts and behavior for some children who are

prescribed certain anti-depressants.

Mr. Chairman, the FDA is responsible for protecting the public

health by assuring the safety and efficacy of these prescription

drugs. We all know that. The widespread use of these anti-depressants should provide even more incentive for this FDA to fulfill its

stated mission. At the very least, the drugs in question should contain strong warning labels to help physicians and parents evaluate

the risks.

So truly, all of us here hope that this hearing will help us get

to the bottom of these disturbing findings and that we will have a

chance to fully explore the findings with the panel.

So I look forward to this hearing and to learning more about the

FDA’s role in making sure anti-depressants used by children are

safe and do what they are supposed to do.

Thank you, Mr. Chairman.

Chairman BARTON. We thank the distinguished gentleman from

Florida for his opening statement. Seeing no other members of the

subcommittee on either side of the aisle present, the Chair would

ask unanimous consent that all members of the subcommittee not

present have the requisite number of days to put their formal opening statement in the record. hearing no objection, so ordered.

[Additional statement submitted for the record follows:]

PREPARED STATEMENT OF HON. EDWARD J. MARKEY, A REPRESENTATIVE IN

CONGRESS FROM THE STATE OF MASSACHUSETTS

Thank you Mr. Chairman for calling this important hearing.

As we continue the Subcommittee’s examination of how the FDA and the pharmaceutical industry evaluated, reported, and responded to data linking certain anti-depressants to an increased risk of suicide in children and adolescents, I think it is

important to recognize that these drugs have played a very positive role in expanding the treatment options for so many people around the country who have been

struggling with depression. For them and their families, anti-depressant medications have been a real life line.

However, we have learned that until very recently we did not have the whole

truth about the impact of these drugs on our children. Today’s hearing will help the

Subcommittee understand how this could have occurred.

Based on what I have heard and read so far, it seems to me that our current system for informing the public about potential risks associated may be broken. It

failed to inform the public about potential risks of anti-depressants at two points.

The first failure was when the pharmaceutical companies did not disclose the negative results of their clinical trials. Congressman Waxman and I will soon introduce

legislation to address this issue. We are proposing the creation of a federal registry

of clinical trials. This will ensure that companies cannot pick and choose what information they want to share with the public.

The second failure was when the pharmaceutical companies told the FDA about

negative trials, the FDA did not move quickly and aggressively to fulfill its role as

the watchdog for public health. After conducting their own study and confirming the

risk, the Agency hesitated, suppressed their own data and left the public in the dark

for months. Meanwhile, regulators in Great Britain were already taking action to

protect their citizens from the same risks revealed by the data.

The public absolutely needs to know about the risks associated with the drugs

that they are taking. Even if Dr. Mosholder’s conclusions were wrong (which does

not appear to be the case) it was completely inappropriate for the FDA to suppress

his findings. Instead, the he should have been allowed presented his findings and

21

conclusions to the FDA’s Advisory Committee and allowed the experts to evaluate

the data, question the study and have a complete discussion of the available information. Instead the FDA hid the data, got embarrassed when the public found out

about their actions from the press, and initiated an internal criminal investigation

that appears aimed at scaring its own employees into silence.

Today we are going to examine the nature of the FDA’s failure. The FDA plays

a critical role in protecting the public health so I am very concerned about the maintaining the integrity of the FDA process. It is my hope that in the future the FDA

will provide a fair, thorough evaluation of the risks associated with drugs and

promptly inform the public of those conclusions in a timely fashion. I am looking

forward to hearing what steps the FDA is taking to restore the public’s trust. I look

forward to hearing the testimony of today’s witnesses.

Chairman BARTON. The Chair would now call forward our first

witness, the distinguished representative from the Food and Drug

Administration, Dr. Andrew Mosholder. Would you please come forward and be seated.

Welcome, Dr. Mosholder. You are aware that the committee has

the tradition of taking all testimony under oath. Do you object to

testifying under oath?

Mr. MOSHOLDER. Thank you. As a member of the Religious Society of Friends or Quakers, I would prefer to affirm rather than

swear.

Chairman BARTON. We have the oath so that you can affirm

rather than swear. But you don’t oppose to affirming under oath?

Mr. MOSHOLDER. That is correct.

Chairman BARTON. Thank you. You also have the right as a citizen of the United States of America under the Constitution of our

great Nation to be advised by counsel during your testimony. Do

you wish to be so advised during your testimony?

Mr. MOSHOLDER. No, I do not.

Chairman BARTON. Would you please stand and raise your right

hand.

[Witness sworn.]

Chairman BARTON. Be seated. Dr. Mosholder, we welcome you to

the subcommittee. Your testimony in its entirety is in the record.

We would recognize you for 7 minutes to elaborate on that formal

testimony.

TESTIMONY OF ANDREW D. MOSHOLDER, FOOD AND DRUG

ADMINISTRATION

Mr. MOSHOLDER. Thank you. I have a brief oral statement which

I can read now.

Mr. Chairman and members of the subcommittee, I am Dr. Andrew Mosholder, a medical officer in the Office of Drug Safety at

FDA’s Center for Drug Evaluation and Research. My statement

will briefly summarize my role in FDA’s review of suicidality in pediatric anti-depressant drug trials.

Before joining the Office of Drug Safety, or ODS, I was medical

officer in the Division of Neuropharmacological Drug Products,

DNDP, where I reviewed a number of submissions of pediatric data

for anti-depressant drugs, including Paxil. In my review of the

Paxil pediatric data, I noted that some of the clinical trial adverse

events classified as emotional ability involved suicidal behavior or

ideation.

So DNDP requested clarification from the manufacturer,

GlaxoSmithKline. In May 2003, GlaxoSmithKline provided new

22

analyses showing an increase in suicidal thoughts and behaviors

with paroxetine compared to placebo. Dr. Russell Katz, the Director

of DNDP, requested my assistance in the evaluation of these data,

and my managers in ODS agreed.

In July, DNDP asked the sponsors of other anti-depressant drugs

to reproduce GlaxoSmithKline’s analysis of suicidal events for Paxil

by applying the same method to their own pediatric trial data

bases.

By September 2003, I had completed an analysis of the

paroxetine data and a preliminary analysis of pediatric data on

seven other anti-depressant drugs. I presented these analyses at a

briefing for CDER management September 16, 2003.

DNDP forward responses from the other manufacturers to me for

review. I completed the first written draft of my report in December 2003. DNDP apparently was reaching a conclusion that these

data were not adequate for definitive analysis. DNDP requested

additional data from each sponsor, and also arranged for the possible suicidal events in these trials to be reclassified by outside experts.

On December 18, 2003, at a planning session for the February

2 Advisory Committee meeting on this issue, I shared a proposed

outline of my Advisory Committee presentation. I noted that suicidal events designated as serious in pediatric clinical trials for

major depressive disorder were 1.9 times more frequent with antidepressant drug treatment than with placebo, and that this was

statistically significant. There was some discussion of the pros and

cons of my analysis.

On January 6, Dr. Katz informed me by telephone that someone

else would present the clinical trial data at the February 2 meeting, since I had a different view of the data from that of DNDP.

News of my analysis and the fact that it would not be presented

at the February 2 AC meeting reached Mr. Rob Waters, a reporter

for the San Francisco Chronicle. The Chronicle ran the story on

February 1, 1 day prior to the AC meeting.

On February 18, I completed my written report. In it I recommended discouraging off-label pediatric use of the anti-depressant drugs. When my report received supervisory signoff March 19,

Dr. Mary Willy concurred, and Doctors Anne Trontell and Mark

Avigan attached cover memoranda indicating their areas of disagreement.

On March 3, 2004, two special agents from the FDA Office of Internal Affairs interviewed me regarding the disclosure of my findings in the February 1 San Francisco Chronicle article. I later provided the Office of Internal Affairs with a written statement about

the matter. I indicated that I was not the source of the disclosure.

On March 22, FDA issued a public health advisory stating in

part, ‘‘health care providers should carefully monitor patients receiving anti-depressants for possible worsening of depression or

suicidality.’’

In mid-July Dr. Tarek Hammad of DNDP shared the results of

his analysis of the clinical trial events as reclassified by a panel of

suicide experts convened by Columbia University. The new analysis

confirmed the previous finding: Definitive suicidal behaviors and

ideation in short term pediatric trials were 1.8 times more frequent

23

with anti-depressant drug treatment compared to placebo, and this

was statistically significant.

Shortly thereafter, data from a new study of paroxetine, the

treatment of adolescent depression study or TADS, became available. The TADS data indicated a therapeutic effect of fluoxetine,

but also showed an excess of suicidal events among those receiving

fluoxetine compared to patients who received placebo, which was a

new finding for fluoxetine.

On September 13 and 14, FDA held an AC meeting to consider

this issue. I was among the presenters, and I provided a comparison of my analysis to the current analysis. The Advisory Committee members voted 15 to 8 in favor of a boxed warning to the

labeling of anti-depressant drugs.

Thank you.

[The prepared statement of Andrew D. Mosholder follows:]

PREPARED STATEMENT OF ANDREW D. MOSHOLDER, MEDICAL OFFICER, OFFICE OF

DRUG SAFETY, U.S. FOOD AND DRUG ADMINISTRATION

Mr. Chairman and Members of the Subcommittee: I, Andrew D. Mosholder, am

a licensed physician and board certified in child and adolescent psychiatry. I obtained my medical degree from the University of Virginia. I also have a Master of

Public Health degree from Johns Hopkins University.

I am currently employed by the U.S. Food and Drug Administration and have

been so employed since 1992. During my employment, I have been a medical officer

with the Center for Drug Evaluation and Research (CDER) for twelve years. For

about the past 20 months, I have worked as an epidemiologist in the Division of

Drug Risk Evaluation, Office of Drug Safety (ODS). Prior to that, I was a medical

officer in CDER’s Division of Neuropharmacological Drug Products (DNDP) for over

10 years.

In this statement, I will briefly summarize my role in FDA’s review of pediatric

use of antidepressant drugs, with particular attention to recent concerns about the

effects of these drugs on suicidal thoughts and behaviors in children and adolescents.

As a medical officer in DNDP, I reviewed a number of submissions of pediatric

data for antidepressant drugs, including pediatric data submitted for Paxil

(paroxetine), manufactured by GlaxoSmithKline. In my review of the Paxil pediatric

supplement, I noted that a number of clinical trial adverse events designated as

‘‘emotional lability’’ involved suicidal behavior or ideation. Accordingly, DNDP requested clarification regarding such behavioral adverse events from

GlaxoSmithKline. In May of 2003, after I had transferred to ODS, DNDP received

new data analyses from the manufacturer, indicating an increase in suicidal

thoughts and behaviors with paroxetine compared to placebo in pediatric clinical

trials. A consultation request from DNDP to ODS signed June 6, 2003 by Dr. Russell Katz stated: ‘‘Since the original review of the Paxil supplement, as well as the

reviews of most other pediatric supplements for SSRIs, was done by Andrew

Mosholder, M.D, . . . we ask that this consult be assigned to him. We seek his advice

on further analysis and interpretation of the Paxil results, as well as more general

advice on what might be done to re-evaluate the risk of suicidality in the pediatric

databases for other SSRIs . . .’’

My managers in ODS agreed to Dr. Katz’s request and assigned me to this consultation on June 9, 2003. To determine whether the apparent increase in suicidal

events applies to pediatric use of other antidepressant drugs as well, I started to

review FDA’s pediatric data for other antidepressant drugs. DNDP ultimately decided that the best way to proceed would be to ask the sponsors of other

antidepressant drugs to reproduce GlaxoSmithKline’s analysis of suicidal events for

Paxil, with each sponsor applying the same method to their own pediatric trial databases. In July of 2003, DNDP sent requests for such analyses to other

antidepressant drug sponsors.

By September of 2003, I had completed an analysis of the paroxetine data and

a preliminary analysis of pediatric data on seven other antidepressant drugs. At the

request of management, I presented these analyses at a CDER Regulatory Briefing

for upper level management on September 16, 2003. During the briefing, I presented the paroxetine pediatric data, along with preliminary findings for other

24

antidepressant drugs. As noted in the briefing minutes, there was discussion about

the clinical significance of some of the events in the analysis: ‘‘We need to get a better sense of what the events from these studies really are, i.e., are they legitimate,

suicide-associated thoughts/actions or self-mutilation acts that are becoming increasingly common in the adolescent population today and are not generally associated

with a sincere intent to die.’’

The Federal Register on October 31, 2003 contained this announcement to the

public regarding an Advisory Committee meeting scheduled for February 2, 2004:

‘‘The Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee will discuss reports of

the occurrence of suicidality (both suicidal ideation and suicide attempts) in clinical

trials for various antidepressant drugs in pediatric patients with major depressive

disorder (MDD). The committee will consider optimal approaches to the analysis of

data from these trials, and the results of analyses conducted to date, with regard

to the question of what regulatory action may be needed pertinent to the clinical

use of these products in pediatric patients. The committee will also consider further

research needs to address questions on this topic.’’

As DNDP received responses from the other manufacturers to the July information requests, those responses were forwarded to me for review. I then worked on

my analysis of these responses over the next couple of months and completed the

first written draft of my results in December of 2003.

DNDP apparently was reaching a conclusion that the responses from the sponsors

to the July requests were not going to be adequate for a definitive analysis. In October of 2003, DNDP sent requests to the manufacturers asking for patient level data

sets, to permit a more sophisticated statistical analysis than what I could accomplish using only the responses to the July requests. DNDP also decided that all of

the possible suicidal events in these trials should be reclassified by outside experts

in suicidology.

On December 10, 2003, the U.K.’s Medicines and Healthcare products Regulatory

Agency issued their statement, ‘‘Use of Selective Serotonin Reuptake Inhibitors

(SSRIs) in children and adolescents with major depressive disorder (MDD)—only

fluoxetine (Prozac) shown to have a favourable balance of risks and benefits for the

treatment of MDD in the under 18s.’’

On December 18, 2003, we held one of our planning meetings for the February

2 Advisory Committee (AC) meeting. A draft agenda distributed for the December

18 planning meeting included a 45-minute presentation by me entitled, ‘‘Limited

Overview of Paxil Controlled Trials and Controlled Trials of Other Antidepressants.’’

At that meeting, I shared a proposed outline of my presentation, which included my

finding that suicidal events designated as ‘‘serious’’ in pediatric clinical trials for

major depressive disorder were 1.9 times more frequent with antidepressant drug

treatment than with placebo, and that this was statistically significant. I recall

some discussion of the pros and cons of my analysis.

On January 6, 2004, Dr. Katz sent me an email asking to speak with me by phone

regarding my presentation at the February 2 AC meeting. In our subsequent telephone conversation on that date, he told me that someone else would present the

clinical trial data at the February 2 AC meeting since I had reached a different view

of the clinical trial data from that of DNDP. On January 7, 2004, I sent an email

to the team members planning the February 2 meeting, confirming that I would not

be giving the presentation as originally planned and attaching a draft of my slides

for their use and interest.

On January 12, 2004, the Agency issued a Federal Register notice with a revised

agenda for the February 2 meeting. The notice stated, ‘‘The committee will not be

considering options for definitive regulatory action at this meeting because definitive analyses of the data have not been completed. This topic will be covered in a

second meeting to be scheduled by summer 2004.’’

News of my analysis, and the fact that the findings would not be presented at

the February 2 AC meeting, reached Mr. Rob Waters, a reporter for the San Francisco Chronicle. I was not the source of this information, however, and in the course

of a number of contacts from Mr. Waters I did not disclose to him any confidential

information. Nonetheless, his story about this matter ran on February 1, 2004 in

the San Francisco Chronicle, one day prior to the AC meeting.

At the February 2, 2004 AC meeting, I delivered a presentation entitled, ‘‘Office

of Drug Safety Data Resources for the Study of Suicidal Events Associated with Pediatric Use of Antidepressants.’’ This presentation emphasized postmarketing surveillance (MedWatch) data regarding suicidal events with pediatric use of

antidepressants, but it did not include findings from my analysis of the pediatric

clinical trial data. Dr. Anne Trontell, the Deputy Director of ODS, instructed me to

prepare brief remarks regarding my analysis of the pediatric clinical trial data, to

25

be used if any members of the Advisory Committee inquired about it. No AC members asked any questions about this, however, and so I did not deliver the brief remarks that I had prepared.

Subsequent to the February 2 AC meeting, I completed my written consultation

memorandum regarding suicidality in pediatric clinical trials of antidepressants,

dated February 18, 2004. In it, I recommended discouraging off-label pediatric use

of antidepressant drugs, chiefly because the one drug that appeared to have the

least risk of suicidal adverse events from the data available at that time was also

the only drug to have won approval for pediatric depression, i.e., fluoxetine. I had

extensive discussions with my management in ODS regarding my findings and their

interpretation, and when my report received final supervisory sign-off on March 19,

Dr. Mary Willy concurred, while Drs. Anne Trontell and Mark Avigan wrote separate cover memoranda indicating their areas of disagreement. That essentially

ended my involvement with this project until mid-July when the results of the Columbia University reclassification analysis became available.

On March 3, 2004, two Special Agents from the FDA Office of Internal Affairs

interviewed me regarding the disclosure of my findings in the February 1 San Francisco Chronicle article. I was also asked to produce a written statement regarding

this matter for the Office of Internal Affairs, and in that statement I indicated that

I was not the source of the disclosure.

On March 22, 2004, FDA issued a public health advisory which included the following statement: ‘‘Health care providers should carefully monitor patients receiving

antidepressants for possible worsening of depression or suicidality, especially at the

beginning of therapy or when the dose either increases or decreases. Although FDA

has not concluded that these drugs cause worsening depression or suicidality, health

care providers should be aware that worsening of symptoms could be due to the underlying disease or might be a result of drug therapy.’’

During the spring and summer of this year, I had several meetings with investigative staff of this Committee and of the Senate Finance Committee, as part of

each committee’s examination of this issue. FDA’s written response to this Committee, dated April 14, 2004, summarized the rationale for withholding the results

of my analysis at the February 2 AC meeting as follows: ‘‘. . . given the Agency’s concerns regarding the limitations of the data and the plans to pursue case reclassification and more in-depth analyses, CDER decided that having Dr. Mosholder present

his conclusion to the Advisory Committee, with the appearance that it was an Agency determination, would be potentially harmful to the public health as it might lead

patients who were actually benefiting from the use of these drugs to inappropriately

discontinue therapy.’’

My next involvement with the analysis of the clinical trial data came in mid-July,

when Dr. Tarek Hammad was completing the DNDP analyses of suicidal adverse

events as reclassified by a panel of suicide experts convened by Columbia University. The reclassification of potential suicidal events by the panel of experts had apparently confirmed the finding; definitive suicidal behaviors and ideation in shortterm pediatric trials were 1.8 times more frequent with antidepressant drug treatment compared to placebo, and this was statistically significant. I was asked by my

management to work with Dr. Hammad to prepare a comparison of his analysis to

my previous analysis. We both participated in an August 9 briefing for CDER management on this issue, during which I presented such a comparison.

Subsequently I prepared a memorandum summarizing this comparison, along

with some additional supplemental topics, and this memorandum received supervisory sign-off August 16.

Shortly after this, Dr. Hammad obtained data from a new study of fluoxetine

(Prozac), called the Treatment of Adolescent Depression Study (TADS). The TADS

data indicated a therapeutic effect of fluoxetine, as seen in the previous fluoxetine

pediatric depression trials, but TADS also showed an excess of suicidal events

among those receiving fluoxetine compared to patients who received placebo. The

latter was a new finding, since there did not appear to be such an excess in previous

fluoxetine trials.

On September 13 and 14, FDA held an AC meeting to consider this issue. The

consult document signed March 19 and the follow-up memorandum dated August

16 were both included in the briefing materials for the AC meeting, and in fact FDA

posted these documents on its web site several weeks in advance of the meeting.

At the first day of the AC meeting, I was among the presenters and provided a comparison of my previous analysis to the current analysis, this time including the new

findings from the TADS data, which were not included in the August 16 memorandum. The following day, the AC members voted 15-8 in favor of a boxed warning

for the labeling of antidepressant drugs, to note the observed increase in suicidal

26

behavior and ideation among pediatric patients treated with antidepressant drugs

in clinical trials.

Chairman BARTON. Thank you, Dr. Mosholder.

The Chair would recognize himself for the first series of questions, and we will set the clock at 10 minutes.

Before I ask questions, I want to commend you for your work on

behalf of the American people. I want to thank you for your perseverance. I want to applaud you for insisting on honesty and integrity in the review process. My guess is it has not been easy. So on

behalf of at least this subcommittee and the full committee, and I

would think I can say on behalf of the American people, just let me

say thank you. We appreciate you being here today.

Mr. MOSHOLDER. Thank you very much.

Chairman BARTON. My first question to you is: Do you feel that

you have been pressured in any way at the FDA to suppress or

change your conclusions regarding your consult or consults—I

think there were two of them—with regard to the efficacy of antidepressant drugs being prescribed off-label for children in this

country?

Mr. MOSHOLDER. With regard to efficacy, not per se, but as far

as the suicidality issue, at the time of finalizing the March consult

document I had considerable discussion with my managers in the

Office of Drug Safety about my interpretation of the data and the

recommendation, and at one point alternative conclusions were offered to me which I declined to incorporate into my written document. Accordingly, we had the document finalized with cover

memoranda which in our system indicated disagreement between

the manager signing the document and the original author of the

document.

Chairman BARTON. Okay. What are your thoughts on why you

were refused to participate in the February 2004 Advisory meeting?

Mr. MOSHOLDER. Well, I would describe that as lack of confidence in the data and the meaning of the data on the part of

those who made the decision to remove my presentation from the

agenda. My understanding is that that lack of confidence centered

around concern about whether the cases that I had counted in my

analysis were really bona fide suicidal events or were perhaps

events that were more clinically trivial or not meaningful.

Chairman BARTON. My understanding is that you are a medical

doctor, an M.D. Is that correct?

Mr. MOSHOLDER. Yes, that is correct.

Chairman BARTON. And it is pediatric psychiatry. Is that correct?

Mr. MOSHOLDER. Child and adolescent psychiatry. Yes.

Chairman BARTON. Okay. So you feel that you are qualified—because of your medical training and your background, you are professionally qualified in the medical field to make some of the judgments and decisions that you had to make in the analysis of this

data. Nobody has questioned your credentials. Is that correct?

Mr. MOSHOLDER. Not as far as my clinical background, no.

Chairman BARTON. So there was no—It is not one of the reasons

you were not allowed to participate in the February Advisory, because somebody questioned your credentials or anything like that?

Mr. MOSHOLDER. Not to my knowledge.

27

Chairman BARTON. Okay. Do you agree with the British decision

to prohibit the use of these anti-depressant drugs in children?

Mr. MOSHOLDER. Well, my comment there is—well, of course, in

the sequence of events, that came shortly before I was completing

my own report, and I am sure it had some influence on my thinking.

A close reading of the British contraindication actually would

suggest that, under certain circumstances, physicians might choose

to use the drugs for children. So that the term contraindication

means something a bit different on either side of the Atlantic perhaps.

In the U.S. a contraindication basically means never, that the

risk is never justified. So that I did support the British action with

the understanding that their term contraindication is not an absolute and recognizing the fact that there might be selected circumstances where a clinician and patient might choose to use the

drug.

Chairman BARTON. This is a personal question. You don’t have

to answer it if you don’t want to. Do you have children?

Mr. MOSHOLDER. I have one step-son who is married, grown and

married.

Chairman BARTON. If you did have young children, would you

prescribe these anti-depressant drugs for them if they exhibited

some of the symptoms of depression and suicidality?

Mr. MOSHOLDER. Well, my own opinion would be that, based on

the evidence we have, the so called evidence based approach to

clinical practice would be that fluoxetine appears to have the best

data for depression as far as its efficacy.

We now have data that indicate, even with fluoxetine, there

could be an increase in the suicidal events. So that that would have

to be weighed, the risk and the benefit. So I would think that

fluoxetine would sort of emerge as the default choice among the

drugs for depression. But even there, it would have to be with careful attention to the potential risks.

Chairman BARTON. So I take that, if you personally had a child,

what I heard you say is the best of a bad choice is this fluoxetine,

but you really didn’t say whether you would recommend that it be

prescribed or not.

Mr. MOSHOLDER. Well, in certain circumstances—I think my

view of the data that we have now is that we should think more

carefully about the place of medication in the broader treatment of

juvenile depression. And just again on a personal note, I trained

long enough ago in psychiatry where we did not have Prozac or any

of the other SSRIs, and in those days using medication was something that was not necessarily the first choice.

So I would say I would not never use it if it was my child or my

patient, for that matter, but I would do it with careful attention to

all the risks and benefits.

Chairman BARTON. Why do you think that the FDA, in spite of

all these studies and all the evidence and all of the analysis that

you have done, has been so reluctant to withdraw or more firmly

encourage the medical community to stop prescribing these drugs

off-label? Why wouldn’t our FDA, which is viewed as the gold

standard of the world, given the studies that have been done and

28

your work—why do you think they haven’t followed the lead of the

British? Why have they continued to, even after last week—you

know, this 51 to 8 decision which has just put a black box warning—It just seems to me that the cautious, prudent, conservative

approach would be to strongly indicate to the medical prescribing

community that these drugs shouldn’t be used in children.

What has caused this reluctance at the FDA which, in my view,

is quite contrary to their normal procedure, which is to be totally

cautious?

Mr. MOSHOLDER. Well, I’m not sure I can give a complete explanation, but I think, on the other hand, there is some concern with

abandoning the utility of these drugs perhaps to quickly—there’s

concerns about whether the studies which failed to show efficacy,

whether that is due to the drug not being effective or whether the

trial was not done properly, and it is often difficult to tell.

Another limitation is that we don’t have good data on long term

effects of these drugs. All of the studies that I looked at and that

Dr. Hammad looked at were just a matter of several weeks. So

there is also the possibility there could be long term benefits but

short term risks. We just don’t know.

So I think those are the caveats that perhaps the other people

in the agency are looking at.

Chairman BARTON. Well, my time has expired. The Chair recognize the distinguished gentlelady from Colorado, Ms. DeGette, for

10 minutes.

Ms. DEGETTE. Thank you, Mr. Chairman. Dr. Mosholder, you

told the chairman that after you presented your initial findings, alternative conclusions were offered to you. I wonder if you could tell

us what those alternative conclusions were.

Mr. MOSHOLDER. Well, this was, as I recall, an e-mail from Dr.

Trontell, one of my supervisors who wrote a cover memorandum to

the report. As I recall, the difference was whether to take the step

of channeling patients toward fluoxetine, as I said, as sort of a default choice or——

Ms. DEGETTE. That is Prozac, which has been approved for pediatric use.

Mr. MOSHOLDER. Yes, for both depression and obsessive compulsive disorder—whether to sort of actively advise people that that

looks like the best choice or to be more cautious and just say sort

of to use the drugs with caution.

Ms. DEGETTE. And they were recommending that you change it

to say just use the drugs with caution?

Mr. MOSHOLDER. That is my recollection, yes.

Ms. DEGETTE. And you said you rejected that. Right?

Mr. MOSHOLDER. Yes, and the reason was I thought we had some

good reasons to sort of point toward fluoxetine as perhaps——

Ms. DEGETTE. To take the stronger position, saying this is the

drug that’s been approved for pediatric use, this is what you should

be prescribing. Right?

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. Okay. I want to ask you, Doctor, in layman’s

terms what did you consult reveal about the link between

suicidality and anti-depressants?

29

Mr. MOSHOLDER. Well, to put it simply, in the short term studies

events which involved suicidal thoughts or behaviors were almost

twice as frequent among the children and adolescents who received

drug compared to the placebo or sugar pill control.

Ms. DEGETTE. So, basically, what your research showed: Kids are

twice as likely to commit suicide on anti-depressants, at least in

the short term, than on placebo?

Mr. MOSHOLDER. Well, I don’t think I would say suicide, because,

of course, there were no actual suicides. So suicidal thoughts and

behavior.

Ms. DEGETTE. Okay. Thanks. Now did these conclusions apply to

all anti-depressant drugs?

Mr. MOSHOLDER. That is a very good question. That is the conclusion from putting all of the studies together. When you break

that apart by individual drug, the numbers become much smaller,

and it is harder to have the same level of confidence that you have

when you combined all the studies, as I did to get that figure.

So—But it is certainly true that in almost all of the drugs that

have been looked at individually, there is at least an excess of such

events with the drug versus the placebo.

Ms. DEGETTE. It would probably be helpful to have additional research, wouldn’t it? More data?

Mr. MOSHOLDER. There is no question about that. Yes.

Ms. DEGETTE. That is what I think, too. Were any of your conclusions or findings about increased risk of suicidality ever disproved

by the FDA, by the Columbia data review, or by Dr. Hammad’s reanalysis?

Mr. MOSHOLDER. In general, I think Dr. Hammad’s analysis and

mine were consistent.

Ms. DEGETTE. Did anybody else disprove your findings?

Mr. MOSHOLDER. Not that I am aware of.

Ms. DEGETTE. Okay. Now I am curious about the February 2 Advisory Committee meeting that you testified about. I am wondering, if you know, why they decided not to let you present your

findings at that meeting?

Mr. MOSHOLDER. Well, it was explained to me by Dr. Katz that

I had reached a different point of view about the data from the

Neuropharm Division, and by that I understood that I felt the data

were of sufficient quality to perform an analysis, which I did, while

the Neuropharm Division felt that any analysis should await the

Columbia University reclassification project.

Ms. DEGETTE. So they felt like your data was not as conclusive

as you thought it was? Would that be a fair characterization?

Mr. MOSHOLDER. Yes, you could characterize it that way.

Ms. DEGETTE. Okay. Let me ask you this. The chairman was

asking you about some of your background, and you have been at

the FDA quite sometime. Is that right?

Mr. MOSHOLDER. Twelve years.

Ms. DEGETTE. And how long have you been in your current position?

Mr. MOSHOLDER. Just over 11⁄2 years.

Ms. DEGETTE. And before that, what did you do at the FDA?

Mr. MOSHOLDER. I was a medical officer in the Neuropharm Division.

30

Ms. DEGETTE. And part of your job, as I understand, is you were

a reviewer of adult anti-depressants in that job. Correct?

Mr. MOSHOLDER. Yes, that was part of my assignments. Yes.

Ms. DEGETTE. In your 12 years at the FDA, I am wondering if

you have ever been in a situation like this before where you were

asked to do a medical consult, where you completed the consult,

where you presented the findings to your supervisors and got approval, and then where ultimately the FDA said, well, don’t worry

about it, just keep your conclusions to yourself?

Mr. MOSHOLDER. Well, certainly, disagreements are not an uncommon event. Personally, I had never had the experience of having my presentation removed from an Advisory Committee meeting

agenda.

Ms. DEGETTE. Have you ever known that to happen at the FDA?

Mr. MOSHOLDER. Not by direct knowledge, but I have heard reports of other types of events like that.

Ms. DEGETTE. Is it your impression that it is a rare or a common

occurrence at the FDA?

Mr. MOSHOLDER. Well, it is hard to give an exact frequency, I

guess, but I would say I have heard of several such circumstances,

just incidentally.

Ms. DEGETTE. And how often is it that people are asked to do

consults like this and make presentations as to their finding? I

mean, you said you have heard of people being told they can’t do

their presentations a couple of times. I am wondering how often

that happens, how often we have these types of presentations at

the FDA.

Mr. MOSHOLDER. Advisory Committee meetings, I think, are fairly frequent, probably on a monthly basis. There’s probably other

people who can give you real figures.

Ms. DEGETTE. So the Advisory Committee meetings happen fairly often. How many cases do they review at the meetings?

Mr. MOSHOLDER. Typically, one issue or one drug per meeting.

Ms. DEGETTE. Okay. So your view would be it has been infrequent that people have been told that they can’t—and again it is

anecdotal, I know, because this only happened to you this one time.

Mr. MOSHOLDER. That is correct.

Ms. DEGETTE. Okay. Now is it—I think that you—now you did

present at the February 2 meeting, but you didn’t present on your

findings from the analysis of the pediatric clinical trial data. Is

that right?

Mr. MOSHOLDER. That is correct.

Ms. DEGETTE. What did you testify about?

Mr. MOSHOLDER. I did a presentation which looked at the Office

of Drug Safety’s resources to evaluate this issue, the chief resource

being, of course, the post-marketing reports, as we call them, or reports obtained through the MedWatch program from patients and

doctors about adverse experiences with drugs—that is outside of

clinical studies—along with examining some other potential sources

of information, the conclusion being that the best source of information was the actual clinical studies.

Ms. DEGETTE. But you didn’t testify about your latest consult?

Mr. MOSHOLDER. No, that is correct.

31

Ms. DEGETTE. Mr. Chairman, I have more questions. I will ask

them during the next round. Thank you.

Mr. WALDEN [presiding]. I assume we will have one. Dr.

Mosholder, thank you for being here. Thank you for your good work

on all these issues.

I would like you to turn to Tab 1 in that giant notebook in front

of you there, and I would ask unanimous consent to be able to put

the binder with all the data in our official record. Without objection, so ordered.

This is an e-mail, and I will read it or parts of it at least, to you

and then your response to Dr. Katz. It is an e-mail from Rusty

Katz to you, and then your response. Can you tell us—Well, let me

read part of it, and then maybe you can respond to it, sir. This is

dated June 2, 2003, and Dr. Katz says:

‘‘We have recently become aware of a presumed association between Paxil and suicidality in pediatric patients. We received a call

from the EMEA a little over a week ago. Dr. Raines told us the

company, GSK, had submitted data that demonstrated that use of

Paxil in kids was associated with increased suicidality compared to

placebo and that the company proposed labeling changes. I believe

she also said that it was in the news, and it was a big issue. Tom

and I told her that the company had not informed us of any of this,

and we agreed to look into it.’’

Then it goes on to talk about some things, and it says: ‘‘The

sponsor has not proposed labeling changes and makes a feeble attempt to dismiss the finding. We are also awaiting the submission

of what the sponsor submitted to UK. We want to move quickly to

evaluate this signal. We are planning to look at the NDAs for other

SSRIs to see whether or not similar events are being hidden by

various inappropriate coating maneuvers.’’

Then they want to compare other things. Then they go on to say

to you: ‘‘Given your history with this application and this general

issue, we think you would be the right person to help us think

about the best approach to the data in the other NDAs and their

sponsors, as well as to provide ideas for further sources of potential

relevant data and possible approaches to better evaluate this signal

study.’’

They go on to say, you know, we want to know if you want to

do this, basically, and want to move soon.

Can you tell us, basically, what you were tasked to do as a result

of this?

Mr. MOSHOLDER. Well, I approached my own management, and

they agreed to assign me to this issue, and it involved, initially last

summer, a review of the Paxil submission that was referred to, and

then a preliminary search of submissions for the other drugs, looking for any kind of similar pattern with these events.

Mr. WALDEN. So you looked at all the drugs, similar drugs being

prescribed to kids for anti-depression?

Mr. MOSHOLDER. All the ones that we had the pediatric supplement NDA applications for.

Mr. WALDEN. And you were specifically looking at suicidality

among adolescents? Wasn’t that——

Mr. MOSHOLDER. That is correct. Children and adolescents, yes.

32

Mr. WALDEN. When did you first report the results of your consult to your superiors?

Mr. MOSHOLDER. As I recall, I completed a written consult in

early September 2003, and then there was a briefing for CDER

management also in September.

Mr. WALDEN. I believe it was September 16, our records would

indicate, of 2003, that the regulatory briefing took place.

Did you attend an internal regulatory briefing then in September

2003, and at that briefing did you present the results of your first

consult to FDA’s Neuropharm Division?

Mr. MOSHOLDER. Yes, I did.

Mr. WALDEN. And was Robert Temple and Tom Laughren and

Russell Katz among those who attended the briefing?

Mr. MOSHOLDER. As I recall, they were.

Mr. WALDEN. What were your general conclusions about the pediatric suicidality data you reviewed and your September 2003 consult in Tab 3, if you need to refer to it—or excuse me, Tab 8, if

you need to look at that? What were your general conclusions about

suicidality?

Mr. MOSHOLDER. Well, I need to refer to my summary here.

Mr. WALDEN. Sure. Absolutely.

Mr. MOSHOLDER. Well, basically this had two components. One

was a thorough look at the Paxil data, and then a preliminary look

at the data for the other drugs. Basically, I was saying that there

did seem to be a risk with Paxil based on the data the company

had submitted and that a first look at the other drugs showed that

it was not limited necessarily to Paxil. That was the question at

the time, and it might be what we call a class effect, which means

that it applies to all of the drugs in a particular type of drug.

Mr. WALDEN. So am I correct then in understanding that what

you were saying in that document is that Paxil definitely showed

potential suicidality increase in adolescents, and that the others

may also show that in a whole class?

Mr. MOSHOLDER. Yes, and I recommended looking further at the

other drugs, which was already underway at that time.

Mr. WALDEN. And that was September 16, 2003?

Mr. MOSHOLDER. Yes. The briefing presentation basically mirrored the written document.

Mr. WALDEN. When this consult was first given to you and you

had experience previously in looking at some of these pediatric

anti-depressant trials, did you have any sense of what the conclusion would likely be?

Mr. MOSHOLDER. No, I did not.

Mr. WALDEN. What type of data did you review from the other

SSRIs to come to the conclusion you did come to?

Mr. MOSHOLDER. For this work, it involved a manual review of

the reports from those pediatric trials.

Mr. WALDEN. That would be the adverse event reports?

Mr. MOSHOLDER. Right, as written up in the clinical trial reports

for those drugs.

Mr. WALDEN. And at that time, were you waiting to receive more

data from the pharmaceutical companies. So, therefore, this was a

preliminary consult?

33

Mr. MOSHOLDER. Yes, and I think, as I mentioned earlier, what

GlaxoSmithKline did was they had an electronic search of their

clinical trial data base, looking for certain key words that had been

used to describe adverse events, and that is how they produced the

data which yielded the signal for Paxil.

So what DNDP had done in July was ask all the other sponsors

to reproduce that, using the same methods that GSK had used for

Paxil, so that we had, you know, a reasonable comparison between

the drugs. Then that was still being awaited at the time—I think

those data were just arriving at the time I was finishing this September report.

Mr. WALDEN. And were you the one who was going to review

those data?

Mr. MOSHOLDER. Yes.

Mr. WALDEN. Okay. And did anyone at that meeting express to

you that your work was done and not to continue with it?

Mr. MOSHOLDER. No, although there was considerable discussion

about how to pursue it and how to classify the events, but nobody

thought it was finished, although there wasn’t—there was a lot of

discussion about what the next steps should be.

Mr. WALDEN. Incidentally, who signed off on this consult, because I see that the last page of it only has signature blocks for

you and Dr. Willy. Did you need to get anyone else’s approval to

finalize the September consult?

Mr. MOSHOLDER. Let’s see. In my copy, if you turn to another

couple of pages, you will see that Dr. Avigan, who is my Division

Director, signed it electronically, which is our system for sign-off.

Mr. WALDEN. All right. But not Anne Trontell?

Mr. MOSHOLDER. No. Dr. Trontell did not.

Mr. WALDEN. Okay. So it was finalized shortly after you completed it, and there was not a significant lag time between you

completing it and getting it signed off?

Mr. MOSHOLDER. Well, let’s see. The date I have is September 4,

and then it looks like it was signed off September 5.

Mr. WALDEN. Okay. If you would turn to Tab 10 then, this is an

e-mail from Russell Katz to you dated September 17, 2003 in which

he stated you had done a superb job. Is this in reference to the

presentation you made about the signal of suicidality in children

taking anti-depressants?

Mr. MOSHOLDER. This was in reference to that September briefing.

Mr. WALDEN. Okay. But on that issue. Right?

Mr. MOSHOLDER. On this issue. Correct.

Mr. WALDEN. Did he or any other person in an advisory role express any concerns with your conclusion at this time? That is, did

anyone take the position that your analysis was wrong?

Mr. MOSHOLDER. Not wrong per se, but there was a lot of discussion about whether the events could be more appropriately classified and whether—which—that is the concern that led ultimately

to the Columbia reclassification project.

Mr. WALDEN. But one more question. Then I will yield to my colleagues. Were there any concerns expressed by anyone within

Neuropharm or the agency at that time that the method in which

34

you approached the data and your analysis was incorrect or problematic?

Mr. MOSHOLDER. As I recall, there was—I had some suggestions

from the statisticians about how to improve the methodology from

that standpoint.

Mr. WALDEN. But did you ever think that—I mean, yes, how confident were you in that consult in your methodology? Was it any

different than what Columbia ended up when they reclassified the

data?

Mr. MOSHOLDER. Well, I mean, I would say I was reasonably confident. People may have different opinions about that, you know.

The Columbia project was—their involvement was to classify the

events into whether they were definitive suicidal behaviors or not,

basically, and they had a more refined methodology than what I

had used.

Then the other part of that is that Dr. Hammad’s analysis from

a statistical standpoint is more sophisticated than what I did.

So——

Mr. WALDEN. But the outcome was the same, wasn’t it?

Mr. MOSHOLDER. The results were very similar.

Mr. WALDEN. Thank you. I now recognize the gentleman from

Michigan, Mr. Stupak, for questions.

Mr. STUPAK. Thank you, Mr. Chairman. Doctor, Ms. DeGette

asked a question about not being allowed to testify at the Advisory

Committee. Is it your understanding that Dr. Graham has not been

allowed to testify at the Accutane Advisory Committees?

Mr. MOSHOLDER. I am not—I don’t have direct knowledge of the

Accutane Advisory Committees.

Mr. STUPAK. Okay. When we talk about these anti-depressants,

Paxil, Zoloft, Prozac, etcetera, we are talking about SSRIs, which

is selective serotonin reuptake inhibitors. Correct?

Mr. MOSHOLDER. Correct. There are also—in the group of drugs

that were looked at, there are some so called atypical anti-depressants which are not SSRIs.

Mr. STUPAK. Sure. Let me show you a document. We will give

the doctor one and the rest of the committee members a copy of

this document. I am going to show you three of them, but the first

one is a September 19, 2001, FDA pharmacology/toxicology consultation.

In there, they are reviewing three previously unreported

Accutane studies, and a pharmacologist reported—and I am on

page 3, the last paragraph, sort of the conclusions. It is a seven or

nine-page document there, but on page 3 there are conclusions, and

I am quoting now. I think it is the second to last line. ‘‘Although

possible psychiatric correlates of excessive serotonagenic function

cannot be ruled out, it should be noted that increased

serotonagenic function is presumed to be the mechanism of action

of a major class of anti-depressants, the SSRIs, i.e., selective serotonin reuptake inhibitors.’’

Since the excessive serotonic function discovered with Accutane

use mimics the SSRIs of these anti-depressants, I as you then: Do

you believe that this relationship between Accutane and the SSRIs

warrant the same type of notification to patients, to the parents,

consisting of an informed consent, a clear and concise package

35

warning, a Med Guide, and a certification of the physician and the

registry of all patients, as is recommended for Accutane? Do you

think we should have that same kind of notice, if we are talking

about SSRIs which somehow, some are similar to function we find

in Accutane?

Mr. MOSHOLDER. That is a good question. As I understand it, you

are suggesting that a risk management program——

Mr. STUPAK. That has been recommended for Accutane, which

Accutane, according to this consult 3 years ago, talks about SSRIs

and the mechanism which is similar—it is the same thing we are

talking about right here with Paxil and Zoloft and Prozac.

So if we are going to have that kind of a recommended warning

for Accutane, shouldn’t we have that kind of notification or warning to patients who are using these anti-depressants that again

have the SSRI function in them?

Mr. MOSHOLDER. That is something I haven’t really thought

about. I guess that would be going beyond the boxed warning and

more——

Mr. STUPAK. Sure, it is.

Mr. MOSHOLDER. The real issue being how can we be sure that

patients——

Mr. STUPAK. Have the full information before they make this decision. Right? As you said earlier talking to Mr. Chairman, the benefits and the risks have to be known before you can have had the

whole thing—before a parent should make that decision. Correct?

Take a look at the second document I showed you there. This

document, if you look, is a PET scan of the orbital frontal cortex

in the area of the brain that mediates depression. The PET scan

is of a 17-year-old, and the brain starts—17-year-old brain. It

starts with baseline of the orbital frontal cortex, and then it shows

this area of the brain after 4 months on Accutane. Please note the

changes. As demonstrated in color, the brain after 4 months on

Accutane, there’s some clear differences.

The PET scan clearly shows changes in the brain after 4 months.

The researcher took PET scans of Accutane patients and patients

who received a different oral antibiotic. The researcher took a baseline PET scan of all the patients’ brains and then again at the 4

month stage of their Accutane or oral antibiotic treatment.

Some of the Accutane patients showed a pronounced difference in

the brain’s metabolism in the area that we recognize causing depression.

Since the FDA in their previous memo has equated Accutane

with SSRIs, and we know from this research that, while metabolic

changes are occurring in the brain of Accutane user, then my question is this. Is the FDA, by allowing anti-depressants be used in

young people, creating another situation like we have in Accutane

where these drugs are destroying part of the brain, destroying

young people, but the evidence is ignored as not being scientifically

established and, therefore, the drug manufacturer continues to

market their products, despite the research which suggests that

the drugs are actually destroying a person’s brain, causing depression, and is doing more harm than good? Based on the PET scan,

research of this metabolism that is going on in the brain may or

may not be reversible. Can the brain regenerate itself to repair the

36

damage done by the SSRIs? What are we telling parents whose

children have not improved after taking the anti-depressants? That

the drug their children are taking may have actually destroyed

part of the brain?

You and I don’t have the answers to this, but in summation:

Since there appears to be an established link, at least in one research project, by giving our children Accutane and these SSRIs,

Prozac, Zoloft and Paxil, we may actually be causing more harm

than good in the brains of young people.

Should the FDA—and here is my question. Should the FDA prevent the use of these drugs in children until these very serious

questions are answered? I think it is the same question—maybe we

have a little bit of evidence here that Mr. Barton didn’t have—that

Mr. Barton asked you about the risk versus benefits, and I think

in response you said to him, risk is never justified in dealing with

suicidal behavior.

So if we have some evidence here showing changes in the brain

in Accutane, which is equated to the previous documents SSRIs,

should we not be very cautious on continuing to prescribe these

SSRIs to young people under the age of 18 until we answer these

questions?

Mr. MOSHOLDER. Well, I would say that the findings from—actually from the clinical trial data—you know, without turning to even

neuroimaging, one can look at the clinical trial data, and that

would certainly give one pause about the usefulness of these drugs

for children and adolescents for depression.

It is also true that we don’t know nearly enough about the long

term effects of these anti-depressant drugs or other drugs on children and adolescents who are growing and developing.

Mr. STUPAK. Well, as you said, we don’t know enough about it.

So as I said in my opening statement, shouldn’t we really err on

the side on caution? You know, suicide is final, and we have had

a number of suicides related to these SSRIs and, say, with

Accutane. I mean, if there is a question here as to the safety, and

to date this is probably the only evidence we have showing a

change in the brain in some of these Accutane patients which

equate to your SSRIs—if we have brain changes, until we answer

these questions, if it is reversible, can the brain rehabilitate itself,

grow new cells, shouldn’t we really be very, very cautious in how

we use these drugs, and should we not even consider not prescribing to young people under age 18?

I asked that same question of the drug manufacturers 2 weeks

ago, and they really wouldn’t give me an answer. They thought it

was still okay to prescribe drugs to people under 18, even though

the jury is still out, as they wanted to say. Shouldn’t we err on the

side of caution here?

Mr. MOSHOLDER. Well, my own opinion is, as I said before, that

we should be mindful of the fact that the best data, the best evidence for benefit is limited to the single drug, Prozac, at least in

terms of depression. Obsessive compulsive disorder is a different

story, but for depression.

So that faced with the question of possible harm, on the one

hand, and then lack of evidence of benefit, on the other, that

37

should certainly be part of the evaluation of whether or not to use

the drugs.

I am not prepared to say that the drugs shouldn’t be used in children.

Mr. STUPAK. I believe you got one more document there. My time

has almost run out. Let’s go to that. In dealing with pediatric studies, and again we are still in question here, dosage is usually a

question as to the proper amount that should be given, of the

amount, the percentage, things like that.

For example, in Accutane we know that the dosage is way too

high, and in one FDA source—in fact, it is there with you—it states

that the Accutane formula dose may be 240 times more than necessary for safe treatment, and that was followed up with discussions to have Hoffman La Roche do a dosage study and, as far as

I know, it was never done.

So my question is: Since these anti-depressants and Accutane

have sort of been linked here today, has there been shown to be—

has the FDA given any thought to determine whether proper dosage is given to children and adolescents with these anti-depressants, because they were developed for adults. So are we dealing

with the proper dosage when we are dealing with young people and

adolescents?

Mr. MOSHOLDER. Well, that is a very good question, and unfortunately, to the best of my recollection, the clinical trials that we

have for the anti-depressants in children were done with what we

call flexible dosing where it is left up to the clinician/investigator

to determine the dose within a certain range.

So there might have been one or two exceptions to that, but what

is really needed is a study in which patients are assigned to a specific dose, and then both the benefits and the side effects can be

compared to get a judgment of what the best dose is.

So there is clearly—apart from even figuring out if the drugs are

effective in children, there is clearly more need for data on the

proper dosage.

Mr. WALDEN. I want to thank the gentleman.

Mr. STUPAK. Thank you. Mr. Chairman, I ask that those three

documents referred to by Dr. Mosholder and given to the committee

be made part of the record.

Mr. WALDEN. Without objection.

[The documents referred to follow:]

38

39

40

41

42

43

44

45

46

47

48

Mr. STUPAK. Thank you.

Chairman BARTON. Thank you.

Mr. WALDEN. Dr. Mosholder, given the new TAD study on

fluoxetine, do you believe that that raises any issues parents and

physicians should be concerned about relative to suicidality?

Mr. MOSHOLDER. My opinion is that it does raise some concerns

about that, and as I was saying earlier, when I did my initial—

well, actually, the March consult document didn’t have the TADS

study, and it looked at sort of conveniently the one drug that had

the best efficacy for depression, also didn’t seem to have this risk

of increasing suicidal events, which made a certain amount of

sense. But I think now it is a little different picture that, although

the TAD study again showed that Prozac is effective in ameliorating the symptoms of depression, it suggests there is a certain

number of patients who have an increased risk of suicidal behaviors or thoughts at the same time.

So there is both a risk and a benefit, in other words.

Mr. WALDEN. Do you recall what the suicidality rate was in the

TAD study and how that compares to the other studies?

Mr. MOSHOLDER. As I recall from Dr. Hammad’s analysis, the

relative risk, as we call, which is—or risk ratio is between 4 and

5. I can look that up.

Mr. WALDEN. And what does that mean to a layperson like me?

Mr. MOSHOLDER. Well, one way that we measure these risks is

to do what we call a risk ratio, and that is—I guess the simplest

way to explain would be with a brief example. A study with 100

patients on drug, 100 on placebo, if one had 10 suicidal events on

drug and 5 on placebo, the ratio would be 10 out of 100 to 5 out

of 100, or 2.

So we would say that that relative risk is 2, and that is—and as

I recall, in the TAD study it’s actually higher than that.

Mr. WALDEN. And is that a—is 4, if that was the number, is that

one that should raise a flag? I mean, you do this work all the time.

Mr. MOSHOLDER. Well, I think it raises a flag, and it has to be

judged against the benefit. so that there is a study in which in the

same study, you can look at the benefits and the risks simultaneously.

Mr. WALDEN. All right. The question is: Does it suggest a point

of underreporting in the other studies?

Mr. MOSHOLDER. No, I’m not sure that is the—I’m not sure the

answer is as simple as that. There are some differences between

the TAD study and the other studies that might or might not account for the different in the data. It is kind of hard to tell after

the fact.

Mr. WALDEN. Could you turn to Tab 11 in our notebook there.

This is an e-mail dated October 2, 2003. Mary Willy who is your

direct supervisor—correct?—in the Office of Drug Safety at that

time, suggests to the Neuropharm Division and others that you

should present your Paxil suicidality conclusions that were first

presented in September to a Pediatric Advisory Subcommittee

meeting that was meeting in October.

Then Russell Katz writes back to her and states: ‘‘We recognize

that some folks outside the Division have concluded there is

enough of a signal already established to make some sort of a

49

meaningful statement about the data, but we haven’t, and we think

that publicly presenting part of the data in its current state has

the great potential to be misleading and uninformative.’’

Do you agree with Dr. Katz’ statement that publicly presenting

your data and conclusions you reached at that time has the great

potential to be misleading and uninformative?

Mr. MOSHOLDER. Well, my opinion was—and that of Dr. Willy at

the time was that we thought it could be done and might have been

useful, which is why she proposed it. But as you see, there was a

difference of opinion about that.

Mr. WALDEN. You know, it strikes me that when word came over

from Europe that there may be a problem here, they went right to

you quickly and said we have to act quickly.

I guess what is troubling to us is it appears there was a fairly

long delay between the time you did your quick review, your consult, came back and said I see some problems here, if I am characterizing that correctly, and then when it finally gets presented up

the chain. It seems like somebody put a brake on somewhere. Did

you ever feel that way?

Mr. MOSHOLDER. You know, it is really hard to be specific and

say that—I’m not sure I have much of an answer to that, really.

Mr. WALDEN. All right. Did you present at that October Pediatric

Advisory Committee meeting?

Mr. MOSHOLDER. No.

Mr. WALDEN. Throughout the fall of 2003, did you continue to

work on this consult and, if so, can you briefly describe what you

were looking at?

Mr. MOSHOLDER. During that fall, what I was doing was an analysis of the responses from the other anti-depressant manufacturers.

As you recall, in July they had been asked to reproduce GSK’s

methods that found the problem with Paxil. So we wanted to—for

comparability purposes, we wanted to have that reproduced by

each of the other manufacturers.

We received that information in the late spring/early fall of 2003,

and that is what I was working on.

Mr. WALDEN. You were reviewing all those data?

Mr. MOSHOLDER. Yes.

Mr. WALDEN. Would those data have been ready for the October

presentation? Were you ready?

Mr. MOSHOLDER. For the October presentation, it would not have

been the—what we would have had at that point would have paralleled the regulatory briefing that I had given in September to

CDER management.

Mr. WALDEN. Okay. So at the end of October, the FDA noticed

a public Advisory Committee meeting for February 2 and 3, 2004.

Was it your understanding that you were going to present at this

meeting on the topic of your consult and what your findings were

regarding suicidal behavior in these pediatric clinical trials?

Mr. MOSHOLDER. Yes, that was my understanding.

Mr. WALDEN. That’s what you were going to go do. Did the fact

that in October 2003 Neuropharm decided to involve Columbia

University in reclassifying the events provided by the companies

mean that you were to stop working on your consult?

50

Mr. MOSHOLDER. I remember wondering that and discussing it

with Dr. Willy, my team leader, and we decided that at that point

I had gone far enough and had devoted a lot of time to this project

that it made most sense just to have me finish with my analysis,

which was the one that I completed the draft in December.

Mr. WALDEN. So it was your understanding, both your consult

and any work that Columbia did would be pursued simultaneously?

Mr. MOSHOLDER. Correct, although the timeline—it seemed obvious that the Columbia—it seemed obvious pretty early that the Columbia data would not be ready for analysis and presentation by

February 2.

Mr. WALDEN. But it was important enough that you wanted to

get answers sooner than that?

Mr. MOSHOLDER. Yes, which is not to say that it had to be either

one or the other, but both efforts were continuing full speed, you

know, as far as I was concerned.

Mr. WALDEN. Were you involved in the planning meetings for the

February 2 Advisory Committee meeting?

Mr. MOSHOLDER. Yes, I was.

Mr. WALDEN. When did you complete your final meta analysis of

all the data from the SSRI pediatric clinical trials?

Mr. MOSHOLDER. As I recall, my draft was turned in to my management around mid-December.

Mr. WALDEN. Of 2003?

Mr. MOSHOLDER. Of 2003. I made some refinements to it in the

subsequent couple of months.

Mr. WALDEN. And basically—correct me if I am wrong, but didn’t

those data, or didn’t your findings show a 1.9 or 1.89 times more

likely serious suicide-related event on drug than placebo?

Mr. MOSHOLDER. Yes.

Mr. WALDEN. Across the trials. Right?

Mr. MOSHOLDER. That’s correct, yes.

Mr. WALDEN. All right. And didn’t you recommend interim measures?

Mr. MOSHOLDER. Yes. I recommended—I wasn’t very specific, I

realize, but I had in mind some kind of interim measures to announce that there could be a problem.

Mr. WALDEN. Did you feel a sense of urgency?

Mr. MOSHOLDER. Yes, I did.

Mr. WALDEN. To get this information and your findings out?

Mr. MOSHOLDER. Yes, I thought it was—and that was one of the

points I made at the September regulatory briefing, that these

drugs are widely used in this population, and so that it was an important public health issue.

Mr. WALDEN. Did you reclassify any of the events that the sponsor gave? That is, did you change the classification from serious to

nonserious or discount it completely?

Mr. MOSHOLDER. What I did for my meta analysis, I took the

events which had been identified by each sponsor, using GSK’s

method, and then the result that I emphasized was the subgroup

of those events which also met a regulatory definition for seriousness. That is a definition that—it is in the Code of Federal Regulations. It is something that each sponsor designates when they reVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00058 Fmt 6633 Sfmt 6602 96099.TXT HCOM1 PsN: HCOM1
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port the studies to the FDA as to whether or not a particular adverse event is serious or not.

Mr. WALDEN. And didn’t your consult focus on serious suicidal

events?

Mr. MOSHOLDER. Yes, it did.

Mr. WALDEN. Including the famous girl slapping face?

Mr. MOSHOLDER. Well, that was not a serious event which

was——

Mr. WALDEN. So that wasn’t——

Mr. MOSHOLDER. Well, that was the rationale that, without being

able to do anything as elaborate or sophisticated as the Columbia

University project, as a first cut to eliminate some of the questionable cases, I took the subgroup that met the criteria for seriousness, which in this case is mostly either life threatening or resulting in hospitalization.

Mr. WALDEN. Okay. So the girl slapping face scenario was not

even included in your data that resulted in a 1.9 times——

Mr. MOSHOLDER. No.

Mr. WALDEN. I mean, you were pushing the upper end here in

terms of suicidality issues then. Is that right? My reading as a

layperson.

Mr. MOSHOLDER. Well, it was an attempt to hone in on the

events that were clinically meaningful.

Mr. WALDEN. But it also says there are other events below that,

including the girl slapping face situation that—I guess my point is,

that could be occurring out there in adolescents——

Mr. MOSHOLDER. Yes.

Mr. WALDEN. [continuing] are not even in your data. That is not

a criticism. I am just trying to get the range here.

Mr. MOSHOLDER. Well, I did look at it with the broader category,

too, but I thought the more important result was with the subgroup of the serious events.

Mr. WALDEN. Indeed. My time has long since expired. I turn to

my colleague from Colorado.

Ms. DEGETTE. Thank you, Mr. Chairman. Dr. Mosholder, if you

could turn to Tab 67 of the notebook in front of you, do you see

that statement? It is entitled Written Statement.

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. Was this statement prepared by you?

Mr. MOSHOLDER. Yes, it was.

Ms. DEGETTE. Can you tell me how you came to prepare that

document?

Mr. MOSHOLDER. I was—well, this is a statement that I provided

to the Office of Internal Affairs, and this was pursuant to an interview that I had with two Special Agents of the Office of Internal

Affairs regarding the San Francisco Chronicle story about my analysis of the suicidal events.

Ms. DEGETTE. Did those agents ask you to prepare that?

Mr. MOSHOLDER. Yes, subsequent to the interview they asked me

to provide a written statement.

Ms. DEGETTE. And that is how you came to prepare that?

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. Okay. And that statement was under oath. Correct?

52

Mr. MOSHOLDER. It was given——

Ms. DEGETTE. It was an affidavit?

Mr. MOSHOLDER. Right. That’s correct, yes.

Ms. DEGETTE. And what it was about was the circumstances surrounding the removal of your analysis of the incidence of pediatric

suicidality in clinical studies of anti-depressants from the agenda

of the Advisory Committee meeting that we talked about, and also

the conversations that you had with the San Francisco Chronicle

reporter about that analysis and the decision to omit it from consideration by the Advisory Committee. Is that right?

Mr. MOSHOLDER. That is correct.

Ms. DEGETTE. And so what this written statement was attempted to be was an accurate account of the events as you knew

them about the presentation and the decision to cancel that presentation, and also about your contacts with the reporter. Right?

Mr. MOSHOLDER. That is correct, and importantly, to include the

statement that I did not divulge the information to the reporter.

Ms. DEGETTE. Right, and you wanted to—so part of what you

wanted to do was set out a chronicle of the events, including how

and why and in what way you communicated with this reporter.

Right?

Mr. MOSHOLDER. That is correct. And that was part of the request that they gave me to include in the statement.

Ms. DEGETTE. Okay. Now when did you provide that statement

to the OIA?

Mr. MOSHOLDER. I believe it was—it was middle of March, I

think maybe March 15.

Ms. DEGETTE. That is the information I’ve got as well. Did there

come a time when the U.S. Senate Finance Committee made inquiries regarding the events described in your statement?

Mr. MOSHOLDER. Yes, that’s correct.

Ms. DEGETTE. And when did you know about that? How did you

find out about that?

Mr. MOSHOLDER. I believe I saw a news report in late March of

this year.

Ms. DEGETTE. And then were you contacted by the Office of Legislative Affairs?

Mr. MOSHOLDER. Yes, I was, when the Senate Finance Committee investigators wanted to arrange an interview.

Ms. DEGETTE. So it was sometime after March 15?

Mr. MOSHOLDER. That’s correct.

Ms. DEGETTE. Okay. Did you meet with folks from the Office of

Legislative Affairs subsequent to the TV report that you saw or the

media report?

Mr. MOSHOLDER. Yes. We had a couple of preparatory meetings,

as I recall, to prepare me for the Senate Finance Committee interview.

Ms. DEGETTE. Okay. Was that with Patrick McGarry and Karen

Meister?

Mr. MOSHOLDER. I believe they were some of them.

Ms. DEGETTE. And there were others as well as them?

Mr. MOSHOLDER. Yes. We had a series of meetings, and I am not

entirely clear on who precisely was at which meeting, but there

was a number of them.

53

Ms. DEGETTE. Okay. Doctor, take a look at Exhibit 64, which is

an e-mail from Ms. Meister to you regarding a May 3, 2004, meeting in Mr. McGarry’s office. Do you see that memo, Tab 64?

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. There are some people who are copied on that email: Ann Hennig, Donna Katz, and Kim Dettlebach. Do you see

those names?

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. Do you know those individuals?

Mr. MOSHOLDER. Yes, I do.

Ms. DEGETTE. Do you know who they are?

Mr. MOSHOLDER. Ms. Hennig works with the CDER Office of Executive Programs, as I believe it is called. Ms. Katz and Ms.

Dettelbach are, as I understand, with the Office of Chief Counsel

at FDA.

Ms. DEGETTE. Okay. Now can you tell me what the subject of

that meeting was?

Mr. MOSHOLDER. As I recall, it was a preparatory meeting for my

Senate Finance Committee interview.

Ms. DEGETTE. And after that meeting, were there exchanges of

various revisions to the written statement that you talked about a

little while ago that you had prepared earlier that was to be provided to the Senate Finance Committee?

Mr. MOSHOLDER. Yes. That became an issue, and I can explain

it this way. Having given the statement under penalty of perjury,

as we said, I had a legal interest, and my attorney confirmed this,

in being consistent with that statement. So that——

Ms. DEGETTE. And telling the truth, because you were under

oath.

Mr. MOSHOLDER. Yes. And also not even inadvertently contradicting a previous statement. So——

Ms. DEGETTE. A previous statement made by you?

Mr. MOSHOLDER. Right. So to ensure my own consistency and

knowing that the Senate Finance Committee would be asking

about the same sequence of events, it was to my advantage to

make use of that statement for the Senate Finance Committee investigation as well.

So I wanted to provide them with a copy of the statement as sort

of my official record.

Ms. DEGETTE. Right, your take on what happened, to the best of

your recollection.

Mr. MOSHOLDER. The issue was that at that time the Internal

Affairs investigation, as I understand it, was still an open investigation, and apparently FDA’s policy or the executive branch policy is not to reveal the existence of such investigations. So that I

was advised to redact the statement so that it didn’t have any reference to the Internal Affairs investigation.

Ms. DEGETTE. And they also wanted you to take the names out?

Mr. MOSHOLDER. Right. The other issue was personal privacy of

not revealing the names of other people who were subject of an Internal Affairs investigation. So although I was free to reveal my

own involvement, but that it wouldn’t be appropriate to divulge

other people who were subject to that same investigation.

Ms. DEGETTE. And were you willing to make those redactions?

54

Mr. MOSHOLDER. I said that I was uncomfortable redacting the

document in a way that it wasn’t transparent that it had been redacted.

Ms. DEGETTE. So you didn’t mind taking out the names or the

reference to the internal investigation, but you wanted the document to reflect that it had been altered. Correct?

Mr. MOSHOLDER. That is correct.

Ms. DEGETTE. And they wanted to alter it so that there would

be no record of the redactions. Correct?

Mr. MOSHOLDER. That is my understanding. That is how I understood it, yes.

Ms. DEGETTE. Now ultimately you decided not to sign the revised document that they had sent you. Correct?

Mr. MOSHOLDER. Well, I said that, when I went to the Finance

Committee for my interview, that I preferred to use my version,

which indicated that the document had come from a previous document, and in the—actually, what happened was in the interim the

Internal Affairs investigation was closed. So that that made that

issue moot. So I was able to ultimately provide the Finance Committee with my affidavit, only minus the names for personal privacy.

Ms. DEGETTE. Okay. Take a look at Exhibit 57. That is an e-mail

from Donna Katz to you with copies to various people. Do you see

that there?

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. Now attached to that e-mail is a copy of the written statement, your written statement, with lines through a number of sentences, and a copy where the deletions had been made.

Do you see that?

Mr. MOSHOLDER. I see the—I only have the copy with the deletions indicated.

Ms. DEGETTE. All right. We are going to hand it to you. Apparently, it is not attached in the notebook, but do you recall seeing

a draft of a document that Ms. Katz wanted you to look at?

Mr. MOSHOLDER. Yes. That is actually the situation I just described.

Ms. DEGETTE. Right, and here it is.

Mr. MOSHOLDER. Thank you.

Ms. DEGETTE. Is that the document?

Mr. MOSHOLDER. Well, this is the document showing where the

lines have been dropped. Yes.

Ms. DEGETTE. Right, where she wanted to redact it, and in fact,

her e-mail to you says, ‘‘Andy, I have taken a look at your written

statement and made some suggested edits. Given this will be a new

document created to give to the Senate Finance Committee, albeit

based on an earlier document, I think it is cleaner to make this a

stand-alone document, i.e., to include everything in it that is current and you would like to include, and just delete out anything

you would like to leave out. I don’t think it is necessary to indicate

that this document represents a version of the earlier one by noting

that the things that have been omitted. This simply invites the

Committee to ask further questions about what was omitted in the

earlier document. Please let me know if you have any questions,

etcetera. Thanks, Donna.’’

55

Is it your understanding that, had you signed the revised statement, it would have been submitted to Senator Grassley and probably also this committee without notation regarding its alteration?

Mr. MOSHOLDER. Well, it wasn’t a matter of signing it, but the

plan was that I would provide this to the Committee at the start

of my interview with them. So——

Ms. DEGETTE. Right. So if you had gone alone with this, this redacted document without the—I mean the lines would have been

taken out. It would have been cleaned up, and that is what would

have been given to the Senate and also probably to us, without notation of the things that had been taken out. Right?

Mr. MOSHOLDER. That is my understanding of what was proposed.

Ms. DEGETTE. And that is what you objected to?

Mr. MOSHOLDER. Yes. I said I was not comfortable with that.

Ms. DEGETTE. Okay. Now take a look at Tab 58. What that is,

your reply to Ms. Katz the same day, which says, attached is a

version of the statement that you say you would have been comfortable with. Right?

Mr. MOSHOLDER. Yes, that’s correct.

Ms. DEGETTE. And the e-mail reads: ‘‘Thanks very much, Donna.

Your version is actually very similar to the one I came up on my

own this a.m. See attached. Although it might be cleaner to do so,

as you say, I am uncomfortable with concealing from the Committee the fact this is not a new document. Accordingly, I prefer

to use the version I edited as in the attached e-mail which otherwise incorporates all the edits we have discussed. Thanks, Andy.’’

Right?

Mr. MOSHOLDER. Yes.

Ms. DEGETTE. And it is clear that you chose against the wishes

of Ms. Katz and, I assume, the other lawyers to revise that document in such a way as to put the interest of Congressional committees on notice the document had been altered. Right?

Mr. MOSHOLDER. Well, that was my intent.

Ms. DEGETTE. Right. Thank you very much, Mr. Chairman.

Mr. WALDEN. The Chair recognizes the gentleman from Michigan, Mr. Stupak, for 10 minutes.

Mr. STUPAK. Thank you. Did you incur legal expenses while you

were doing all these interviews with your Internal Affairs and all

this?

Mr. MOSHOLDER. I did obtain legal representation. In point of

fact, I have a Federal employee liability policy which provided for

that. So my only expense was the insurance premium.

Mr. STUPAK. I can see an internal investigation on something

about some newspaper leak or something, but sounds like here,

and I think Ms. DeGette was being much too polite, you were being

squeezed here to change your testimony. Correct?

Mr. MOSHOLDER. I’m not sure I would——

Mr. STUPAK. I was police officer for 12 years. I would have

squeezed you and got it, too, you know. I mean, look, let me ask

you this. Go to Tab 89.

Mr. MOSHOLDER. I’m sorry. Eighty?

Mr. STUPAK. Eighty-nine, please. It is a June 16 letter from Representative—I guess it is Senator Grassley to the FDA, and on the

56

fourth page the letter states—it is on Tab 89. It says on page 4:

‘‘Perhaps most troubling, however, was the fact that the OND attempted to have Dr. Mosholder present reporting rates of suicidal

thoughts rather than the available clinical trials data on anti-depressants in children which form the foundation of his analysis.’’

Can you please clarify the difference between the reporting rates

of suicidal thoughts and available clinical trials data? Which is

more reliable and relevant?

Mr. MOSHOLDER. A reporting rate is a term we use when we

have spontaneous reports obtained through the MedWatch program, and as the enumerator. Then that is divided by some measure of the number of prescriptions in the U.S.

The problem with reporting rates is that it is usually assumed

we only have only a small fraction of the number of events that are

actually occurring in the population.

Mr. STUPAK. Well, clinical trial data is far more reliable than reporting rates. Right?

Mr. MOSHOLDER. That is correct. When——

Mr. STUPAK. And isn’t it true that you were asked to present the

reporting rates instead of the clinical trial rates or clinical trial

data?

Mr. MOSHOLDER. You could put it that way. That is true, yes.

Mr. STUPAK. Okay. Then why did you choose not to present the

reporting rates instead of your clinical trials data?

Mr. MOSHOLDER. Well, this was an issue we had considerable internal discussions about in preparation for the February 2 meeting.

Ultimately, we in the Office of Drug Safety felt that, given that suicidal behaviors are part of the reason why the patients would be

receiving the drug in the first place, giving a rate of such events

really is not very useful information, and that the better data is

done from trials where there could be comparisons.

Mr. STUPAK. So the better data is from the clinical trials data,

and they were requesting, pressuring you—whatever word you

want to use—to use the reporting rates and not the clinical trials

data. OND asked you to present reporting rates instead of the clinical trials data. They wanted you to soften your conclusions.

Mr. MOSHOLDER. Well, at that point I was not presenting the

clinical trials data at all.

Mr. STUPAK. But it was in your paper, your affidavit, if you will.

So you had it. Correct?

Mr. MOSHOLDER. In my presentation to the Advisory Committee

February 2 I presented simply a number of reports, as I recall,

without the reporting rates in the end.

Mr. STUPAK. Right, but you used clinical trials data, because it

is more reliable.

Mr. MOSHOLDER. Yes. My opinion is that is better data. Yes.

Mr. STUPAK. And OND wanted you to use reporting rates instead

of clinical trials data. Correct?

Mr. MOSHOLDER. That is correct that they asked for that.

Mr. STUPAK. Correct. And the reason for that is it softens your

conclusions that you put down in this paper, the affidavit. Isn’t

that correct?

Mr. MOSHOLDER. I’m not——

57

Mr. STUPAK. Let me put it this way. The numbers look better if

you use reporting rates as opposed to the more reliable clinical

trials data. Isn’t that correct?

Mr. MOSHOLDER. My own opinion—well, that was a concern of

the Finance Committee investigator. My own opinion is that the reporting rates simply are not informative. You can interpret it as an

attempt to—I wouldn’t go——

Mr. STUPAK. I’m not trying to put words here, but look it, we established that the clinical trials data is more reliable than the reporting rates. You were asked to change your clinical trial data to

reporting rates, which is not as reliable. The reason to do that is

then your affidavit, your conclusions are not as firm and solid. It

is a softening of your conclusions, is it not? Softening is my word,

not yours.

Mr. MOSHOLDER. Well, I would say that the reporting rates are

inconclusive. There are no conclusions that you can draw from reporting rates, in my opinion. So——

Mr. STUPAK. Then why would OND want you to use reporting

rates, if they are not as solid, not as reliable?

Mr. MOSHOLDER. Well, again there was difference of opinion

about that. My understanding was that it was for completeness, because ordinarily this had been done and——

Mr. STUPAK. How do you get completeness if you don’t use the

most reliable data?

Mr. MOSHOLDER. Well, that was——

Mr. STUPAK. Completeness is the conclusion that one wishes to

draw from the report that you did, completeness in the eye of the

beholder. Right?

Mr. MOSHOLDER. Well, my own preference would have been to

present the clinical trial data. Yes.

Mr. STUPAK. Correct. Okay. Reporting rates—to your knowledge,

how many other instances were reporting rates provided when

more reliable data was available? Is this a common thing? You

medical officers do your reports. You look at the most reliable evidence, which may be your clinical trials data, and then you are

told, well, geez, don’t use that, let’s look at the reporting rates, and

let’s use reporting rates as opposed to clinical data? Does that occur

fairly often at the FDA?

Mr. MOSHOLDER. Not that I can recall, for just those reasons,

that situations where reporting rates are useful are for very rare

events that wouldn’t necessarily be part of the reason why the patient was receiving the drug. So that it——

Mr. STUPAK. Absolutely. I agree with 1000 percent. Clinical trial

data is always better than reporting rates. My question is: In the

past, to your knowledge, has the FDA pressured medical review officers who review the drugs and deal with the data all the time to

change from clinical trial data to reporting rates?

Mr. MOSHOLDER. I am not aware of any comparable situations,

personally.

Mr. STUPAK. Your statement you gave here today—did the FDA

have to approve your statement you are giving here today before

the committee, your written statement?

Mr. MOSHOLDER. No, they did not.

58

Mr. STUPAK. Okay. If we do this labeling, packaging labeling that

was suggested in the Advisory Committee, will you be involved in

that process?

Mr. MOSHOLDER. Not to my knowledge.

Mr. STUPAK. I think someone may have asked you this, but let

me just clarify this.

What is your impressions of Dr. Hammad’s study?

Mr. MOSHOLDER. Well, I think the important point is that it is

very consistent with the findings I had in my analysis.

Mr. STUPAK. That was my second question.

Mr. MOSHOLDER. You know, it lends strength to the finding.

Mr. STUPAK. So you would—Dr. Hammad’s study is good work,

and you would agree with it?

Mr. MOSHOLDER. Yes, and in many respects it is more sophisticated than my first crack at the data.

Mr. STUPAK. And it confirmed what your initial findings were?

Dr. Hammad’s report confirmed what your initial preliminary report showed. Correct?

Mr. MOSHOLDER. That is my—my own biased opinion is that it

did confirm it, yes.

Mr. STUPAK. Someone, I think, asked you this one, too, on Tab

15 in which Dr. Avigan writes on your consult, ‘‘Andy, great job.’’

If Dr. Avigan thought you did a great job with your analysis, why

did he later issue a dissenting memo to your consult? It is in Tab

15.

Mr. MOSHOLDER. Yes. I believe Dr. Avigan did not feel that the

data were ready to make the—or was sufficiently conclusive to

make the recommendations that I made in my consult.

Mr. STUPAK. So you went from great job to being inconclusive?

Mr. MOSHOLDER. Well, to be fair, he did say that—at the time

of the first draft, I remember him telling me that we would have

to think about the recommendations some, but in the end he felt

that the data were not persuasive enough to endorse my recommendations.

Mr. STUPAK. Thank you, Mr. Chairman.

Mr. WALDEN. Thank you. Dr. Mosholder, I want to refer you to

Tab 78, if you would, sir, and go to—this is a memo. You were the

medical officer on review and evaluation of clinical data. It is dated

12/13/96, received 12/16/1996, to Sulvay Pharmaceuticals regarding

Luvoxamine maleate.

Mr. MOSHOLDER. Maleate, yes.

Mr. WALDEN. Thank you.

Mr. MOSHOLDER. Or Luvox.

Mr. WALDEN. Thank you. That is even easier. I want to refer you,

though, to the second page, and it says: ‘‘it’s of interest that in the

adult studies the incidence of agitation was 2 percent and 1 percent

for fluoxomine and placebo, respectively, while the pediatric study,

the corresponding incidences were 12 percent and 3 percent. That

is, the risk ratio for adults was two and for children was four. It

is possible this reflects a real difference in adverse reactions between adults and children. There is an emerging literature pointing

to behavioral reactions to SSRI drugs in children.’’ Then you make

some references there or some references are made here. ‘‘It may

59

be that this is a reaction to SSRIs that is more prominent in children than adults. Further data would help clarify this.’’

Now I think what is interesting about this, this is a December

1996 memo. The review was completed in February 1997. Was this

a flag you were raising in 1997?

Mr. MOSHOLDER. Well, as I said, this was one of the very first

pediatric clinical trials we had seen with this class of drugs, and

although there had been some other reports, apparently—I don’t

recall that reference at this point, but it seemed to be raising the

question of whether the behavioral adverse effects might be different for kids versus adults.

Mr. WALDEN. Right. And you also said this is also reflected in

Pfizer’s recently submitted study of Certraline in the treatment of

juvenile OCD as well in that reference. I guess the reason I asked

is it looks like from this documentation, perhaps others, that this

was sort of coming up as an issue back in 1996-1997.

I wonder, as we go into these pediatric clinical trials, could they

have been designed better to go look at this issue of suicidality in

children and adolescents? Should we have picked up on that sooner?

Mr. MOSHOLDER. Well, that is a good question. Historically, these

two, as I recall, were the first actual studies we had with this class

of drugs in kids. So it suggests that a pattern was starting to

emerge. We, of course, didn’t get more data until several years

later, but the——

Mr. WALDEN. But should the FDA have sought more data in the

way they designed the clinical trials for children?

Mr. MOSHOLDER. Well, the question being, as we were writing

the request for pediatric studies, part of the pediatric exclusivity,

could we have done more to get at this issue. Well——

Mr. WALDEN. In retrospect.

Mr. MOSHOLDER. Yes, in retrospect, you know, perhaps more attention could have been given to that. On the other hand, these

trials had done nothing special to look for this type of event, and

it seemed to be turning up. So that would be on the side of saying

routine adverse event monitoring was sufficient to turn up this possibility.

Mr. WALDEN. Were you aware that apparently Dr. Knudsen also

had some warnings that go back to 1996?

Mr. MOSHOLDER. I recall the——

Mr. WALDEN. For Zoloft.

Mr. MOSHOLDER. [continuing] something about that at the time.

Then, of course, in preparation for this hearing I’ve been reminded

of that. Yes.

Mr. WALDEN. I guess that the question we keep going back to is:

Should this signal have been spotted sooner?

Mr. MOSHOLDER. Well——

Mr. WALDEN. Because it raises the issue, are there other signals

that are bouncing around out there on other drugs being prescribed

off-label for people that we are not catching. How do we fix the system, I guess, is part of it. Should we have spotted this one sooner?

Should FDA?

Mr. MOSHOLDER. Well, one always wants to spot a problem as

soon as possible, of course. The issue here, I think, at least in my

60

own mind, was that we were lacking clinical trials in children until

the past few years, that the Luvox and Zoloft studies were really

sort of on the forefront of that, and so it was more just a plain lack

of data rather than lack of any specific attention to it.

Mr. WALDEN. Okay. And I guess—but if we designed trials right,

you would have the data. You would have had the data. Right?

Mr. MOSHOLDER. And in fact, that is what we have currently.

Mr. WALDEN. And I guess what I also want to make sure of is

that, when we do have the data and they are evaluated by people

of your credibility, that those data then are applied appropriately

and the results are put out there appropriately.

I am troubled by an article that appeared in the August 7, 2004,

British Medical Journal, and it states that Dr. Thomas Laughren

reported the relative risk ratios of all the anti-depressants evaluated at the Pediatric Drug Advisory Committee meeting, and that

it was—‘‘it was Dr. Mosholder’s conclusions and not the data that

were withheld.’’

Do you agree with Dr. Laughren’s reported characterizations?

Mr. MOSHOLDER. Is this what was——

Mr. WALDEN. This is the article. He also says—you will see in

the second graph on this particular page—I’m sorry, second column, the last paragraph on the page, both the raw data and Dr.

Mosholder’s interpretation ‘‘were imperfect,’’ said Dr. Temple, adding that some of the behaviors labeled suicidal were highly suspect

and could have been accidents, such as a child ‘‘who hit her head

with her hand.’’ FDA officials acknowledged, however, that some

cases classified as accidental injury could be suicide related. Because of this, they have gone on then to Columbia University.

That is why I raise that issue about whether or not your study

included the incident of the girl slapping her head, because it didn’t

include that, did it?

Mr. MOSHOLDER. I included it in one analysis but not the result

that I——

Mr. WALDEN. But not in the results, not in your conclusions.

Mr. MOSHOLDER. Yes.

Mr. WALDEN. And so why would then Dr. Temple tell this, allegedly, I suppose—it is printed here—say that that may be part of

the problem here, that it is imperfect. Did you think your conclusions were imperfect?

Mr. MOSHOLDER. Well, I’m not sure I can give an unbiased answer to that. I think there was——

Mr. WALDEN. Well, do you think—let me ask this. Do you think

his characterization of your consult is correct?

Mr. MOSHOLDER. I think we have had some—perhaps some communications issues where I am not sure that it was—I perhaps

could have done more to make it obvious that I was trying to get

away from the question of the clinically trivial events, if you will,

such as the slapping in the face.

Mr. WALDEN. And I know we are putting you in a tough spot

here with some of these folks that are, you know, your superiors

sitting right behind you. I mean, I don’t envy that position. Trust

me. But these are critically important issues we have to get to.

Was your data analysis fully and fairly presented at the February 2004 Advisory Committee meeting and, if not, what should

61

have been presented? What was presented, first of all, since you

didn’t do the presentation?

Mr. MOSHOLDER. As far as the clinical trial data, Dr. Laughren

gave the presentation of that.

Mr. WALDEN. Was it full and fair?

Mr. MOSHOLDER. It did not include all of the results or data that

I had in my draft presentation.

Mr. WALDEN. I guess the point is did it include the most important recommendations?

Mr. MOSHOLDER. Well, it didn’t include—well, apart from the

recommendations, the data I think that I would have included—let

me put it that way—would——

Mr. WALDEN. If you had been there presenting it, what would

you have included that wasn’t included?

Mr. MOSHOLDER. I would have included the analysis of the serious subgroup of suicidal events and the meta analysis where the

data was combined across studies. I think that—if I were doing or

if I had a chance to do the presentation, that is what I would have

included.

Mr. WALDEN. So the way you would have presented it would

have painted a much more serious situation to that Advisory Committee than the way it was painted, when it comes to the risk of

suicidality in adolescents and children? Is that accurate?

Mr. MOSHOLDER. I guess we will never know what the Advisory

Committee might have made of——

Mr. WALDEN. No, no, no. The difference in the two presentations.

Mr. MOSHOLDER. I think, if I had been doing it, it would have

perhaps been more obvious.

Mr. WALDEN. The chairman at the outset of this hearing thanked

you on behalf of the committee for your work, and I think our country feels the same way. I know you have been honored many ways.

Somebody told me you had been selected, too, to be the ABC Person of the Week. Is there any truth to that?

Mr. MOSHOLDER. I was told that I was nominated, but I did not

run.

Mr. WALDEN. Well, there is always next week, I guess.

All right. We are going to add, without objection, this newspaper

article from the British Medical Journal, August 7, 2004, to the

record. Without objection, so ordered.

[The newspaper article follows:]

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63

Mr. WALDEN. Do you have further questions? We have been

called to votes on the House floor, and it would—Mr. Stupak, do

you have anymore questions for this witness at this time?

Mr. STUPAK. No. I just thank Dr. Mosholder for being here.

Mr. WALDEN. Thank you. And, Dr. Mosholder, we would like you

to stay with us, even though we probably won’t have you on the

next panel. We would like to have you available, should there be

some questions that we need to seek your expert advice on. So if

you could stay with us.

We are going to recess the committee until after these votes.

There are four of them, which probably tells me it will be 45 minutes before we are back here. So it is a good time for everyone to

go grab a quick bite, and we will reconvene the committee immediately after those votes have concluded.

The committee is in recess.

[Brief recess.]

Mr. WALDEN. I am going to call this hearing back to order and

ask our next panel of witnesses to come up: Dr. Robert Temple,

Food and Drug Administration; Dr. Paul Seligman, Food and Drug

Administration; Dr. Thomas Laughren, Food and Drug Administration; Dr. Tarek Hammad, Food and Drug Administration; and Dr.

James Knudsen, Food and Drug Administration. Please come up to

the witness table, if you would.

You are aware the committee is holding an investigative hearing

and, when doing so, has the practice of taking testimony under

oath. Do you have any objection to testifying under oath? Do any

of you have an objection?

Let the record show they all indicated they have no objection.

The Chair then advises you that, under the rules of the House

and the rules of the committee, you are entitled to be advised by

counsel. Do you desire to be advised by counsel during your testimony today? Mr. Knudsen? Could you turn on your mike, sir, and

then we will need you to identify your counsel. Dr. Knudsen.

Mr. KNUDSEN. My name is Dr. James Knudsen.

Mr. WALDEN. Okay. Yes, you actually have to get kind of close

to that. Sorry. If you could identify for the record, Dr. Knudsen,

your counsel, please.

Mr. KNUDSEN. My counsel?

Mr. WALDEN. Oh, I thought you said you wanted to be represented by counsel.

Mr. KNUDSEN. No, I did not.

Mr. WALDEN. Okay, fine. No? Okay. Dr. Temple? Dr. Laughren?

Mr. LAUGHREN. No, sir.

Mr. WALDEN. Dr. Seligman?

Mr. SELIGMAN. No.

Mr. WALDEN. Okay. So let the record show, none of them is being

represented by counsel.

In that case then, would you please rise and raise your right

hand, and we will take your testimony under oath. Let the record

show, they all indicated yes.

[Witnesses sworn.]

Mr. WALDEN. Thank you. You may be seated.

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You are now under oath, and you may now give a 5-minute summary of your written statement, and we will start with Dr. Knudsen.

Mr. WALDEN. Dr. Hammad? No opening statement. Dr. Temple?

Actually, I am not sure your mike is on yet.

Mr. TEMPLE. Now?

Mr. WALDEN. There it is, sir, yes. Thank you, and welcome.

TESTIMONY OF JAMES KNUDSEN, FOOD AND DRUG ADMINISTRATION; ACCOMPANIED BY ROBERT TEMPLE, FOOD AND

DRUG ADMINISTRATION; PAUL SELIGMAN, FOOD AND DRUG

ADMINISTRATION; THOMAS LAUGHREN, FOOD AND DRUG

ADMINISTRATION; AND TAREK HAMMAD, FOOD AND DRUG

ADMINISTRATION

Mr. TEMPLE. Mr. Co-Chairman, I guess, and members of the

committee, I am Robert Temple, CDER’s Associate Director for

Medical Policy. I welcome the opportunity to participate in this

hearing on FDA’s regulation of pediatric uses of anti-depressants.

My colleagues and I recognize that the entire discussion of the

past year has been very painful and difficult for people—both for

people whose loved ones have committed suicide while on an antidepressant and for people whose family members are seriously depressed and are uncertain as to what they can do for them.

Today I will briefly review the importance of detecting and treating depression in children, the available treatments and recent efforts to encourage studies of drugs in children, the history of the

concern, the subject of this hearing, about the possibility that antidepressants might provoke suicidal thinking or behavior, and

FDA’s evaluation and data—of the data from the pediatric depression studies.

Throughout my testimony and later, I will want to emphasize an

important concern that we had from the beginning of this. We were

concerned that overemphasis or premature conclusion about an increased risk of suicidality related to anti-depressant use could discourage treatment of serious pediatric depression, which is a potentially life threatening condition.

At the same time, failure to take adequate note of the risk could

lead to inattention to the possibility for emerging suicidality or to

too casual use of the anti-depressants.

We dealt with this concern by making the public fully aware of

the issue and of the data that led to our concern, but we thought

it was responsible to withhold an agency conclusion about what the

data showed until it had been fully evaluated.

Depression in children is a serious mental illness that affects up

to 2.5 percent of children and 8 percent of teenagers. In the U.S.

there are about 1600 suicides in teenagers per year, many of them

in people who are diagnosed as having depression.

The difficulty of obtaining good data on the effectiveness and

safety in drugs in children is well recognized. A provision of the

Food and Drug Administration Modernization Act which was renewed in the Best Pharmaceuticals for Children Act in 2002 provides 6 months of patent extension to sponsors who carry out pediatric studies that have been requested by the FDA.

65

This provision has enormously stimulated the conduct of these

studies, and it was FDA’s analysis of the depression studies submitted under these laws that led to the question of whether the

drugs could cause suicidality in children.

Specifically, review by Dr. Mosholder of adverse effects collected

under the term emotional lability in five Paxil studies that were

submitted under the Act detected an excess of such cases, some of

which appeared to represent suicidal thinking or behavior in patients.

I can’t emphasize too strongly that, although as you will hear

there were some disagreements on our part with some of Dr.

Mosholder’s conclusions or whether they were right, this discovery,

this observation was of immense value and has kicked this whole

thing off. So let there be no question about whether that was an

important observation.

A request for a more focused analysis of the Paxil suicidality

data led to a further suggestion of an increased rate of suicidality

in the Paxil treated patients, and this was more credible because

the analysis was better than their initial one.

FDA issued a Public Health Advisory on June 19, 2003, describing the results of the Paxil evaluation and stating that, although

FDA had not completed its evaluation, we recommended that Paxil

not be used in children and adolescents to treat major depressive

disorder.

Subsequently, the Review Division asked all manufacturers of

newer anti-depressants for an analysis that was similar to what

GlaxoSmithKline had done for Paxil, and this was provided by late

September 2003. These reports were sent to Dr. Mosholder and

were also considered by the Review Division.

On October 27, 2003, FDA issued an updated Public Health Advisory, again noting the suggestion of excess suicidality in anti-depressant treated patients and the need for further data and analysis.

The Review Division had been examining the data submitted by

the sponsors, too, as had Dr. Mosholder, and had significant concerns about it. It, therefore, began in September-October 2003 to

make arrangements to have the reported suicidality events reviewed and reclassified by the Columbia Department of Psychiatry.

Our concern was that the companies had cast a wide net in seeking cases of suicidality, of suicidal thinking or instances of selfharm, but not all such cases—for example, a superficial cutting—

represent attempted suicide.

I also want to say that I am somewhat embarrassed about my

BMJ quote from before, because at least by the time that came out,

I was well aware that Dr. Mosholder had excluded cases like that.

I think that reflected an earlier conversation. So there is no question that he did exclude many such things, and the banging of the

head. So I feel bad about that. However, remained concerned that

the cases themselves needed close evaluation, and I can talk later

about how those data were collected and why we thought they

needed that.

Given our conclusion that they needed to be looked at closely, we

concluded that a blind expert classification of the cases was needed.

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In addition, we sent the Columbia reviewers narrative descriptions of additional adverse reaction cases that had not been included by the companies, because we thought there might be excess—might be cases of suicidal behavior or thinking in there, and

that proved to be correct.

It is worth emphasizing that we had no idea what the results of

the reclassification would be. We didn’t know whether it would

strengthen the findings or weaken the findings. We had no way of

knowing and no expectation, and not to state the obvious, no preference. We just wanted to get at what the right answer was.

At a February 2, 2004, Advisory Committee meeting we presented the results of the company submissions, as you have heard

before, study by study, in part to make the point that the results

were very variable from one study to another, and from one drug

to another. But many of the drugs clearly showed an increased risk

of suicidality. That’s the sum of suicidal behavior and suicidal

thinking.

We noted to the committee our concerns with the data submissions and explained why we considered additional review by Columbia necessary.

We also acknowledged that some in the agency thought the results were, in fact, definitive and could be a basis for change in labeling to discourage use of the drug, except for Prozac, in children.

Although no specific question was put about this to the committee, discussion indicated that they clearly understood the agency’s reservations, and they in fact expressed doubt that anything

arising from this kind of data collection would be useful, a conclusion that they modified at the most recent Advisory Committee.

The Advisory Committee recognized that, whatever the relationship of anti-depressants to suicidality, it was perfectly clear even

then that the period after initiation of treatment for depression

was of great concern and that physicians needed to be warned

about this, the need to be careful and make close observations.

On March 22, we asked manufacturers of anti-depressants to add

warning language to their labeling and issued a third Public

Health Advisory describing our request. The new warning emphasized the critical importance of observing newly treated patients for

emerging suicidality or other problems.

All manufacturers added this warning to their labeling by late

summer. We have no received the reclassified cases from Columbia

and analyzed the data.

The analysis by Dr. Hammad was presented to the Advisory

Committee on September 13, 2004. The analysis included the study

you have heard about, the TAD study, a new study of Prozac carried out by the National Institutes of Mental Health.

The analysis showed that, as a group, the anti-depressants studied, both SSRIs and the so called atypicals, increased the risk of

suicidality. There was variation from drug to drug and variation

from study to study, but the roughly twofold increased risk was

reasonably consistent across drugs. As has been pointed out, there

were no actual suicides in these trials.

At the September 13-14 Advisory Committee meeting, the combined Pediatric and Psychopharm Drugs Advisory Committees

agreed with FDA’s conclusions that the data in aggregate indicated

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an increased risk of suicidality in pediatric patients, and made several critical recommendations.

First, they believed the conclusion should apply to all of the studied drugs, even though it was more prominent in some than others.

They also strongly urged that we apply it to any new anti-depressant and to the older anti-depressants, including the tricyclics.

They thought that partly because the logic seemed to be that this

is a property of anti-depressants, and they were quite concerned

that people would be driven to the tricyclics, which are rather more

dangerous.

They did not believe the anti-depressants, other than

fluoxetine,should be contraindicated in children, and repeatedly expressed concern that these drugs may be valuable even if that has

not been shown, and they were quite aware that it had not yet

been shown.

They strongly supported a patient and family directed Med

Guide which we had suggested to them, and two-thirds of them

thought the new warning information should be boxed.

On September 17 we announced publicly that we generally support the recommendations and had begun working on new labeling

to reflect that. The term generally applies only to the thought that

we are going to read closely what they said collectively about the

boxed warning, and think about it.

Obviously, two-thirds of them thought that was reasonable, but

the discussion indicated concern that over-discouraging use was potentially very dangerous, too, and they wanted a balance. So we are

going to be thinking about that.

I appreciate the opportunity to present these remarks, and I look

forward to your questions.

I am aware that you have also invited Dr. Russell Katz to appear

here this morning. Unfortunately, he is not able to attend because

a member of his family is having surgery today. He will be happy

to answer any questions you have for him in writing or speak with

your staff at a later date. Thank you.

Mr. WALDEN. We appreciate that, Dr. Temple. We were aware of

that, obviously, too, and did not want to interfere in his very difficult time.

[The prepared statement of Robert Temple follows:]

PREPARED STATEMENT OF ROBERT TEMPLE, DIRECTOR, OFFICE OF MEDICAL POLICY,

CENTER FOR DRUG EVALUATION AND RESEARCH, U.S. FOOD AND DRUG ADMINISTRATION

INTRODUCTION

Mr. Chairman and Members of the Subcommittee, I am Dr. Robert Temple, Director, Office of Medical Policy for the Center for Drug Evaluation and Research

(CDER) at the U.S. Food and Drug Administration (FDA or the Agency). We appreciate the opportunity to discuss FDA’s review of the safety and efficacy concerns in

anti-depressant drugs for use in pediatric populations.

BACKGROUND ON DEPRESSION

Depression is a serious mental illness that affects the way nearly 19 million adult

Americans feel, think, and interact. While everyone experiences occasional sadness,

particularly in response to loss or adversity, a person with depression has persistent

symptoms that can significantly interfere with their ability to function. People with

depression cannot merely ‘‘pull themselves together’’ and get better. Depression cannot be willed or wished away.

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The two most severe types of clinical depression are major depressive disorder

(MDD) and bipolar depression, which is the depressed phase of bipolar disorder.

Within these types, patients experience variations in the severity and persistence

of mental symptoms associated with these disorders. A person experiencing MDD

suffers from, among other symptoms, a depressed mood or loss of interest in normal

activities that lasts most of the day and nearly every day, for at least two weeks.

Such episodes may occur only once, but more commonly occur several times in a lifetime. People with bipolar disorder cycle between episodes of major depression, similar to those seen in MDD, and highs known as mania. In a manic phase, a person

might act on delusional grand schemes that could range from unwise business decisions to romantic sprees. Both MDD and bipolar disorder can lead to suicide. The

treatment of the two conditions is quite different. In general, anti-depressants alone

are not an appropriate treatment for bipolar disorder.

DEPRESSION IN THE PEDIATRIC/ADOLESCENT POPULATION

According to a 2000 National Institute of Mental Health (NIMH) Fact Sheet on

Depression in Children and Adolescents, depression affects up to 2.5 percent of children and about eight percent of adolescents in the United States. These disorders

often go unrecognized by families and physicians because behaviors associated with

depressive disorders may be seen as normal mood swings typical of a particular developmental stage. In addition, health care providers may be reluctant to prematurely ‘‘label’’ a young person with a mental illness diagnosis.

At the February 2, 2004, meeting of FDA’s Psychopharmacologic Drugs Advisory

Committee (PDAC), Dr. Cynthia Pfeffer of Cornell University addressed the issue

of pediatric depression and its treatment. She noted that pediatric depression is

very common and often recurrent, is often accompanied by very poor psychosocial

outcomes for children and adolescents, and is associated with high risk for suicide

and substance abuse. She reported that in 2001, about 1,600 15 to 19-year-olds committed suicide in the U.S. Suicide is the third leading cause of death in the U.S.

in this age group and accounts for more deaths in this age group than all other

major physical conditions combined.

At that meeting, Dr. David Shaffer of Colombia University reported on rates of

suicidal ideation (thinking about suicide) and suicide attempts. He obtained his information from large community studies, particularly the Youth Risk Behavior

Study (YRBS), a study carried out by the National Center for Health Statistics. In

this study, officials from the National Center interviewed a broad population of between 15,000 and 20,000 high school students every two years using self-reporting

measures. Based on this data, it was determined that suicidal ideation in high

school students is extraordinarily common. Almost 20 percent of American high

school students think about suicide. Suicide attempts are also very common. Experts

report that the overall rate is about nine percent. Only about a quarter of these attempts are brought to medical attention. It is widely recognized that adolescents are

frequently reluctant to disclose suicidal thoughts or even suicide attempts to parents

or others. There are about 4,000 female suicide attempts for every female suicide

death, and about 400 male attempts for every male death.

Dr. Shaffer also showed rates of pediatric suicide over several decades. The rate

has fallen by about 25 percent over the last decade, the period in which the use of

anti-depressants has grown steadily. This association does not prove that the increasing use of anti-depressants is the cause of the decline in suicide, but it is at

least suggestive.

DRUGS FOR TREATING DEPRESSION

Existing anti-depressant drugs influence the levels of one or both of two

neurotransmitters in the brain: serotonin and norepinephrine. Older medications—

tricyclic anti-depressants (TCAs) and monoamine oxidase inhibitors (MAOs)—affect

the activity of both of these neurotransmitters. The disadvantage of the older medications is that they can be difficult to tolerate due to significant side effects. MAO

use may also be subject to dietary and medication restrictions. TCAs and MAOs are

of limited value in the pediatric population because of serious, potentially lifethreatening adverse events. These include tachycardia, convulsions, and shock-like

coma. Moreover, TCAs are a potential tool for adolescents attempting to commit suicide because overdose can cause serious and protracted cardiac arrhythmias.

Newer medications, such as the selective serotonin reuptake inhibitors (SSRIs),

have fewer side effects than the older drugs, making it easier for people to continue

treatment. They have become very widely used to treat depression, especially in the

pediatric population. FDA approved Prozac, the first SSRI, for adults, in December

1987, and for children in January 2003. Experts believe that SSRI drug products

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work by increasing the level of the hormone serotonin in the brain. There were no

approved drugs for the treatment of depression in children before the January 2003

Prozac approval.

ANTI-DEPRESSANT TREATMENT AND SUICIDALITY

Suicidality in the context of treating patients with depression and other psychiatric illnesses has been a genuine concern and a longstanding topic of debate. In

fact, for many decades, anti-depressant labeling carried the following standard language under the ‘‘Precautions’’ section of the label alerting clinicians to the need to

closely monitor patients during initial drug therapy due to concern for the possible

emergence of suicidality:

Suicide: The possibility of a suicide attempt is inherent in major depressive

disorder and may persist until significant remission occurs. Close supervision

of high-risk patients should accompany initial drug therapy. Prescriptions for

[name of drug] should be written for the smallest quantity of tablets consistent

with good patient management, in order to reduce the risk of overdose.

This standard precaution statement did not explicitly warn of the possibility that

anti-depressant drug products have a causal role in the emergence of suicidality

early in treatment. Several mechanisms have been proposed to explain the clinical

observation that some depressed patients being treated with anti-depressants, particularly early in treatment, have an increase in suicidality. In September 1991,

FDA convened a meeting of the PDAC to discuss this issue. At that meeting, Dr.

Martin Teicher, a psychiatrist from Harvard Medical School, proposed various mechanisms to explain the emergence of suicidality early in treatment of depression:

• Roll back phenomenon: anti-depressants with prominent energizing effects might

actually increase suicidal behavior in severely depressed patients who are suicidal but also have psychomotor retardation and are thus inhibited from acting

on their suicidal thoughts. • Paradoxical worsening of depression: in rare cases, the patient’s depressed mood

might actually worsen as a result of anti-depressant treatment. • Akathisia (inability to sit still): some anti-depressants are associated with

akathisia, which might lead to suicidal behavior in certain depressed patients. • Induction of anxiety and panic attacks: some anti-depressants may induce anxiety

and panic attacks, and these might lead to suicidal behavior in certain depressed patients. • Stage shifts: anti-depressants may lead to switching the patient from depression

into mixed states in bipolar depressed patients, possibly leading to suicidality. • Insomnia: insomnia associated with certain anti-depressants might lead to suicidal behavior in certain depressed patients.

While all of these theories have some plausibility, it is difficult to know whether

these mechanisms are real. In addition, proposing a mechanism is quite different

from actually demonstrating that there is a causal association between anti-depressant use and suicidality. It might be possible to demonstrate that anti-depressants

cause an increase in suicidality through randomized clinical trials, but these trials

would need to be quite large because suicidality is not common. It might be possible

to pool results of many trials, but if this involves results from studies of different

drugs, the question remains whether some drugs could behave differently from others. Furthermore, assessing this risk in uncontrolled data is particularly difficult because depression itself causes suicidality. In any given case, one cannot usually distinguish whether the suicidality occurred because of the drug or despite it.

ANTI-DEPRESSANT-INDUCED SUICIDALITY IN ADULTS

Thus, the question of whether anti-depressants can provoke suicidality has been

the subject of considerable discussion. With regard to the adult population, the debate intensified in 1990 when Dr. Teicher and several colleagues published a paper

describing six adult patients with depression who, in their view, became suicidal because of treatment with Prozac. This paper and subsequent discussions led Eli Lilly,

the manufacturer of Prozac, to conduct new analyses of data from their controlled

trials for Prozac to look for suicidality. These events also led FDA to fully re-evaluate its spontaneous reports database to determine whether we could observe a signal of increased risk.

During a September 1991 PDAC meeting, family members raised concerns about

suicide by loved ones whose deaths they attributed to Prozac. Representatives from

FDA, NIMH and Lilly also gave presentations. FDA gave an update on the very

substantial number of spontaneous reports of suicidality in association with Prozac

use, but also noted the marked increase in reporting following the publication of the

Teicher paper and the publicity about the paper. A representative from NIMH gave

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their perspective on the issue, essentially making the case that depression is a serious disorder that itself is associated with suicidality, and arguing that the data

available to date did not support the view that anti-depressants further increase the

risks of suicidality in this population. Finally, Lilly presented the results of its analysis of data pooled over its extensive clinical trials, revealing no signal of increased

suicidality in association with the use of Prozac. Following these presentations, a

majority of the Advisory Committee members concluded that there was no clear evidence of an increased risk of suicidality in association with Prozac, and did not recommend any changes to Prozac labeling.

Over the next several years, researchers accumulated additional data as new antidepressant drugs came to market. All of these additional data related to the treatment of adults. In recent years, several groups have conducted pooled analyses of

data on completed or attempted suicides from these studies in an effort to identify

a possible signal of risk from active treatment. They have also searched for risk signals from patients assigned to a placebo group, since some have challenged the use

of placebo controls in a disease with potentially serious outcomes. Arif Khan, a psychiatrist from the Northwest Clinical Research Center, and other researchers published a paper in 2000 based on adult data obtained from FDA reviews. Dr. Khan

concluded that the risk of completed suicide was the same, regardless of treatment

assignment. A similar study reached the same conclusion. FDA researchers also

analyzed completed suicides in 234 randomized controlled depression trials of 20

anti-depressant drug products. Based on all our analyses to date of these data, we

reached a similar conclusion: there does not appear to be an increased risk of completed suicide associated with assignment to either active drug or placebo in adults

with MDD.

ANTI-DEPRESSANTS AND SUICIDALITY IN PEDIATRIC PATIENTS

Whether anti-depressant drug use causes suicidal thinking or behavior in pediatric patients (or adults) is a critically important question that we must answer in

a careful, thoughtful manner. A premature conclusion or emphasis in either direction could have adverse consequences for those who are suffering from depression.

Missing or understating a signal of increased risk of suicidality could result in

greater reassurance than is warranted about the safety of these drugs, insufficient

attention to the patients being treated, and perhaps too casual use of the drugs. On

the other hand, overstating the risk could result in overly conservative use of these

drugs or excluding their use for the pediatric population, and inadequate treatment

of a potentially fatal condition. Below we discuss the origins of the concern that

anti-depressants could provoke suicidal ideation in children.

USE OF ANTI-DEPRESSANTS IN THE PEDIATRIC POPULATION

Many people have expressed concern about pediatric use of products approved for

MDD in adults where clinical trials in children were negative. Prozac is the only

product for which efficacy has been established sufficiently to meet FDA’s standards

for approval in the pediatric population. To date, clinical trials evaluating six other

current generation anti-depressants approved for adults have not met FDA’s standards for establishing efficacy in the child/adolescent population. Nevertheless, there

is widespread belief among treating physicians that these products do in fact work

and that the ‘‘negative’’ results are in fact inconclusive. Negative trials are not necessarily informative in MDD trials because they may be an indication of inadequate

trials rather than evidence of benefit.

Because Prozac is the only product for which efficacy has been establish for treatment of pediatric/adolescent MDD, it is often the first product prescribed by a physician. However, in 30-40 percent of cases, Prozac does not work for the patient. In

such cases, it is standard care for physicians to prescribe one of the other current

generation anti-depressants approved for adults. The older medications, tricyclic

anti-depressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have not been

approved for use in pediatric/adolescent population. Moreover, as noted previously,

they are of limited value in the pediatric population because of serious, potentially

life-threatening adverse events. They may cause life-threatening arrhythmias in

overdose or even at normal doses in individuals who are unable to efficiently metabolize these drugs.

FDAMA AND BPCA STIMULATE NEW PEDIATRIC SUICIDALITY DATA

The question of suicidality arose in the course of FDA’s review of clinical trials

of anti-depressants in children. When Congress enacted the FDA Modernization Act

(FDAMA) in 1997, it provided incentives to manufacturers to conduct pediatric clinical trials. Section 111 of FDAMA authorized FDA to grant additional marketing exVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00078 Fmt 6633 Sfmt 6621 96099.TXT HCOM1 PsN: HCOM1
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clusivity (known as pediatric exclusivity) to pharmaceutical manufacturers that conduct studies of their drugs in pediatric populations. To qualify for pediatric exclusivity, sponsors must conduct pediatric studies according to the terms of a Written

Request from FDA and submit the results of those studies in a new drug application

or supplement. Congress renewed this authority in 2002, in the Best Pharmaceuticals for Children Act (BPCA).

BPCA contains important, new disclosure requirements. For studies other than

those submitted under the BPCA, the Agency generally may not publicly disclose

information contained in investigational new drug applications, unapproved new

drug applications, or unapproved supplemental new drug applications. Only after a

new drug application or supplemental new drug application is approved can the

Agency make public certain summary information regarding the safety and effectiveness of the product for the approved indication. However, section 9 of BPCA regarding the dissemination of pediatric information gives the Agency additional disclosure authority and differs from FDA regulations that generally preclude the

Agency from disclosing to the public information in an unapproved application.

BPCA requires that, no later than 180 days after the submission of studies conducted in response to a Written Request, the Agency must publish a summary of

FDA’s medical and clinical pharmacology reviews of those studies. Moreover, we

must publish this information regardless of whether the action taken on the pediatric application is an approval, approvable, or not-approvable action. Thus, although under FDAMA information on pediatric studies conducted in response to

Written Requests is not available until after the supplemental application is approved, under BPCA, a summary of FDA’s medical and clinical pharmacology reviews of pediatric studies, conducted in response to a Written Request issued under

BPCA, is publicly available irrespective of the action taken on the application.

BPCA WRITTEN REQUESTS FOR ANTI-DEPRESSANTS

Prior to the enactment of BPCA, under the pediatric exclusivity authority of

FDAMA, FDA issued seven Written Requests to manufacturers of drugs approved

for the treatment of depression (Prozac, Zoloft, Remeron, Paxil, Celexa, Serzone, and

Effexor). The sponsors of three of these drugs (Prozac, Zoloft, and Remeron) performed the studies and submitted the reports of their studies before FDAMA expired on January 1, 2002 (and thus, before BPCA took effect). The manufacturers

of two of these drugs, Prozac (which has been approved for the treatment of pediatric depression) and Zoloft (which was studied but not approved for the treatment

of pediatric depression) received pediatric exclusivity for having conducted studies.

The third sponsor, the manufacturer of Remeron, did not receive pediatric exclusivity. Under FDA’s general disclosure provisions regarding the availability of data

and information in approved applications, information on the approved pediatric use

of Prozac is publicly available at: http://www.fda.gov/cder/foi/nda/2003/18936s

064lProzac.htm. Just as it has for other product approvals, FDA posted this information because we granted approval for Prozac for use in treating pediatric depression. The pediatric data for Zoloft and Remeron would not normally be available for

public disclosure because their pediatric supplements have not yet been approved.

However, FDA nonetheless asked the sponsors to allow us to make summaries of

these studies public. The sponsors agreed to our request and summaries are now

available on FDA’s website at: http://www.fda.gov/cder/pediatric/Summary

review.htm.

Following enactment of BPCA in January 2002, FDA determined that the provisions of this new law should apply as broadly as possible to outstanding Written

Requests for which studies had not yet been submitted. In a July 2002 letter, the

Agency notified drug sponsors with outstanding Written Requests issued under

FDAMA that FDA considered those Written Requests to be reissued under BPCA.

In its July 2002 letter, FDA further advised manufacturers that any studies submitted in response to the reissued Written Requests would be subject to the terms

of the BPCA, including, among other things, the provisions governing public availability of study summaries. However, the Written Requests for three anti-depressants (Paxil, Celexa, and Serzone) were not considered as reissued under BPCA in

July 2002 because the manufacturers had already submitted their pediatric studies

to the Agency before FDA issued its July 2002 letter (albeit after BPCA was enacted). Therefore, FDA considered the studies for Paxil, Celexa, and Serzone, to

have been submitted under FDAMA; did not consider their Written Requests to be

reissued, and did not apply the public disclosure provisions of BPCA to these studies. Nonetheless, the Agency has received permission from the sponsors of these

drugs to post summaries of the safety and effectiveness reviews of their pediatric

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studies on FDA’s website, and this information appears at: http://www.fda.gov/cder/

pediatric/Summaryreview.htm.

Only one of the outstanding and reissued Written Requests under BPCA was for

studies relating to the treatment of pediatric depression. This Written Request was

for Effexor. FDA granted pediatric exclusivity for this product and posted the study

summaries on the FDA Pediatric Summary Review website, according to the requirements of BPCA. No new Written Requests for anti-depressants have been

issued since the passage of the BPCA.

We want to emphasize that although these anti-depressants have all been shown

to be effective in adults, in its Written Requests FDA asked manufacturers to conduct two pediatric studies because we knew from experience that it is very difficult

to show the effectiveness of anti-depressants in children. In all studies submitted

in response to Written Requests, no completed suicides occurred in the trials. Nonetheless, FDA reviewers of these Written Requests identified a suicidality concern

during the course of their review.

RESULTS OF THE PAXIL WRITTEN REQUEST

FDA has been reviewing the results of anti-depressant studies in children since

June 2003 after an initial report on studies with paroxetine (tradename, Paxil) appeared to suggest an increased risk of suicidal thoughts and actions in the children

given Paxil, compared to those given placebo. During the review of the supplemental

new drug application submitted by GlaxoSmithKline (GSK) for the use of Paxil in

children, FDA reviewers noted a greater number of adverse events coded under the

term ‘‘emotional lability’’ in patients treated with Paxil compared to the placebo

group. FDA reviewers in the Division of Neuropharmacological Drug Products

(DNDP) of FDA’s CDER noted this in some, but not all, of the Paxil studies. The

reviewers also noted that the actual events coded under this term included suicidal

thoughts and attempts as well as a wide range of other events.

In an effort to better understand these events and to focus on suicidal thoughts

or behavior, DNDP asked the sponsor to reanalyze its data and better characterize

the adverse events identified under the term ‘‘emotional lability.’’ This FDA request

resulted in additional work by GSK and a report on suicidality, submitted first to

the UK (UK), and, shortly thereafter, to FDA.

GSK APPROACH TO ACCUMULATING PAXIL SUMMARY DATA

GSK’s re-analysis of the Paxil data focused exclusively on placebo-controlled trials

(of which there were six). This has been FDA’s focus as well. As noted earlier, in

their original pediatric supplement, GSK classified adverse events suggestive of

suicidality (as well as various other behavioral events) under the general term ‘‘emotional lability.’’ In response to our request for a separate approach to better identify

events that suggested suicidality, GSK conducted searches to find events of potential interest. GSK’s adverse event data was in an electronic file that allowed them

to search for text strings that suggested suicidality, e.g. ‘‘overdose,’’ ‘‘suic,’’ ‘‘hung,’’

‘‘cut,’’ etc. The company conducted a blind evaluation of all events detected by this

text search to select those considered possibly suicide-related. A subset of these

events that could represent self-harm was then classified by GSK as suicide attempts. GSK’s examination of events was limited to those occurring within 30 days

of the patient’s last dose.

GSK submitted its report to FDA on May 22, 2003. This report suggested an increased risk (Paxil vs. placebo) of various thoughts and behaviors coded as events

considered ‘‘possibly suicide related.’’ In addition, there was a suggestion of increased risk for the subgroup of events that met the sponsor’s criteria for ‘‘suicide

attempts.’’ The signal for increased risk was clearest in 1 of the 3 trials involving

pediatric patients with MDD.

It is important to note that these analyses were difficult because investigators

used a large variety of terms to describe what might have been suicidal behavior

and provided variable amounts of detail when identifying these events. The standard assessments of depression used to evaluate effectiveness all had an item indicating suicidal thoughts, and an evaluation of these scales showed no increased

suicidality compared to placebo. However, the trials were not designed to focus on

the question of suicide risk with drug treatment. To address this concern, we plan

to develop guidance for subsequent trials that will lead to a standard nomenclature

and assessment by investigators.

INITIAL RESPONSE TO SIGNAL OF INCREASED RISK OF SUICIDALITY FOR PAXIL

The reaction to the GSK report by the Medicines and Healthcare Regulatory

Agency (MHRA) in the UK was to issue a public statement explicitly stating that

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Paxil ‘‘should not be used in children and adolescents under the age of 18 years to

treat depressive illness,’’ and to institute a labeling change contraindicating Paxil

in pediatric MDD.

On June 6, 2003, Dr. Russell Katz, the director of DNDP, asked the Office of Drug

Safety (ODS) to perform a consult review of the newly submitted GSK safety data.

Dr. Katz requested that ODS assign Dr. Andrew Mosholder as the primary reviewer for the consult because Dr. Mosholder had previously been involved in reviewing data on the safety and efficacy of anti-depressants and had generated the

original request to GSK. On June 19, 2003, FDA issued a public health advisory

stating that: ‘‘Although FDA has not completed its evaluation of the new safety

data, FDA is recommending that Paxil not be used in children and adolescents for

the treatment of [major depressive disorder].’’

FDA also requested data similar to that submitted by GSK from the manufacturers of eight other anti-depressant drugs that were studied in children. On July 22,

2003, the Agency sent requests for data to the manufacturers of the following drugs:

Prozac, Zoloft, Luvox, Celexa, Wellbutrin, Effexor, Serzone, and Remeron. In those

letters, we asked manufacturers to identify suicide-related events for their pediatric

studies in a blinded manner using two search strategies. We modeled our request

to these manufacturers on the approach used by GSK, and asked manufacturers to

conduct an electronic search for text strings relevant to suicidality similar to the approach employed for Paxil. We also asked manufacturers to blindly search narrative

summaries for any serious adverse events to identify additional instances of ‘‘suicide-related events.’’

FDA RE-REVIEW OF DATA FROM PEDIATRIC SUPPLEMENTS FOR OTHER ANTI- DEPRESSANTS

While waiting for the various manufacturers of anti-depressants other than Paxil

to respond, we went back to the adverse event data in the pediatric supplements

for the other eight drugs to re-examine the question of suicidality. Our major question was whether there were other anti-depressants with possible signals of increased risk for suicidality, as was observed for Paxil.

There were several limitations to this re-examination. First, the methods for detecting and coding events were not standard across these studies. Second, because

we wanted to have categories similar to those used for the Paxil data for purposes

of comparison across drug programs, we classified events described in the adverse

event listings for these drug programs into two categories: ‘‘possibly suicide-related’’

and ‘‘suicide attempt.’’ One obvious flaw in this approach was that FDA’s reviewer

was not blinded during this reclassification process. Nevertheless, we believed this

re-examination of summary data might shed some light on the possibility of signals

emerging from other anti-depressant programs. We discovered that there were signals of increased risk of suicidality for patients assigned to drugs other than Paxil.

We also found that the findings were not consistent across the studies, even for individual drugs.

AUGUST 2003 EFFEXOR LABELING CHANGE AND FDA’S RESPONSE

While we were beginning to receive responses to our requests for summary data

from the sponsors for the other anti-depressants, Wyeth Pharmaceuticals, the manufacturer of Effexor and Effexor XR, decided to make labeling changes for its products to address reports of suicidality and hostility. Sponsors have the authority to

make changes to strengthen labeling to address safety issues without prior FDA approval. This action was based on the company’s re-analyses of data from the Effexor

pediatric trials. The labeling change was the addition of a statement to the ‘‘Usage

in Children/Pediatric Use’’ section in the ‘‘Precautions’’ section of the label to note

increased reports of hostility and suicidality. This labeling change was accompanied

by an August 22, 2003, ‘‘Dear Health Care Professional’’ letter noting the findings

and noting that these products are not recommended for use in pediatric patients.

In September 2003, the UK MHRA issued a regulatory response on Effexor similar to its response to the report on Paxil suicidality data. It issued a public statement advising prescribers against the use of Effexor for the treatment of pediatric

MDD. This statement was accompanied by a labeling change to contraindicate the

products for that pediatric indication. FDA did not take any specific regulatory action on Effexor because we viewed the data as preliminary. Like data for other antidepressant drug products, it required a more detailed review.

SEPTEMBER 2003 FDA INTERNAL REGULATORY BRIEFING

An important milestone in our consideration of the pediatric suicidality data was

the September 16, 2003, internal briefing for upper level CDER management. This

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briefing occurred at a time when we only had a preliminary review of the summary

data for Paxil and a crude internal re-analysis of suicidality data from the other pediatric supplements. We had not yet received and reviewed the requested new analyses from all the sponsors of pediatric drugs.

There were several agreements reached at this meeting, including two that were

of particular importance for our further plans to address this issue. We recognized

that we had cast a very broad net to attempt to capture events of potential interest

for possible suicidality. This was appropriate, but it meant that individual cases

needed closer examination to determine what they actually represented. Our first

conclusion was that it would be useful to try to have all events of potential interest

blindly reclassified by outside experts in suicidality in order to have greater confidence in what the signals represented. This conclusion eventually led to the Columbia Classification Project, described in greater detail below. Second, because it

was apparent that there was inconsistency in the signals of suicidality among the

individual studies of the various drugs, we also concluded that it would be useful

to attempt to obtain patient-level data sets for all of these trials. This would permit

analyses that are more refined and allow adjustments for potentially important covariates. These agreements strongly influenced the subsequent course of our efforts

to better understand these data.

RESPONSES TO FDA’S REQUEST FOR SUMMARY DATA FOR OTHER ANTI-DEPRESSANTS

The responses to FDA’s request for summary data for all of the anti-depressants

arrived by late September 2003. These responses were received within DNDP and

forwarded to Dr. Mosholder in ODS as they arrived, over roughly a six-week period.

Unfortunately, as we began reviewing these responses, it became clear that different

sponsors had interpreted the July 22, 2003, request differently. This caused us to

doubt whether all eight manufacturers used similar approaches in selecting,

classifying, and presenting cases of suicidality for review. There was also a concern,

due to the methods used by the manufacturers to search their database, about the

possibility that manufacturers had not captured all adverse events of potential interest.

This impression was confirmed when we spoke to individual manufacturers about

their approach to our request. In retrospect, the algorithm we had provided to

search for potential events and select patients experiencing those events was not

sufficiently detailed to result in a common understanding. This discovery presented

a major hurdle in our evaluation of these data, because we needed to have confidence in the thoroughness and uniformity of the methods used to gather and classify these cases. We realized that we would need to be more certain that manufacturers captured all relevant cases, and that the relevant cases were appropriately

classified.

Greater certainty on this point was necessary to accurately assess the ability of

these drugs to provoke suicidality. For example, we did not receive complete descriptions of how manufacturers conducted searches or why manufacturers included or

excluded individual cases. In at least one case, the search for and classification of

cases was not conducted in a blind manner to avoid bias. In another case, what appeared to be a strong signal in our preliminary analysis of the previously submitted

data became a weak signal on re-analysis by the manufacturer. In all, we concluded

that we needed to better understand the classification and analysis process.

FDA DECISION ON INDEPENDENT RECLASSIFICATION OF CASES

FDA also was concerned about case definition and selection by manufacturers in

response to our July 22, 2003, letters. We noted substantial differences across different drug products in the selection of cases included as suicide attempts. Some

sponsors decided to include essentially all captured events as suicide attempts, even

though there was clearly not enough information in some of the cases to justify such

a classification.

For example, there was concern about a number of the adverse events classified

under the category ‘‘possibly suicide related.’’ In one case, a young girl slapped herself on the face and researchers coded this as a suicide attempt. A number of other

events coded as ‘‘suicide attempts’’ involved children who had engaged in superficial

cutting behavior and children who had ingested small numbers of pills in sight of

parents. Such events, while of concern in their own right, would not necessarily be

an indication of suicidal behavior.

This confirmed the view reached tentatively at our September 2003 internal regulatory briefing of the need to have potential events blindly reclassified by an independent group. Although we briefly considered doing this internally, we rejected this

idea because FDA did not have the expertise in suicidality to conduct such a large

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reclassification effort. Furthermore, most employees who might logically participate

in such an effort had already seen many of the cases. These reviewers could also

be biased because they were aware of the treatment assignment (drug or placebo).

FURTHER REQUESTS FOR DATA/INITIATE THE ‘‘COLUMBIA’’ STUDY

Thus, we began to look outside the Agency and initiated a series of discussions

with outside experts. Although we found several experts interested in such an effort,

there remained the problem of who could coordinate this work and establish methods and criteria for reclassification.

Columbia University not only had well-recognized expertise in adolescent

suicidality, but also had developed an approach to classifying events that possibly

were representative of suicidality, and this approach precisely fit our needs. We conducted extensive discussions with this group in order to establish a contract to accomplish this reclassification of cases and to work out the details of a standard approach to finding all relevant cases and setting up categories for the reclassification

effort that would meet our needs.

Additionally, as we reviewed the summary data provided by the various sponsors

in response to our July 22, 2003, letters, we again noted an inconsistency in results

across trials, even within individual programs, that we had observed in our re-review of the pediatric supplements. To further address this issue, on October 3, 2003,

DNDP requested patient-level data sets from all manufacturers of the nine anti-depressant drugs. The availability of these more detailed data has permitted FDA to

perform a more refined analysis, taking into consideration possible imbalances

across study groups in these trials. In order to ensure that we had a complete capture of all relevant events that might possibly be related to suicidality for these

trials, we issued follow-up requests to our

JULY 2003 LETTERS; THESE REQUESTS WERE MADE ON NOVEMBER 24 AND DECEMBER

9, 2003.

This complete set of narratives was sent to Columbia University for review by a

panel of international pediatric suicidality experts. This group was assembled to undertake a blinded review of the reported behaviors using a rigorous classification

system.

FDA’S OCTOBER 2003 UPDATED PUBLIC HEALTH ADVISORY AND TALK PAPER

FDA issued an updated Public Health Advisory and Talk Paper on October 27,

2003, based on our assessment of the pediatric suicidality data at that time. Although we indicated that preliminary data suggested an excess of reports of

suicidality for several anti-depressant drugs, we noted the need for additional data

and analysis. We also noted that we intended to bring this issue to an advisory committee meeting. We advised caution in the use of any of these drugs in treating pediatric MDD, and reminded prescribers of the standard language already in antidepressant labeling alerting clinicians to the need for close supervision of high-risk

patients, particularly during initial onset of drug therapy.

DECEMBER 2003 UK MHRA ACTION ON ANTI-DEPRESSANT TREATMENT OF PEDIATRIC MDD

The UK MHRA made a public announcement on December 10, 2003, indicating

that, in addition to its earlier statements regarding the contraindications of Paxil

and Effexor in pediatric MDD, it was now also contraindicating all SSRI anti-depressants except Prozac for this condition. This announcement noted that the risk

to benefit profile could not be assessed for Luvox, and that, the risk to benefit profile

is favorable in pediatric MDD for Prozac only. Serzone and Wellbutrin are not approved drug products in the UK. Remeron is an approved product in the UK, but

MHRA has offered no specific comment on the pediatric data for this drug.

FDA’S FEBRUARY 2, 2004 ADVISORY COMMITTEE MEETING

FDA uses advisory committees to gain expert advice about scientific and public

health issues and/or regulatory decisions. In preparing for an advisory committee

meeting, scientific team leaders, supervisors and managers—seasoned regulatory

scientists with drug development and public health expertise—exercise scientific

judgment in synthesizing issues to be brought before advisory committees. This

process is designed to ensure that an advisory committee considering an issue is

provided with sufficient data and information to fully discuss the issues.

While CDER was conducting its more in-depth review of the data from the pediatric clinical trials, planning was also under way to hold a meeting of the PDAC

on

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February 2, 2004. Because the BPCA mandates a review of the post-marketing

safety data for products that have been granted pediatric exclusivity, this meeting

was convened to review the post-marketing safety reporting for a number of products (not limited to anti-depressants). One of the drugs scheduled for discussion at

the February 2, 2004, Advisory Committee meeting was Paxil.

In planning for the discussion of the safety of the use of Paxil in children, the

Agency initially intended to broaden the PDAC meeting to include a discussion of

the Agency’s review of the safety concerns arising from the data on the use of antidepressants in children, as these concerns were clearly of public interest. However,

as the reviews and meeting planning progressed, it became clear that the additional

analyses of the data from the clinical trials of anti-depressants in children, particularly the Columbia analysis, would not be completed in time to present the Agency’s

final assessment of these data at the Advisory Committee meeting.

The Agency decided to proceed with the plans to discuss the post-marketing safety

data for Paxil at the meeting, to brief the Advisory Committee on the Agency’s

progress in evaluating data from the clinical trials of anti-depressants in children,

and to solicit advice and comment regarding the Agency’s plans for further analyses.

The plan included returning to the Advisory Committee for another meeting once

the Agency’s more definitive analyses of the clinical trial data were complete. This

would allow us to solicit Advisory Committee input before taking further regulatory

action.

While CDER was moving ahead with plans for the February 2, 2004, Advisory

Committee meeting, Dr. Mosholder was nearing completion of his review of the data

from the clinical trials provided in response to our July 22, 2003, request. Based

on his review, he believed that the available data were sufficient to reach a conclusion about an association between the use of anti-depressants and suicidality in children and to recommend additional regulatory action, without the need for the more

in-depth case classification or analyses that had already been initiated by DNDP.

Dr. Mosholder shared his conclusions with his supervisors and with the DNDP/ODE

I review team involved in reviewing this issue. The review team and Dr.

Mosholder’s direct supervisors did not agree that the available data were sufficient

to reach a conclusion and believed that definitive action should await the re-analysis

by Center staff using the Columbia data. There was a discussion within the DNDP/

ODE I review team, as well as higher CDER management including Drs. Katz,

Laughren, and Temple, as to whether

Dr. Mosholder’s scientific and regulatory conclusions on the data should be presented in some form at the February meeting, given that they did not represent the

Agency’s (but rather an individual staff member-s) determination; it was concluded

that they should not be.

However, at the February 3, 2004, meeting, Dr. Laughren did present the data

that led Dr. Mosholder to his conclusions, although not in detail. These data plainly

showed an excess of suicidality in individual studies and across the studies as a

group.

Dr. Laughren also explained the Agency’s reservations about the classification.

Dr. Katz also acknowledged in his presentation to the Advisory Committee that

some reviewers had reached a conclusion that the data were sufficient to conclude

that there was a link between anti-depressant use and suicidality in children. The

Agency did not present Dr. Mosholder’s conclusion in detail because of concerns that

this would have given his determination the appearance of an Agency position before the Agency had made such a determination. This could have been harmful to

the public health because it might have led patients who were actually benefiting

from the use of these drugs to inappropriately discontinue therapy with potentially

dire consequences, or to avoid treatment when it might be the best option.

Senior CDER staff believed that the best way to serve the public health on this

very complex and important issue was to: 1) disclose the available publicly releasable safety data during the Advisory Committee meeting; 2) describe the limitations

of those data in supporting a definitive conclusion; and, 3) describe the Agency’s

plans to further evaluate the data. The Agency realized its responsibility to the public to find the right answer to this question. A premature conclusion that these

drugs are harmful (when used in the pediatric population) that does not hold up

during a more careful review would be a disservice to the public health given the

serious and potentially life-threatening nature of severe depression. This is of particular concern since there are no acceptable therapeutic alternatives for health care

providers and their pediatric patients with depression.

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CDER’S DECISION-MAKING PROCESS ON SAFETY ISSUES

CDER’s decision-making process is designed to ensure that regulatory actions or

policy formulation take into consideration an array of perspectives and concerns designed to advance public health. The process requires that primary reviewers, team

leaders, supervisors, and managers work together effectively.

In the free and open discussion of CDER issues within a scientific and regulatory

environment, we expect differing professional judgments/opinions. Individual employees are strongly encouraged to discuss their views with co-workers. A number

of opportunities are available to discuss and resolve scientific differences and enhance decision-making. These include meetings among review teams, meetings with

the supervisory and management chains within the Center and Agency, meetings

with sponsors, CDER regulatory briefings and Advisory Committee meetings.

It is never the goal of these discussions to pressure or convince reviewers to reach

any particular conclusion, or to reach a different conclusion that they have already

reached, but only to provide a forum for a free exchange of views by all. After considering all of the relevant data and arguments, individual reviewers are expected

to write reviews that reflect their best judgment. If their supervisor disagrees with

their conclusions and/or recommendations, the supervisor documents the disagreement, and the resolution of the disagreement, in the official administrative file on

a matter.

FDA’S MARCH 2004 ADVISORY: NEW WARNING STATEMENT IN LABELING

At the February 2, 2004, Advisory Committee meeting, experts raised concerns

about the possible relationship between anti-depressant drug products and suicidal

behavior and suicidal ideation and supported a labeling change to warn of possible

suicidality. On March 22, 2004, FDA responded to these concerns by issuing a Public Health Advisory and asked manufacturers of Prozac, Zoloft, Paxil, Luvox, Celexa,

Lexapro, Wellbutrin, Effexor, Serzone and Remeron to include a warning statement

in their labeling recommending close observation of adult and pediatric patients

treated with these drugs for worsening depression or the emergence of suicidality.

In this statement, the Agency informed the public that symptoms such as anxiety,

agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia,

hypomania, and mania have been reported in adult and pediatric patients who are

being treated with anti-depressants for MDD. We warned that patients who experience one or more of these symptoms might be at an increased risk for worsening

depression or suicidality. The Agency pointed out that we did not know whether the

drugs increased suicidality but warned that medications may need to be evaluated

and perhaps discontinued when symptoms are severe, abrupt in onset, or not part

of the patient’s presenting symptoms. FDA urged health care providers to instruct

patients, their families, and their caregivers to be alert for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence

of suicidality and worsening depression, and to report such symptoms immediately

to their health care provider.

‘‘COLUMBIA’’ STUDY RESULTS

The Columbia group submitted its completed review to FDA in July 2004. FDA

then developed its analysis of the pediatric suicidality data based on the case classifications provided by Columbia University. While there were findings among these

data suggestive of an increased risk of suicidality for some of these drugs, inconsistencies remained in the results, both across trials for individual drugs and across

drugs. Thus, an overall interpretation of these findings represented a substantial

challenge to the Agency. The Agency brought these findings to the

Psychopharmacologic Drugs and Pediatric Advisory Committees in September 2004

for further consideration.

FDA’S AUGUST 2004 ADVISORY: AGENCY PLAN TO PRESENT DATA TO ADVISORY

COMMITTEES

As part of its commitment to keep the American public fully informed about the

status of its review of data concerning the use of anti-depressants in pediatric patients, on

August 20, 2004, FDA informed the public of its detailed plan to present new data

to the Psychopharmacologic Drugs and the Pediatric Advisory Committees. This new

data, which FDA posted on its website, included the Agency’s interpretation and

analyses of pediatric suicidality data based on information obtained from the Columbia Study. In addition, the Agency sought advice on appropriate regulatory actions,

such as labeling changes to ensure that the labels of anti-depressants used in pediVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00085 Fmt 6633 Sfmt 6621 96099.TXT HCOM1 PsN: HCOM1
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atric patients reflect the most recent information obtained from current studies and

analyses.

As we noted previously, FDA also announced that it posted additional summaries

on its web site of pediatric efficacy studies for drugs that have been studied for depression in pediatric patients. These summaries are for Paxil, Celexa, Serzone,

Zoloft and Remeron. Although specific new labeling language has yet to be developed, FDA will work to assure that the labels of the anti-depressants used in pediatric patients reflect the most recent information obtained from these studies and

analyses.

FDA’S SEPTEMBER 13-14, 2004 ADVISORY COMMITTEE MEETING

On September 13 and 14, 2004, a joint meeting was held between the

Psychopharmacologic Drugs and Pediatric Advisory Committees to consider the occurrence of suicidality in the course of treatment of pediatric patients with various

anti-depressants. The primary focus of FDA’s presentations at the September 2004

meeting was to provide committee members with (1) a detailed description of FDA’s

approach to evaluating and analyzing the pediatric suicidality data, and (2) the results of this work. The Agency also included presentations on related studies, in

particular, several pertinent epidemiological studies and TADS (Treatment of Adolescents with Depression Study). Committee members heard presentations by both

FDA staff and experts in pediatric suicidality from the academic community outside

of FDA.

The overall consensus of the committee was an endorsement of FDA’s approach

to classifying and analyzing the suicidal events and behaviors observed in the controlled clinical trials. Committee members expressed their view that the new analyses increased their confidence in the results. Further, the committee members concluded that the finding of an increased risk of suicidality in pediatric patients applied to all the drugs studied (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa

Wellbutrin, Luvox and Serzone) in controlled clinical trials. In addition, the members:

• recommended that the products not be contraindicated in this country because the

Committees thought access to these therapies was important for those who

could benefit;

• recommended that the results of controlled pediatric trials of depression be included in the labeling for anti-depressant drugs;

• recommended that any warning related to an increased risk of suicidality in pediatric patients should be applied to all anti-depressant drugs, including those

that have not been studied in controlled clinical trials in pediatric patients,

since the available data are not adequate to exclude any single medication from

an increased risk;

• reached a split decision (15-yes, 8-no) regarding recommending a ‘‘black-box’’

warning related to an increased risk for suicidality in pediatric patients for all

anti-depressant drugs; and

• endorsed a patient information sheet (‘‘Medication Guide’’) for this class of drugs

to be provided to the patient or their caregiver with every prescription.

FDA’S SEPTEMBER 17 ANNOUNCEMENT REGARDING SSRIS

On September 17, FDA announced that the Agency generally supports the recommendations made to the Agency by the Psychopharmacologic Drugs and Pediatric

Advisory Committees regarding reports of an increased risk of suicidality (suicidal

thoughts and actions) associated with the use of certain anti-depressants in pediatric patients. FDA has begun working expeditiously to adopt new labeling to enhance the warnings associated with the use of anti-depressants and to bolster the

information provided to patients when these drugs are dispensed.

EFFECTIVENESS DATA FOR ANTI-DEPRESSANTS IN PEDIATRIC MDD

To date, much of the focus has been on pediatric suicidality and the safety of antidepressant drug products. However, it is also important to consider the efficacy data

for these drugs because a risk-benefit assessment is important to clearly understand

the benefit side of this equation. Of the seven products studied in pediatric MDD

(Prozac, Zoloft, Paxil, Celexa, Effexor, Serzone and Remeron), FDA’s reviews of the

effectiveness data resulted in only one approval (Prozac) for pediatric MDD. (In January 2003, FDA approved Prozac for the treatment of children and adolescents ages

7 to 17 for depression and obsessive-compulsive disorder.)

Overall, the efficacy results from 15 studies in pediatric MDD do not support the

effectiveness of these drugs in pediatric populations. It is understandable that peoVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00086 Fmt 6633 Sfmt 6621 96099.TXT HCOM1 PsN: HCOM1
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ple might conclude that these data show that the drugs, except for Prozac, have no

benefit in pediatric MDD. We think that conclusion is premature, however.

There are many reasons, other than lack of effectiveness, for studies to fail to

show benefit. This phenomenon is a particular problem in depression, and even

more so in pediatric depression.

To begin with, in adult MDD programs for drugs approved for this indication, the

overall failure rate for studies that appear in every respect to be adequate trials is

about 50 percent. This indicates that showing effectiveness in depression is not

easy. In fact, because we expected this difficulty, our Written Requests to sponsors

asked for two studies, not the one that would have been more typical.

Additionally, the history of pediatric MDD studies with the tricyclic anti-depressants (TCAs) is uniformly negative. This finding may have several possible explanations, including flaws in study design or conduct, or the possibility that TCAs

simply do not work in pediatric MDD. It is also possible, however, that there is even

greater heterogeneity among pediatric patients who meet criteria for MDD than is

true for adults. If true, this would also work against study success in pediatric

MDD.

Finally, the context in which sponsors conducted these studies may not have been

ideal. Sponsors do not need positive results when conducting a study in response

to a Written Request in order to gain exclusivity. The studies simply must be conducted according to the terms of the Written Requests, and the results submitted

to meet deadlines specified in those requests. We are not suggesting that sponsors

of these studies did not design and conduct them with good intent and according

to high standards. We merely point out that the failure of a drug registration trial

to show a drug effect represents a more significant loss for the sponsor (i.e., the nonapproval of the drug) than the failure of a study in response to a Written Request.

We do not know whether this could have influenced the conduct of the study in subtle ways that might have worked against getting a positive result, e.g., in recruitment of patients. As an example of how our thought process has changed since the

time we issued the Written Requests, if we were to make a Written Request today

for an anti-depressant, we would ask that the trial include a Prozac arm as well

as placebo to confirm the ability of the study to demonstrate effectiveness. .

Nevertheless, the failure of most of these programs to show a benefit in MDD

heightens the concern about the drugs ability to induce suicidality. The burden is

clearly upon those who believe these drugs do have benefits in pediatric MDD to

design and conduct studies that are capable of demonstrating such benefits. The

problem for practitioners is what to do in the face of the uncertainty. Practitioners

must consider the generally negative findings in the context of several other facts.

In all but one of the failed drugs, there were only two studies in pediatric MDD.

For the remaining failed drug, there were three pediatric MDD studies. Among the

failed drugs, there was one drug where one of the two studies was positive (Celexa),

and two others (Zoloft and Serzone) where the results, while negative by our usual

standards, were at least trending toward positive in one of the two studies.

It has been observed that the published literature gives a somewhat different perspective, suggesting more positivity in two of these programs. A published paper describes one of the Paxil studies as positive on most of the secondary endpoints, while

acknowledging that it failed on the primary endpoint. Another paper describes the

Zoloft program as positive, based on a pooling of two similarly designed studies that,

when looked at individually, failed. As noted, except for Prozac, we do not believe

effectiveness has been shown for any agent in pediatric MDD.

CONCLUSION

FDA was the first to identify a concern about suicidality in several of the submitted pediatric studies. We evaluated the data closely and raised serious questions

about its adequacy. We then took the initiative to acquire further relevant data from

sponsors and used expertise outside the Agency to access the reports of suicidality

thoroughly. FDA’s assessment on this issue is designed to achieve the most scientifically rigorous review possible. The Columbia University classification project has

provided the Agency with a credible basis for analyzing the risks of these drug products.

The results of pediatric depression studies to date raise very important problems.

First, the poor effectiveness results, except for Prozac, make it very difficult for

practitioners to know what to do to treat a very serious, life-threatening illness.

While we believe that these drugs may be effective in children, studies have not

shown this to be true. Second, and of equal importance, the analyses we initiated

in 2002 appear to show that the drugs in the pediatric controlled depression trials

can lead to suicidal behaviors or thinking. While no suicides occurred in the trials,

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suicides certainly have been reported in treated patients, and the devastating results of these suicides were a critical part of the February 2, 2004, Advisory Committee meeting.

FDA generally supports the recommendations that were recently made to the

Agency by the Psychopharmacologic Drugs Pediatric Advisory Committees regarding

reports of an increased risk of suicidality associated with the use of certain antidepressants in pediatric patients. FDA has begun working expeditiously to adopt

new labeling to enhance the warnings associated with the use of anti-depressants

and to bolster the information provided to patients when these drugs are dispensed.

Thank you for inviting us today to discuss this important subject. We would be

glad to answer your questions.

Mr. WALDEN. Dr. Laughren, do you have an opening statement,

sir?

Mr. LAUGHREN. No, I don’t.

Mr. WALDEN. Okay. Dr. Seligman?

Mr. SELIGMAN. No, I don’t.

Mr. WALDEN. Thank you. Well, we appreciate all of you here

today to share with us this information as we continue to look at

what happened in this area and maybe what needed to happen,

and where we are today and where we will be when the FDA

makes it decision relative to the Advisory Committee’s recommendations.

Dr. Knudsen, could you turn in our big binder there to Tab 71

and 72? While you are looking at that, these are the two versions

of a letter under your signature sent to Pfizer Pharmaceuticals on

March 19, 1996, Tab 71 and 72.

Tab 71 has a FAX cover page filled out in someone’s handwriting

to Martha Brumfield of Pfizer from James Knudsen. The top of

that page indicates it was sent at 10:18 and shows FDA

Neuropharm on it as well.

Does this appear to be your handwriting on the FAX cover sheet,

sir?

Mr. KNUDSEN. It does appear to be.

Mr. WALDEN. It does. Okay. The letter attached to this FAX has

lots of typographical errors in it as well as different fonts being

used for various words. If you would turn to Tab 72, it appears to

be the same letter in substance as Tab 71. However, the typos are

removed, and the font is consistent. The letters alone have a different FAX time Sent stamp on them, and show them coming from

a different section of FDA. Yet does the signature on both these letters appear to be yours?

Mr. KNUDSEN. Tough question, isn’t it? They appear to be, but

then again—yes, they appear to be. Back in 1996 when I was—my

penmanship may have been a bit better than now. It varies somewhat. But I will answer the question as it appears to be. I have

to equivocate a week bit, just because of the duration of time and

the instability of my penmanship.

Mr. WALDEN. All of our penmanship tends to suffer with age, sir.

Mr. KNUDSEN. Thank you so much.

Mr. WALDEN. Was it your practice to send a draft letter to a

pharmaceutical company requesting information, then resend a

cleaned-up version later on, though? Would you have sent it as a

draft and then send a different version later?

Mr. KNUDSEN. No, I don’t—I mean, once again I have to preface

a statement by, regrettably, this was done in 1996. So it is someVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00088 Fmt 6633 Sfmt 6602 96099.TXT HCOM1 PsN: HCOM1
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what precarious for me to forage around in the limited gray matter

that is available to answer that concretely.

Mr. WALDEN. Is it a practice you recall doing throughout your career? Do you usually send a draft and then another?

Mr. KNUDSEN. I do not—no, I do not usually send a draft and

another. That’s correct.

Mr. WALDEN. I mean, this wouldn’t be a normal practice, I

wouldn’t think.

Mr. KNUDSEN. No. That’s correct.

Mr. WALDEN. Okay. I don’t know. I mean, I’m not the best speller

in the world, but——

Mr. KNUDSEN. Well, quite frankly, I chatted with this—I mean,

last week I talked with the subcommittee staffers, and I was rather

appalled at what—with the typographical mistakes. I am rather

fastidious most of the time. There are periods whereby I could deviate from that, but I mean, this is—this being Tab 71 is a mess.

Draft or otherwise, I wouldn’t be sending it to Martha, best I can

recall anyway.

Mr. WALDEN. I understand that. Do you have any explanation for

the fact that two versions of this letter exist?

Mr. KNUDSEN. No, but I suspect others do. I am unable to come

up with an explanation.

Mr. WALDEN. Were you able to find this letter in the files at

FDA?

Mr. KNUDSEN. I checked—no, to answer your question. I did

check the document room. My own files are in—not trying to generate excuses, but they are in boxes which I invite you to my office

and it is extremely difficult to even find a box. But they are all

there. We are getting ready to relocate. So maybe with another 40

days and 40 nights I could find it.

Mr. WALDEN. Well, should there have been a copy of this letter

in the NDA files?

Mr. KNUDSEN. I would—yes, and I would have kept a copy myself in my Certraline file. I keep everything.

Mr. WALDEN. Your files are in boxes?

Mr. KNUDSEN. I as unable to locate it in the document room——

Mr. WALDEN. Right.

Mr. KNUDSEN. [continuing] when I was there. I checked in a cursory way in my office, just trying to find the Certraline file that

I have. In fact, I did find the Certraline file, parts of it, but I could

not locate this particular document.

Mr. WALDEN. Where did you obtain a copy of your March 19,

1996, letter, and which version did you see?

Mr. KNUDSEN. I obtained two copies, one from the Division.

Mr. WALDEN. The Division?

Mr. KNUDSEN. HFD, the Division I am in, the day before I left

to go to Maine. I took it with me, in addition to other things, other

documents, and then the subcommittee members sent via Federal

Express another document. I mean the same one.

Mr. WALDEN. Another copy of that same document?

Mr. KNUDSEN. Yes, sir. Yes, sir.

Mr. WALDEN. And where did the agency get the version they sent

to you?

Mr. KNUDSEN. I did not inquire.

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Mr. WALDEN. Dr. Temple, do you know?

Mr. TEMPLE. I could be wrong about this. My understanding is

that Dr. Knudsen got a copy of the letter from the committee.

Maybe I’m wrong about that.

Mr. KNUDSEN. Yes, I just said that.

Mr. TEMPLE. And that we never were able to find it in our files

and got it from Pfizer.

Mr. WALDEN. There you go. So you had to go to Pfizer to get it?

Mr. TEMPLE. Yes.

Mr. WALDEN. That’s what you provided to the committee. Right?

Mr. TEMPLE. I’m not sure, but we could not—what I am sure of

is that we were unable to find a record of this letter anywhere in

our files. That, I am sure of. I am not sure about the rest.

I should say that it is unusual. Letters don’t ordinarily go out

under a medical officer’s signature. They would ordinarily go out

under Dr. Katz’s signature or Dr. Lieber’s or whoever was in

charge at the time, and a copy would be in the New Drug Application, in the file. So this was unusual.

Mr. WALDEN. All right. Dr. Knudsen, was it your practice as a

medical review officer in 1996 to directly correspond with a pharmaceutical company on a matter you were reviewing, and then request information or did you need to apprise any of the supervisors

of your request for additional information from the pharmaceutical

company?

Mr. KNUDSEN. It was not my practice to do so.

Mr. WALDEN. So you would have—was it your practice to tell

your colleagues or supervisors that you were seeking such information from a pharmaceutical company?

Mr. KNUDSEN. Correct, 86 to 95 percent of the time. There is always a slight opportunity for me to—I mean, once again, I mean,

I answered the question as best I could that it is not my practice

to do so. In fact, I received my copy from the Division via—of

course, I guess the Division received it from Pfizer. I wasn’t aware

of that. I had no need to question that anyway. I just wanted to

take some materials with me to Maine.

Mr. WALDEN. Isn’t it a requirement of FDA regulations these

types of correspondent documents be kept on file by the agency?

Mr. KNUDSEN. Yes.

Mr. WALDEN. All right. And yet in this case, that doesn’t appear

to be what happened. Right?

Mr. KNUDSEN. That is correct.

Mr. WALDEN. All right. In these letters, you state ‘‘We note that

there appears to be an increased frequency of reports of suicidality

in pediatric adolescent patients exposed to Certraline compared to

either placebo or Certraline treated adult OCD patients. If this is,

in fact, the case, what would be a plausible explanation?’’ That is

what is in the letter that you signed or you think you signed and

sent to Pfizer.

You asked for summary tables from Pfizer to compare data from

adult and pediatric patients in their data base. Is it fair to say that

you wrote this letter to Pfizer because you noticed an increase in

suicide related behavior in the pediatric OCD trials relative to the

rates in the adult trials, and that that was of concern to you? Is

that why you wrote this letter to Pfizer?

83

Mr. KNUDSEN. Yes.

Mr. WALDEN. All right. And was it of enough concern that you

wanted answers from the company?

Mr. KNUDSEN. Correct.

Mr. WALDEN. And approximately 10 days after you sent this letter to Pfizer, you complete a safety update to Zoloft. We have put

selected pages of your safety review at Tab 81, 81, if you want to

refer to that, sir.

In your safety update you note on page 15 that, ‘‘In the small pediatric adolescent pool population of OCD patients, the incidence of

suicidality in the Certraline treated patients was fivefold greater

than the adult OCD Certraline treated patients.’’

You go on to note that 4 of 6 Certraline pediatric patients had

comorbid depression and, ‘‘Depression is an important risk factor

for suicide.’’ You then cite an article published in the Journal of

American Academy of Child and Adolescent Psychiatry that indicated—that also noted the same phenomenon with kids being treated with Prozac.

What did you do other than note these concerns in the safety update? Where did you take it from here?

Mr. KNUDSEN. I was trying to see whether or not that was instrumental in my sending the letter to Pfizer, just to garner some

additional information. This was March 28, 1996. The letter to

Pfizer was October, was it?

Mr. WALDEN. I think the letter to Pfizer, you will see, is dated

March 19.

Mr. KNUDSEN. March 19, before.

Mr. WALDEN. So like 9 days later——

Mr. KNUDSEN. Well, in fact, in reviewing the NDA, this was a

final document that was signed off, the one that—the document in

Tab 81. So prior to finalizing this document, Tab 81, I found this

information to be—at the time anyway, certainly of concern to me

to make some further inquiries to Pfizer, and realizing, of course,

when I finalize this document, I believed that Pfizer had not responded yet to this.

Mr. WALDEN. That would be correct, based on the timeline I have

seen. But 9 days before you wrote to Pfizer asking for this additional information, why didn’t you include in this update the fact

that you were awaiting additional information from the company to

explain the fivefold increase? Would that have been a prudent

thing to do?

Mr. KNUDSEN. Yes, it would have been.

Mr. WALDEN. Well, my time has expired. I will now recognize the

ranking member of the subcommittee at this time, the gentlelady

from Colorado.

Ms. DEGETTE. Thank you very much. Dr. Temple and Dr.

Laughren, I am wondering if you can tell me, knowing what you

know today, do you believe that Dr. Mosholder’s initial conclusions

about the increased risk of suicidality exists in pediatric populations taking anti-depressant medication to treat MDD? Dr. Temple?

Mr. TEMPLE. The reanalysis that Columbia did, did not change

the overall direction of the results. So——

Ms. DEGETTE. So your answer would be yes?

84

Mr. TEMPLE. Would be yes. Dr. Hammad’s analysis and Dr.

Mosholder’s are slightly different analyses, but in fact the relative

proportions of suicidality are similar to what Dr. Mosholder found.

Ms. DEGETTE. What about you, Dr. Laughren?

Mr. LAUGHREN. Yes, I agree. The relative risk for both analyses

is roughly twofold. So it is essentially the same. There are some

differences across drugs. The signal gets a little stronger for some

drugs, a little weaker for others, but overall I agree that it is

roughly the same result.

Ms. DEGETTE. There was about 8 months between his findings

and when, I think, the FDA took action. I guess my question to

both of you: Do you wish that the agency would have taken him

more seriously and allowed him to present the findings so that we

could have warned parents and physicians about the increased

suicidality rates instead of waiting these 8 months?

Mr. TEMPLE. Let me say a few things. Our concern, as I said before, was that the action we take be based on the best possible

data. Let me describe the kind of data we had here.

The usual way we expected to evaluate increased suicidal risk is

by looking at the scales that patients in trials are given that ask

them how suicidal they are. Dr. Laughren in his comments on Dr.

Knudsen’s review points out that we are going to have more data

on this question.

Those analyses revealed nothing in any of these trials. There was

no increased suicidality by that measure. What we got was something unexpected, namely the adverse reaction reports, when interpreted, when translated, revealed an excess of these suicidal behaviors. What we had very little experience with was what those

things mean.

We thought, as we looked at them, that somebody—that people

expert in interpreting these behaviors needed to look at them. Dr.

Mosholder specifically in his review says he did not try to reevaluate each of these cases, because he was no longer blinded. That

conclusion——

Ms. DEGETTE. But Dr. Mosholder also said that he only looked

at the most—I’m not a researcher, but he only looked at the most

serious cases and, in fact, Dr. Temple, you yourself in your opening

statement said that the comment you had made about the face

slapping you now regretted that, because he didn’t take those

things into account.

Mr. TEMPLE. Let me explain. He had—in response to the concern

that these cases might not be a true bill, might not be what they

seemed to be, he offered several approaches. One was to only look

at the serious cases. That is clear, and you can see in his review,

if you look at the cases that were included and not included, that

many of the trivial cases were excluded by the decision to look only

at the serious cases. That is perfectly true.

There were, however, additional cases where you didn’t know

what they meant, and he was in no position to reevaluate them.

Let me just——

Ms. DEGETTE. I apologize, but they only give me 10 minutes. So

if you can make your answer concise, I would appreciate that.

Mr. TEMPLE. Okay. I wanted to explain one other point about it.

Ms. DEGETTE. Very briefly.

85

Mr. TEMPLE. He also said that, if there is noise in the system,

if it is inaccurate, that would tend to hide a finding rather than

to create one, and that is true.

What is also true, however, is if there was a bias toward interpreting certain things that the drugs do, like agitating people or

making them hostile, as suicidality, that could give you the wrong

picture. It could cause you to think there were suicidal events

when, in fact, they were not.

That is why we thought we needed an independent look at these

cases in——

Ms. DEGETTE. Okay. But at the time that Dr. Mosholder came

up with his findings, there was already the British study that had

come out earlier that year.

Mr. TEMPLE. No, the British were using the same data we were.

Ms. DEGETTE. Right, but they had concluded this increased risk

of suicidality.

Mr. TEMPLE. But we don’t know that they——

Ms. DEGETTE. But I mean there were two.

Mr. TEMPLE. Let me make it clear. There was nothing wrong

with Dr. Mosholder’s analysis, the ratios he designed, any of those

things. That is not——

Ms. DEGETTE. Well, right. In fact, it has now turned out he was

completely right.

Mr. TEMPLE. No, that is not at issue. What was at issue was

what the cases were, whether they really showed suicidality, and

to answer that question you either have to look at them closely or

decide that they could not have been biased.

Ms. DEGETTE. Well, let me ask you this. In the spring or summer

of 2003, Wyeth came to the FDA, and they wanted on their own—

we heard this in the last hearing—to strengthen warnings on

Efexir, and the FDA asked them not to do that. Is that right?

Mr. TEMPLE. Not quite. They were allowed to do that, and they

did it until we created a new stronger warning or—you can call it

strong or not—a different warning in march of 2004. That warning

was in the warning section. It prominently said you really need to

watch patients, and we thought that was a more trenchant warning. That was in response to the Advisory Committee.

Ms. DEGETTE. Okay. Now do you think that the FDA is going to

adopt this most recent recommendation about the black box warnings?

Mr. TEMPLE. Our public statement said that we were going to do

all the things they said. We want to think about the conversation

they had about the black box. It is true it was 15 to 8, but there

were a lot of people that said a lot of things.

You know, I don’t want to——

Ms. DEGETTE. Does that mean no?

Mr. TEMPLE. No, it absolutely doesn’t mean no. It means we

haven’t finished our decision yet. We want——

Ms. DEGETTE. Well, what is the FDA’s goal with respect to labeling of these anti-depressants for off-label use for pediatrics? What

is the goal at this point, knowing the information you know about

increased risk of suicidality?

Mr. TEMPLE. Well, we are unquestionably going to explain that

the drugs themselves appear to be—are associated with or cause an

86

increased risk of suicidality. That is a given. The only question is

what form it will take.

The discussion the Advisory Committee had was——

Ms. DEGETTE. What kinds of forms do you have that you can

take with it?

Mr. TEMPLE. Oh, you could put a warning—I mean, the alternative, you could put a warning in dark print, something like that,

or you can put it in a box. Those are probably the two choices.

Ms. DEGETTE. So the choice would be to put it on the bottle. No?

Mr. TEMPLE. No, no.

Ms. DEGETTE. To put it on the box?

Mr. TEMPLE. Well, a box warning is the very first thing you read

in the label.

Ms. DEGETTE. Right. Open it up.

Mr. TEMPLE. A warning comes a little bit later. Those are prominent, too, and we sometimes do one and sometimes do the other.

The particular——

Ms. DEGETTE. If there is a black box, that has to be in the advertising, too. Right? So if Zoloft has an ad, it has to have a warning,

may cause suicidality in pediatric use, or something like that.

Mr. TEMPLE. Yes. The contents of the black box would have to

appear, but——

Ms. DEGETTE. It seems to me you would want to do that.

Mr. TEMPLE. Wait, wait, wait. The content of the warning would

have to be there, too.

Ms. DEGETTE. Well, sure. I understand, but that’s the effect of

a black box versus some of these other warnings. Right?

Mr. TEMPLE. No. The requirement for advertising is you have to

balance the information. If there was a prominent dark print box,

that would have to be there, too. I’m not trying to discourage a

black box. I am just trying to reflect the fact that people who spoke

to us were concerned that people who were at risk of killing themselves would not be treated if we scared people too much.

I’m not saying I agree with that. We put the idea of the black

box before the committee. You know, we are not shrinking from it,

but they said multiple things.

Ms. DEGETTE. Well, I would imagine you would share my concern. My concern is that off-label prescription of these nonapproved

drugs for pediatrics with, at best, no effect on these depressed kids

and, at worst, increased risk of suicidality will continue unabated.

I would assume that is the FDA’s role to decide that. Right?

Mr. TEMPLE. One of the problems with off-label use and not having enough data is that you don’t know what the answer is. The

Advisory Committee—many, many people said we know how the

studies came out; they are not impressive; they weren’t able to

show effectiveness. But they clearly were concerned that maybe as

a second line drug these drugs probably should be available and

probably worked in people.

That is not the same as knowing, because we know the studies

largely failed.

Ms. DEGETTE. I think we can probably all agree that it would

help to have more clinical trials in this area, would it not?

Mr. TEMPLE. Yes, but they—Again, I am talking for them. I am

not telling you what we decided to do. They were very concerned

87

that we would scare people so much that people who didn’t respond

to, say, Prozac wouldn’t use it or would be afraid to use it, and they

were afraid of the consequences. They were worried about them.

You know, these are expert people who treat these conditions.

They know a lot more about it than I do.

Ms. DEGETTE. Can I just ask you a question. Do you think it

would be a good idea if we had more clinical trials so we could get

more data on what the effects of these anti-depressants are, or

should we just rely on faith?

Mr. TEMPLE. Oh, no, we live by getting more data. We can’t always manage to get it.

Ms. DEGETTE. Can you require more clinical trials as part of

your ongoing effort?

Mr. TEMPLE. That is going to be an interesting question. We

have a number of thoughts about how to do further studies, which

I would use up your 10 minutes if I told you, but I would be glad

to.

Ms. DEGETTE. It’s okay. It’s already over.

Mr. TEMPLE. No, we think there needs to be more data. For example, we were very impressed with the TAD study. It was a very

informative study done by NIMH. We are going to be talking with

them, see if we can convince them to do some more stuff.

Ms. DEGETTE. Great. Now what about the companies? Are you

going to require—what we learned in the last hearing: Pharmaceutical companies are making millions and millions of dollars from

this off-label prescription of these anti-depressants.

Would it be reasonable for the FDA to require further studies by

the companies?

Mr. TEMPLE. It is reasonable, and whether we can—well, there

is a question of our authority. Whether we will be able to require

further studies when they will perfectly happily say we think it is

a settled question, we don’t want the drug used in children—we are

perfectly happy to say safety and effectiveness in children hasn’t

been demonstrated, and they are perfectly happy to say that, as

you pointed out.

Ms. DEGETTE. Because they can still sell these drugs.

Mr. TEMPLE. Whether we will be able to persuade them to do

more studies is not known to me. We definitely——

Ms. DEGETTE. Well, can’t you hold the pediatric exclusivity stick

over their head?

Mr. TEMPLE. Unfortunately, no. They have done what they were

supposed to do under the law. They have done the trials we asked

for, and pediatric exclusivity has been now granted.

Ms. DEGETTE. So if you have these recalcitrant drug companies

who are refusing to do more studies because they can just blithely

say, well, we don’t like this off-label use anyway, we don’t——

Mr. TEMPLE. To be fair, they haven’t refused yet.

Ms. DEGETTE. Okay.

Mr. TEMPLE. I’m not optimistic. That’s all.

Ms. DEGETTE. They might agree to do it, but if not, it would

seem to me it would be in the FDA’s interest then, and this is within the FDA’s authority, to require the strongest possible warnings

so that doctors and parents understand the risk to pediatric patients.

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Mr. TEMPLE. There is no question there is going to be a strong

warning. The other thing is we suggested to the committee that

there ought to be patient labeling, a so called Med Guide, and they

totally agreed with that.

We also told them that we didn’t think a Med Guide works unless you create what is called unit of use packaging, so that it is

always handed out, and I am on lengthy record as saying we are

going to require that, which we will. But we did all of those things.

It needs to be a strong warning.

Ms. DEGETTE. And staff points out to me, the FDA could

counterindicate this drug and stop it form being prescribed, period.

Mr. TEMPLE. Well, we couldn’t. They could still prescribe it. We

don’t control what people do. The Advisory Committee was unequivocal, voted overwhelmingly and uniformly that they did not

think a contraindication was appropriate, for the reasons that I

have just given. They think, without data, without evidence that

these drugs actually work, they think they need to be available.

Ms. DEGETTE. Excuse me, sir. Let me just say, it seems like circular reasoning. We don’t have the data to say what we should do,

but we can’t make them get the data. So we are just going to go

along. I would suggest we work together. Do you need statutory

changes, whatever you need? We need to get a grasp on this, and

I think part of it is getting more data.

My time has long expired. Thanks for your comments.

Mr. TEMPLE. Can I throw one more thing out? The data were not

uniformly negative. There was one positive trial with a drug called

Cetalopram, and there were a couple of trials that were close, not

entirely negative.

So it is not out of the question that these drugs can be shown

to work.

Mr. WALDEN. Are you talking about efficacy or suicidality?

Mr. TEMPLE. Efficacy.

Mr. WALDEN. Well, I am going to go to Mr. Ferguson in a second.

But you could also require that the trials that show no efficacy be

published. Right? Be printed? Doctors could be notified? Couldn’t

you require that?

Mr. TEMPLE. That is a difficult question. Published? Absolutely

not. We have no control over publication.

Mr. WALDEN. I’m sorry. I used the wrong term. Couldn’t you require that on a label it says no efficacy?

Mr. TEMPLE. I believe we can, yes.

Chairman BARTON. Would the gentleman yield before you go to

Mr. Ferguson? I just want to follow up on that question very briefly.

Mr. WALDEN. Certainly, Mr. Chairman.

Chairman BARTON. Dr. Temple, is the FDA now changing its criteria for approval to say, if it can be shown that it is not out of

the realm of question that it might be shown to work, that you are

going to approve it? I’ve never heard such a——

Mr. TEMPLE. We are not approving it. I am trying to reflect the

views of the experts we had on our Advisory Committee.

Chairman BARTON. I understand that.

Mr. TEMPLE. They know perfectly well that these drugs have not

been shown, according to our standards, to work. There is no quesVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00096 Fmt 6633 Sfmt 6602 96099.TXT HCOM1 PsN: HCOM1
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tion about it. I totally agree with that conclusion. That is not the

same as knowing they don’t work, and they were frightened at the

prospect that people would not be able to use the drugs in——

Chairman BARTON. I understand that.

Mr. TEMPLE. That’s all.

Chairman BARTON. One reason your agency has such high esteem in the public is because, almost without exception, all the

time drugs or medical devices don’t get approved until it has been

shown without a shadow of a doubt that they do work unless it is

some cancer therapy or orphan drug where you develop some sort

of an informed consent that the situation is so dire that the patient

is going to die unless almost a Biblical miracle occurs.

That statement you just said, to just cavalierly say, well, we can’t

really say that in some cases it might work, just boggles my mind.

Mr. TEMPLE. I’m obviously not communicating. There is no question that these drugs have not met the standard for approval. I

don’t want to approve them. I cherish the standard. I think the

1962 Act was one of the greatest pieces of legislation in all the

world’s history.

That is not the same as saying that anyone who uses a drug offlabel is doing the wrong thing. The requirement for approval has

to meet—there is a threshold set for approval, and I think that is

entirely appropriate. I value it enormously, and I don’t even believe

it doesn’t apply in orphan drug cases, in cancer drugs either.

But the fact is that data comes in a smear, in a range, and what

may not be anywhere close to what we would need for approval

may inform some people or convince them that they ought to give

something a try. I’m just saying that is a fact. I am not saying it

is a good thing or a bad thing.

What I am saying is that our Advisory Committee was uniformly

concerned that people who hadn’t responded appropriately to

Prozac would have nothing available when they were deeply depressed, suicidal, and the like. That seems a legitimate concern,

too.

That is not talking about making the drug——

Chairman BARTON. I will do this on my own time.

Mr. WALDEN. But don’t virtually every single clinical trial show

there is no efficacy for these drugs in kids and adolescents? Isn’t

Prozac like the only one that shows that for kids and adolescents,

that there is any efficacy?

Mr. TEMPLE. The results are certainly discouraging. Prozac was

three for three.

Mr. WALDEN. No, no. How many studies that have been done in

children and adolescents for this range of drugs showed they had

efficacy for kids?

Mr. TEMPLE. Not counting Prozac, I assume.

Mr. WALDEN. Count Prozac. I don’t care. How many studies have

been done——

Mr. TEMPLE. Three Prozacs, one Cetalopram. There is a study of

Paxil in which all of the endpoints except their primary endpoint

were successful. Some people would think that shows something.

We wouldn’t. We wouldn’t buy it.

Mr. WALDEN. So you don’t buy it.

Mr. TEMPLE. I don’t buy it.

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Mr. WALDEN. All right.

Mr. TEMPLE. Certraline published a report that said we work

when you throw our two studies together. We don’t buy that, but

it is a trend in the right direction. It is not zero, and——

Mr. WALDEN. When it is combined, but not a stand-alone, and I

thought your own agency rejected that.

Mr. TEMPLE. That is what I said. We do not believe that they

have shown effectiveness. Absolutely not. That is the wrong analysis. I am just saying that is not proof that it doesn’t work. I am

obviously not making myself clear. I don’t want to approve these

drugs.

What the Advisory Committee expressed concern about was that

in a world of uncertainty, they thought that you need to be able

to think about using them in someone who hadn’t responded to

anything else and who had no other choices. I am not here to say

that is a stupid thing to do. Those are knowledgeable advisors.

Mr. WALDEN. Yield to the gentleman from New Jersey.

Mr. FERGUSON. Thank you, Mr. Chairman. Dr. Temple, thank

you and your colleagues for being here today. We appreciate you

answering many, many questions that are very important questions.

I may have missed it if someone else asked this question. But

can you tell me why Dr. Mosholder did not present at the February

2 meeting?

Mr. TEMPLE. Yes. We thought that the—let me just try to think

what you’ve heard and what you haven’t heard. Our concern was

that there was uncertainty about what the cases that went into his

analysis meant. They were collected from adverse reaction reports

that were not particularly designed to look at suicidality, and determining whether a given clinical picture represents suicidality is

not entirely simple.

The people at Columbia specialize in trying to sort those things

out, and we were aware of that. Our concern was not with the

analysis that Dr. Mosholder did, which was perfectly right, but

with the very cases that went into the analysis and whether they

were credible instances of suicidality.

So we arranged well before that meeting, the Advisory Committee meeting, and well before his final report, we arranged for

Columbia to blindly review each of the cases and reclassify them.

We didn’t want to present what appeared to be an FDA conclusion

at the February 2004 Advisory Committee.

Mr. FERGUSON. Certainly, he would be capable of explaining that

himself, though, wouldn’t he?

Mr. TEMPLE. Well, no. He believed the analysis was fine. You

know, people can probably disagree about this. We didn’t think he

was wrong. We thought it wasn’t ripe yet. So for us to—you know,

for us to go up and say, oh, he’s all wet, that wouldn’t have been

appropriate, and it is not that we thought it was wrong. We

thought the cases needed to be looked at before conclusions should

be reached.

Mr. FERGUSON. Isn’t that the role of the Advisory Committee, is

to gather information like this and analyze it and make a recommendation? Did you think they would be confused? Are they an

easily confused group?

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Mr. TEMPLE. The Advisory Committee was in no position to review each of the cases. We had no capacity to ask them to do that.

That would have, you know, taken them months. When we discussed this matter with them, they clearly sympathized with the

need to find out what these cases meant. We didn’t get a vote. So

I can’t prove what they thought, but they understood the problem

perfectly well, and expressed no dissatisfaction with it.

In fact, at the most recent Advisory Committee meeting, they

said the review by Columbia was very impressive, that the data

looked better than they could have imagined, and expressed sort of

gratitude that they had something they could readily work with.

Mr. FERGUSON. Wouldn’t the committee be equipped to analyze

the arguments? Isn’t that what they are supposed to do?

Mr. TEMPLE. Well, that’s sort of what I am saying. It wasn’t a

matter of making arguments. We didn’t have a counter-argument.

We didn’t think that Dr. Mosholder’s review was wrong. What we

thought was that the basis for doing the review, for creating the

numbers, was imperfect, because the cases hadn’t been

analyzed——

Mr. FERGUSON. And the Advisory Committee couldn’t possibly

understand that?

Mr. TEMPLE. Well, I think they did understand it, and they

nodded in agreement. But they didn’t vote on it. We didn’t ask

them to vote.

Mr. FERGUSON. They didn’t hear his side. He never got to present

on February 2.

Mr. TEMPLE. Well, let me make it clear. What——

Mr. FERGUSON. They had information withheld from them.

Mr. TEMPLE. What Dr. Laughren showed was the results of each

of the trials, many of which showed more suicidality in the treated

group than the other group. Now he didn’t show exactly Dr.

Mosholder’s data or the cumulative data, but it was easy to see,

and we emphasized this in the professional advisory that we sent

out, that there was more suicidality in the treated group in many

of the studies.

So they knew what the issue was perfectly well, and they also

heard from Dr. Laughren what our reservations about the data

were.

Mr. FERGUSON. I am not at all satisfied with the reason why Dr.

Mosholder was somehow blocked from presenting on February 2,

for the record. Let me move on.

I’d like to go to Tab 40 in the committee’s binder. This is the

minutes from the February 2 meeting. Tab 40 is the minutes. I

want to go to the top of the last page of Tab 40.

Mr. TEMPLE. Hang on.

Mr. FERGUSON. Sure.

Mr. TEMPLE. Top of the last page?

Mr. FERGUSON. The last page of Tab 40, and I am quoting. The

text states: ‘‘The committee advised the FDA to inform the public

and health care workers, including pediatricians and family practitioners’’—it goes on—‘‘of the level of concern regarding possible

harm to a minority of children on anti-depressants and the signs

associated with the side effect.’’

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It is clear that the Advisory Committee wanted you to inform the

public about the risk to children, not the risk to the general population but specifically the risk to children, as reflected in these

minutes. Is that correct? Do you agree with that? That is what the

minutes say.

Mr. TEMPLE. Yes, but I guess we interpreted that as——

Mr. FERGUSON. I am real short on time.

Mr. TEMPLE. Okay. We put a warning that applied to both adults

and children.

Mr. FERGUSON. Right. The Advisory Committee seemed to indicate—they were specific to children, not the general public. That is

what it says. That is what the minutes say. Right? Why didn’t you

issue an advisory specific to the side effects in the pediatric population?

Mr TEMPLE. Because the same side effects occur in adults. Remember, this—we did not write a conclusion that the drugs increased the risk of this, because we thought that was premature,

and the committee didn’t tell us otherwise. But the possibility that

people being given these drugs get worse when they are given them

is a phenomenon that has been observed in both adults and children. We thought the warning should apply to anybody being started on these drugs.

Mr. FERGUSON. But if the committee says in their quotation, in

the quote from the minutes, from your minutes, the possible harm

to a minority of children on anti-depressants and the signs associated with the side effect, why not issue a warning specific to children?

Mr. TEMPLE. Even though we thought the same warning should

apply to adults?

Mr. FERGUSON. Why not? What’s the harm? Why not?

Mr. TEMPLE. Well, in the labeling what would we say about

adults?

Mr. FERGUSON. We consider children and adults different in all

sorts of ways. You do, too. The side effects in children are different

from the side effects in adults. Right?

Mr. TEMPLE. Yes. This was a statement——

Mr. FERGUSON. There is a reason we test on pediatric. There is

a reason we do tests on kids and different tests on adults. We don’t

extrapolate one to the other necessarily.

Mr. TEMPLE. Right, but——

Mr. FERGUSON. We do tests on both.

Mr. TEMPLE. But the potential for getting worse when you are

starting therapy is a phenomenon of both adults and children.

Mr. FERGUSON. Okay. Are the side effects different in children

and kids—between children and adults?

Mr. TEMPLE. Well, we now think that they are, because we have

seen no increase in suicides in adults with a very large data base,

but we now believe there is an increase in suicidal thinking and

behavior in children. But that is what we know now, and the new

labeling will surely say that.

Mr. FERGUSON. Okay. I am going to keep going, because we are

kind of getting fuzzed over here. To me, it is mystifying that, given

this information, that you would not have issued—particularly, because this is what the Advisory Committee seemed to be saying,

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that you wouldn’t have issued a warning specific to kids. Let me

move on.

The minutes go on to note that the committee is concerned that

the public does not know that a strong majority of randomized controlled trials of SSRIs do not demonstrate superiority over placebo

in the treatment of major depression in children and adolescents.

Did you address this concern publicly and through a labeling

change?

Mr. TEMPLE. We did not introduce a labeling change. All the

labeling——

Mr. FERGUSON. Why not?

Mr. TEMPLE. Well, what the labeling all says is that safety and

effectiveness in children has not been demonstrated, and the new

warning moves that statement forward to the warning language.

Mr. FERGUSON. What warning?

Mr. TEMPLE. The warning that all of the drugs got in March—

sorry, after the Advisory Committee meeting.

Mr. FERGUSON. You’re talking about the March 22?

Mr. TEMPLE. We asked for it in March. It was all implemented

by about August, I think.

Mr. FERGUSON. Okay. Which is Tab 44. So it just seems to me

that the agency first tries to determine what information that the

Advisory Committee can handle, for instance pulling Dr.

Mosholder, not allowing him to present his data and information

to the committee, and then when they make a recommendation,

when the Advisory Committee makes a recommendation, you disregard the recommendations that they make.

Mr. TEMPLE. I don’t agree that we disregarded it. The third paragraph of the thing you just showed me says that anxiety, agitation,

panic attacks, etcetera, have been reported in adult and pediatric

patients being treated with anti-depressants. I mean, adults are

people, too. We thought this is a risk that applies to all people who

are started on an anti-depressant.

Mr. WALDEN. Would the gentleman yield?

Mr. FERGUSON. I will yield. I am mystified that, given what is

going on with this issue, that you seem to be incapable or refuse

to decipher the difference between effects on kids and effects on

adults. I will yield to the gentleman.

Mr. WALDEN. Really, I think, what you are asking is: If you knew

it affected children and adults, but you also knew it affected kids

more than adults.

Mr. TEMPLE. We didn’t think we knew that at the time.

Mr. FERGUSON. And worse, more and worse.

Mr. WALDEN. Dr. Mosholder indicated that in his study. This

came out—when did this come out, 2004? This came out in February 2004. Right? You own agency began flagging this in 1996 and

1997.

Mr. TEMPLE. We did not think it had been established—again,

you have heard the debate about that. Obviously, Dr. Mosholder

thought it was well established. We did not think it was established that there was a special risk in children, but we knew that

both adults and children started on therapy, early in therapy, can

have all these things, including increased suicidality. That is what

we wanted to warn about.

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We did not say at this time that there was an increased risk in

children.

Mr. WALDEN. Are you acknowledging that there is an increased

risk in adults?

Mr. TEMPLE. Increased risk compared to no treatment?

Mr. WALDEN. Right.

Mr. TEMPLE. No. We don’t know that.

Mr. WALDEN. So there is no increased risk of suicidality in adults

who are on anti-depressants in the trials?

Mr. TEMPLE. We have done analyses of suicides now, and we

don’t see anything like that. Dr. Mosholder presented at the last

Advisory Committee an analysis of the Paxil adult data using exactly the same approach that was used in the children. That

showed no increase in suicidality in the adults. So at this time,

that appears to be different, but it remains true that, whether

there is an increase or not, increased suicidal behavior and thinking does occur early in therapy.

Mr. FERGUSON. Mr. Chairman, could I reclaim the time that I

don’t have left for one more question?

Mr. WALDEN. Yes, sure.

Mr. FERGUSON. I want to just go to one more, Tab 49, which is

your statement, the FDA’s statement from September 16 on the

recommendations of the Psychopharmacologic Drugs and Pediatric

Advisory Committees. These are the recommendations from September.

Mr. TEMPLE. I’m sorry. Which am I looking at now?

Mr. FERGUSON. Tab 49.

Mr. TEMPLE. Forty-nine? Sorry. Okay.

Mr. FERGUSON. My question is: Given the fact that, in my estimation, you seem to have, No. 1, tried to control the information

that the Advisory Committee was getting; No. 2, seemed to disregard the Advisory Committee’s recommendations that they made

back in February.

What assurance do we have that these recommendations from

September will be followed or adopted?

Mr. TEMPLE. Well, you have the statement about what we are

going to do, and in a couple of weeks you will see the labeling

change.

Mr. FERGUSON. No, no, no, no. The statement says the FDA general supports the recommendations that were recently made. That

is—I mean, my gosh, this is Washington. That could mean anything.

Mr. TEMPLE. Well, let me make it clear. We had some discussion

of this before we came in. The only thing we want to think further

about is the box, for reasons that I explained before and would be

glad to explain again. All the rest of the recommendations are——

Mr. FERGUSON. I heard the conversation about the box.

Mr. TEMPLE. All the rest of them are clearly going to be implemented. We, frankly, suggested half of them.

Mr. FERGUSON. Okay. You said in the New York Times on September 14, ‘‘I think we now—I think that we now all believe that

there is an increase in suicidal thinking and action that is consistent across all the drugs.’’ And you have the Advisory Committee

saying 15 to 8 that they think the black box is a good idea.

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I mean, that is almost the override of a veto. I mean, 15 to 8 is

substantial. What is left? What is the problem?

Mr. TEMPLE. Well, you have to have been to a lot of Advisory

Committees to notice this, but as much as anything else, you want

to hear the words people use to explain why they think what they

think and what the reservations are. All I am saying is we are

going to look at what those are.

I am not predicting that we won’t buy the black box. My guess

is we probably will, but we owe the people who spoke and tried to

advise us a look at what they said.

Mr. FERGUSON. If there is a vote on another issue that is 15 to

8, is it generally adopted or is it something that is not adopted or

do you kind of think about it for a little while longer?

Mr. TEMPLE. Yes, that is a very hard thing to answer, but divided committees recommending approval or not approval—when it

is reasonably close, we don’t necessarily go by the majority, you

know. You sort of have to read what people say and——

Mr. FERGUSON. Is 15 to 8 reasonably close?

Mr. TEMPLE. Well——

Mr. FERGUSON. That is a whitewash.

Mr. TEMPLE. There is no question the majority of the people

thought that it ought to get a box, and they overcame in recommending that their concern that use of the drugs would be overdiscouraged.

Mr. FERGUSON. Recommending a black box is a pretty big deal.

That is not taken lightly. Right?

Mr. TEMPLE. We understand it. One of the questions we asked

them is should we put a black box on it. We put it on their table

so that we could hear their opinion, and we wanted their opinion

and their discussion on the pros and cons, and how they came to

pro, in spite of certain reservations and concerns is extremely informative.

Mr. FERGUSON. You have almost a two to one vote on a—you

don’t see a black box on too many drugs.

Mr. TEMPLE. You see them on a fair number. We are not saying

that we don’t want to do it or don’t plan to do it. We just owe that

one some thought. That’s all.

Mr. FERGUSON. I’m done. Thank you. I yield back.

Mr. WALDEN. Thank you. I now turn to the gentleman from

Michigan, Mr. Stupak, for questions.

Mr. STUPAK. Thank you, Mr. Chairman. This black box—where

is it going to go?

Mr. TEMPLE. Black boxes are always the first thing in labeling.

Mr. STUPAK. Where is the label? Is that for health care professionals or do people get a chance to see that?

Mr. TEMPLE. Sorry. The label refers to the package insert that

is written for physicians.

Mr. WALDEN. Mr. Stupak, I erred. I was committed to the chairman to go to him, because he has to go to mark-up.

Mr. STUPAK. That’s all right.

Mr. WALDEN. Could you——

Mr. STUPAK. Go ahead, Joe.

Mr. WALDEN. Mr. Chairman.

96

Mr. STUPAK. But let me just clarify that. That black box only

goes to physicians. It doesn’t go to the general public?

Mr. TEMPLE. Right. There will be an equivalent emphasis in the

patient labeling, what is called a Med Guide, that we were also

very strongly advised to create. So that will be very prominent in

that form, too.

Chairman BARTON. I apologize for going out of order, but we’ve

got a mark-up on the waste bill upstairs. I thank the courtesy of

Mr. Stupak.

Dr. Temple, have you ever run for any political office?

Mr. TEMPLE. No.

Chairman BARTON. Do you follow Presidential politics?

Mr. TEMPLE. Oh, yes.

Chairman BARTON. Okay. You are aware there is going to be a

debate next week between President Bush and Senator Kerry.

Mr. TEMPLE. So I’ve heard.

Chairman BARTON. How would you feel if you were really looking

forward to that and at the last moment the news reported that it

had been decided that Senator Kerry couldn’t represent himself in

the debate, that Congressman Joe Barton had been appointed to

represent Senator Kerry’s views in the debate with President Bush

about who is qualified to be the next President of the United

States?

Would you think that was a fair thing to do or an unfair thing

to do?

Mr. TEMPLE. Unfair thing to do.

Chairman BARTON. Unfair thing to do. So when the decision was

made that Dr. Mosholder could not present his findings last February, nobody was allowed to even hear what his findings were, but

that when it was finally decided that his findings could be presented last week or the week before last, somebody else did it, and

somebody else did it who probably disagreed with his findings. Was

that fair or unfair?

Mr. TEMPLE. He presented his findings. He compared his findings with the new findings.

Chairman BARTON. Oh, Dr. Mosholder did present his—I was

told he did not.

Mr. TEMPLE. Well, the primary analysis was done by Dr.

Hammad on the new data, but what Dr. Mosholder did was show

how the analyses were similar and different.

Chairman BARTON. Well, now I want to be fair. When I’m wrong,

I’m wrong. I was told that Dr. Mosholder did not get to present his

own findings. That is apparently not true?

Mr. TEMPLE. When do you mean now?

Chairman BARTON. Well, there have been two Advisory meetings,

one last February that I——

Mr. TEMPLE. Oh, I think I misunderstood you. In the most recent

Advisory Committee——

Chairman BARTON. There have been Advisory——

Mr. TEMPLE. A couple of weeks ago.

Chairman BARTON. There was an Advisory at the beginning of

this year in February. Then there was another Advisory just a couple of weeks ago. Isn’t that correct?

97

Mr. TEMPLE. Yes. At the February meeting, he did not present

his analysis. If that is what you mean, that is true. That is what

we talked about.

Chairman BARTON. Well, at that meeting did anybody present

any of his findings?

Mr. TEMPLE. I see. I understand. That sort of depends on what

you mean. The results of the numbers, the number of adverse—of

suicidality events were shown, study by study, not Dr. Mosholder’s

analysis, by Dr. Laughren. I mean, these are the data that we had

that were submitted to us. Those were presented. They showed an

excess in some studies, not an excess in other studies, and they did

not——

Chairman BARTON. Which meeting are you talking about?

Mr. TEMPLE. The February 2004 meeting.

Chairman BARTON. But he was not there?

Mr. TEMPLE. He was there, but he didn’t present the results.

Chairman BARTON. He was there, but he wasn’t allowed to

speak.

Mr. TEMPLE. Yes.

Chairman BARTON. Publicly allowed to speak.

Mr. TEMPLE. He presented other data, but he didn’t present

the—he didn’t present the analysis of the controlled trials in depression.

Chairman BARTON. Well, I would argue that that was unfair.

Now let’s fast forward to a couple of weeks ago. There was another

Advisory meeting. Was he allowed to present there?

Mr. TEMPLE. Yes.

Chairman BARTON. Unencumbered?

Mr. TEMPLE. Unencumbered.

Chairman BARTON. Okay. So then I was misinformed on that. I

was told that he was not allowed at the second meeting to present,

that his data was presented, I believe, by Dr. Laughren. That was

at the first one? Okay. Well, then I was misinformed.

Mr. TEMPLE. At the first one Dr. Laughren presented somewhat

different data that were basically derived from the same data

bases. We didn’t try to present Dr. Mosholder’s views. We just tried

to show why we were worried about these things in the first place.

Chairman BARTON. Well, my main point, and I think it is still

valid: If somebody is viewed as credible, which Dr. Mosholder was

initially when he was appointed, when he was still in the Pharmacological Neuropharm Directorate. He was picked to do the review,

apparently because they felt he was the best qualified. Now I understand that he later got transferred to a different division or different directorate.

Mr. TEMPLE. He moved voluntarily. We didn’t want him to go.

Chairman BARTON. Okay. He moved voluntarily. Anyway, he was

no longer in that group.

Mr. TEMPLE. We consider that a loss for us.

Chairman BARTON. Okay. Well, we agree on that. We agree on

that. You know, if he was the one who was picked to do the initial

review, he should be the one that is picked to do the presentation

of the data. We, I think, all agree up here that the impression is

that he wasn’t allowed to present, because higher-ups disagreed

with him and wanted to muzzle him.

98

Mr. TEMPLE. Well, what higher-ups thought was that the data

weren’t ripe for presentation, because they needed the analysis of

the cases by the Columbia group, and you know, it is always a difficulty when there is disagreement about something like that. But

the people at the next level have responsibility for making that decision.

We thought it was potentially dangerous for the community to

present prematurely what appeared to be an FDA conclusion. You

know, I am positive people can argue that judgment, but that is

what the judgment was.

Chairman BARTON. Well, we all agree that the best advocate for

a position is normally the person who is actually most responsible

for developing the position. You agreed with me that Senator Kerry

would be a little hacked off if Joe Barton got to present his position, because if I was doing the presenting and I say, now this is

what Senator Kerry said but this is really what I think ought to

be, you know, and every time President Bush said something, I’d

say, well, I have to oppose that, but you know, really I do agree

with you, it wouldn’t be a very good debate.

Mr. TEMPLE. This may be more nuance than is safe, but it wasn’t

that we disagreed with him. What we thought was that the data

weren’t ready. So what I didn’t want to do——

Chairman BARTON. Why wouldn’t you let the Advisory Committee—it’s not like you are making a presentation to the unwashed like Members of Congress. You are making the presentation to a technical advisory committee of experts that you yourself—not you personally perhaps, but the FDA has picked.

They certainly ought to be able to determine the nuances of the

data and, if they are really on their toes, they are going to ask him

a lot of very pointed questions trying to pick out any flaws in his

presentation.

Mr. TEMPLE. We could probably have done that and offered our

own critique and then let them choose. What we were worried

about, you know, for better or for worse, is that it would appear

to be an FDA conclusion and that we thought it was premature,

and we thought that was not the right thing to do and was potentially a bad thing for the community.

I think Dr. Laughren has been trying to—can I let him?

Mr. LAUGHREN. Can I just try and clarify?

Chairman BARTON. Yes, sir. This is an open hearing. We are not

going to muzzle anybody.

Mr. LAUGHREN. Okay. You know, let me just say, first of all, that

we fully appreciate Dr. Mosholder’s role in this. As Dr. Temple

pointed out, he was the one who discovered the signal initially, the

potential signal in the Paxil pediatric supplement back in 2002,

and alerted us to this problem with the way the data were coded

that led to the report from Glaxo in May 2003. And everyone

agrees that he was the right person to begin looking at those data.

What he did, he looked at the Paxil summary report, which was

the first one. In the meantime, he began looking back at the pediatric supplements for the other drugs while we were waiting for

data from the other drugs and made a very important contribution

at the internal regulatory briefing in September.

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The focus—our focus changed dramatically over the course of the

fall, as we started looking at the cases and recognized that there

might be a problem in understanding—in whether or not they all

represented suicidalities. That was one major theme we were pursuing.

We were also concerned about case finding. We recognized, as

again we started looking at these documents, that we may not have

gotten all the cases, and that is why late in the year we issued additional requests for more cases from the companies.

A third theme that we were pursuing was getting what is called

patient level data so that we could try and understand the striking

differences between trials.

So this was our focus, and gradually it became clear that we

were going to have to do our own analysis of the data, based on

this more complex dataset. That is why Dr. Mosholder’s role

changed during that period of time. So——

Chairman BARTON. Are you saying he wasn’t competent to do

that?

Mr. LAUGHREN. No, I’m not—well, I’m not saying that. We had

the expertise to deal with——

Chairman BARTON. Who is we?

Mr. LAUGHREN. Well, the Neuropharm Division, in particular the

safety team, Dr. Hammad.

Chairman BARTON. And Dr. Hammad is not in the direct line. He

is kind of a staff auxiliary advisory to the main chain of command

in the Center. Is that not correct? I mean, his job is to kind of double check everybody else?

Mr. LAUGHREN. No, no, no. He did the primary analysis, the definitive analysis that we presented to the Advisory Committee last

week.

Mr. TEMPLE. There is a group called the Safety Group in

Neuropharm that specializes in doing safety analyses, and he is a

member of that group. He, too, is actually moving to the Office of

Drug Safety.

Chairman BARTON. But Dr. Hammad’s—I looked at a flow chart

to try to figure out who everybody is, and my understanding is, of

the group that is here, Dr. Temple is the biggest dog and is an Associate Director, and Dr. Laughren reports directly to you, and

Dr.——

Mr. TEMPLE. Well, Dr. Katz who couldn’t be here is the Division

Director, one of three in the office that I run.

Chairman BARTON. You report to him. Right?

Mr. TEMPLE. He reports to me, and Dr. Laughren reports to Dr.

Katz.

Chairman BARTON. And Dr. Hammad is in a staff group that is

not in the direct chain. Is that correct?

Mr. TEMPLE. No. Well, there’s two Psychopharm groups, one of

which is headed by Dr. Laughren, and there is a safety group that

reports the same way as Dr. Laughren does, to Dr. Katz, and Dr.

Hammad is in that group.

Chairman BARTON. Okay. Well, I have kind of gotten off on a

rabbit trail here. My time has expired. Let me refocus this again

to the members of this subcommittee who have really no ax to

grind except that we want the very best for the American people,

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and in this particular case we don’t want children taking anti-depressant drugs if there appears to be quite a bit of evidence that,

not only does it not help them, in some cases it actually hurts

them, increases the risk of suicidality.

Time after time in reviewing the documents and reviewing the

transcripts and the testimony, you know, it really does appear to

me that the FDA has gone out of its way to short circuit the findings of Dr. Mosholder and create this counter-argument that you

epitomized earlier when you said, well, if there is some evidence

that it might help some people some of the time, why should we

stop it, which seems to me exactly contrary to what the normal

FDA standard is, that if you can’t show that it helps a lot of people

all the time, we shouldn’t allow it.

Mr. TEMPLE. I was trying to describe what our Advisory Committee of people in the field who actually do this were worried

about.

Chairman BARTON. I am just really puzzled about that.

My last thing, again back on Dr. Mosholder: Is it true that, when

ABC contacted him to say that they were considering him for man

of the week, that higher-ups at FDA tried to stop that? Is there any

truth to that?

Mr. TEMPLE. I have no idea. I can’t imagine that we would try

to stop it, but I do imagine that it might have to get cleared, something like that. But I have no knowledge of this.

Chairman BARTON. Would Mr. Mosholder—you are still under

oath. Do you know for a fact if anybody at FDA, when you were

asked to be man of the week for ABC, either did not clear that or

tried to prevent that?

Mr. MOSHOLDER. Actually, I had a conversation about that with

Dr. Seligman, whose chair I just took, and Dr. Seligman had some

reservations about it. In my mind, too, was at that time I had been

asked to be a witness at this hearing, and I had some concerns

about whether it would be unseemly, because being person of the

week involves an on-air interview, whether that would be unseemly

coming just a few days before this hearing.

Chairman BARTON. So who withdrew? Did you withdraw?

Mr. MOSHOLDER. I withdrew. Yes.

Chairman BARTON. You withdrew. You didn’t—I am going to ask

Dr. Seligman as soon as he retakes his seat what is concerns were.

Dr. Seligman, we just heard from Dr. Mosholder that, after talking to you, he withdrew from consideration for ABC man of the

week, which I would think would be something the FDA would

want, that they would want their employees being men and women

of the week to show that they are doing good deeds for the American people.

What were the concerns that you expressed to him about that?

Mr. SELIGMAN. I congratulated him for his selection.

Chairman BARTON. That is not expressing a concern.

Mr. SELIGMAN. No, I know. I am just telling you what the nature

of our conversation was. I just expressed the same concern that I

express over any interaction with the media, which is to make sure

that was careful and thoughtful in his presentation and that things

he said were, you know, succinct so that it potentially could not be

taken out of context.

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Chairman BARTON. So did you encourage him to go forward or

did you encourage him to withdraw?

Mr. SELIGMAN. I did neither. I did neither encourage him nor discourage him.

Chairman BARTON. Okay. Well, if ABC is listening, I would encourage ABC to nominate Dr. Mosholder for man of the week, because I think he is doing the kind of things that we want our researchers and evaluators to do. So for what it is worth, the chairman of Energy and Commerce Committee that has jurisdiction over

the FDA thinks that would have been an excellent selection.

Mr. WALDEN. And Telecommunications.

Chairman BARTON. My time has way expired. So with that, I

yield back.

Mr. WALDEN. Thank you, Mr. Chairman. Now I again appreciate

the courtesy extended by the gentleman from Michigan, and we

look forward to your questions. Mr. Stupak.

Mr. STUPAK. Thank you. Dr. Temple, you said the black box

warnings goes to health care professionals hearing this and not to

the public. Are you going to do an informed consent on this drug?

Mr. TEMPLE. The Advisory Committee didn’t vote on that question, but talked about it and did not think that was appropriate.

The problem here is that——

Mr. STUPAK. So are you going to do an informed consent or not?

Mr. TEMPLE. Well——

Mr. STUPAK. Yes or no?

Mr. TEMPLE. I don’t think that is fully settled, but I would say

probably not.

Mr. STUPAK. So we don’t get the black box warning. There is no

informed consent. How are people out here going to know what is

going on with these drugs?

Mr. TEMPLE. Sorry, I missed the first part of your sentence.

Mr. STUPAK. There is no black box warning that people will receive. There is no informed consent. How are they going to know

that these drugs are not effective and increases possibility of suicide behavior?

Mr. TEMPLE. Well, patients will—with unit of use packaging,

every patient who gets the drug gets the patient labeling, so called

Med Guide. That will have a very prominent statement—whether

we box it or not, I think that hasn’t been determined yet; we don’t

necessarily——

Mr. STUPAK. You are going to put the Med Guide, which is supposed to be in very plain, simple English—you are going to put that

into every packet?

Mr. TEMPLE. Yes.

Mr. STUPAK. Every one?

Mr. TEMPLE. Every one.

Mr. STUPAK. Is the pharmacist going to have to dispense it or is

it going to be in every one?

Mr. TEMPLE. No. We despair of success when the pharmacist has

to dispense it.

Mr. STUPAK. Beg pardon?

Mr. TEMPLE. We don’t think it is successful if the pharmacist has

to do it. That is why we create—that is why we insist, in some

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cases anyway, on unit of use packaging. Unit of use packaging

means——

Mr. STUPAK. Right. Familiar with it. You indicated that—we

have heard testimony the last couple of times that everyone was

quick to say there were no suicides in clinical trials. Is that correct? Yes or no? You can’t shake your head.

Mr. TEMPLE. I’m sorry. Yes.

Mr. STUPAK. Okay. So where did you get the information on the

suicides then?

Mr. WALDEN. Just for our audience, we are being called for one

vote. We will wait, though, a few minutes, and then we will recess

while we make that one vote. Then we will come back. Oh, is it

two votes? Okay. Well, we will do the same drill.

Mr. TEMPLE. There were no suicides in the 4,000 or so patients

who were in the controlled trials—in the pediatric trials.

Mr. STUPAK. Correct.

Mr. TEMPLE. In the much larger data bases that have been carried out in adults, there were suicides, and we have compared the

frequency of suicides on-treatment and off-treatment in those.

There, it comes out even. That is our suicide data.

Mr. STUPAK. So your suicide data would be coming from reports

from the drug manufacturers then, right, or unless it is

voluntarily——

Mr. TEMPLE. No. These are results of trials. There have been a

lot of trials altogether. So we have 30-40,000 people. Dr. Hammad

can tell us how many.

Mr. STUPAK. So the suicides were found in the adult population.

You extrapolated that to make some kind of conclusions as to children?

Mr. TEMPLE. No. We have reached the conclusion about adults.

We don’t know that adults and children are the same. As I said,

when Paxil data in adults were examined in exactly the same way

as they were examined in children, and the children’s analysis

showed a clear excess of suicidal behavior and thinking, no similar

excess was seen in adults.

I don’t have a good explanation for that. I don’t know why that

should be true, but that is what the result is so far.

Mr. STUPAK. If you have no suicides in the clinical trials, do you

have suicides in your adverse events file?

Mr. TEMPLE. Yes.

Mr. STUPAK. With children?

Mr. TEMPLE. Oh, yes.

Mr. STUPAK. And what percentage are reported?

Mr. TEMPLE. Well, we have no idea.

Mr. STUPAK. Wasn’t it true that with your adverse events report,

only about at most 10 percent are ever reported?

Mr. TEMPLE. That is a figure commonly given, but we don’t know

what the right answer is.

Mr. STUPAK. In fact, FDA has used that figure many times,

somewhere between 1 percent and 10 percent.

Mr. TEMPLE. We have used that figure to try to make rough estimates, but that is not the same.

Mr. STUPAK. What you have is only 10 percent of what may actually be out there. We can’t say with certainty, but based upon,

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again, extrapolation of the data, it is basically 10 percent of the

known number.

So when you do your black box warning, are you going to use the

word rarely, that suicide behavior, suicide thoughts, suicide ideation, suicides may rarely occur with the use of these anti-depressants in young people?

Mr. TEMPLE. No. The results of the trials would not support the

term rare. Dr. Hammad estimated—well, it is roughly, just roughly, 2 percent in people who get placebo and about 3.5 or 4 percent

in people who get the drug. That doesn’t meet anybody’s test for

rare.

The excess risk is in the neighborhood of 2 to 3 percent. I think

that is the figure Dr. Hammad gets. So that would not be called

rare.

Mr. STUPAK. When will you end your conversations about the

black box?

Mr. TEMPLE. Really, within a few days, we will reach a decision.

Mr. STUPAK. Right. You have stated in your testimony, the little

bit I have been in—we have a mark-up going on upstairs; so I am

running back and forth between the two. You have stated in your

testimony that thus far these anti-depressants in children, ‘‘doesn’t

work; do not meet the standards for approval; results are discouraging.’’ Then why does the FDA allow these anti-depressants be

given to children under the age of 18?

Mr. TEMPLE. Well, we don’t allow it. The labeling all says, except

for Prozac, that safety and effectiveness——

Mr. STUPAK. Are you telling this committee, if the FDA put on

the thing that says not to be distributed to children under 18, you

don’t have that authority? You can’t do that?

Mr. TEMPLE. Not to be distributed?

Mr. STUPAK. Not to be filled by pharmacists.

Mr. TEMPLE. We could, for example, contraindicate the use in

people under 18.

Mr. STUPAK. Yes, you could.

Mr. TEMPLE. We could. We were advised by our committee in the

strongest way—this was not 15 to 8——

Mr. STUPAK. This was the Advisory Committee. Right?

Mr. TEMPLE. Right.

Mr. STUPAK. You don’t listen to advisory committees if you don’t

want to anyway. Take Accutane. We have been waiting for 4 years

for certification and registry. Four years, we still don’t have it.

After two advisory committees tell you do it, we are still waiting

4 years later.

The FDA does what it wants. Now the bottom line here——

Mr. TEMPLE. I have to protest. We take—I can’t speak to the case

you are referring to here. We take——

Mr. STUPAK. The bottom line is you have the authority.

Mr. TEMPLE. We could seek to contraindicate their use.

Mr. STUPAK. Then if it doesn’t work and increases the possibility

of suicidal behavior in people under the age of 18, why don’t you

do it? Aren’t you supposed to protect the safety and welfare of the

American people?

Mr. TEMPLE. Yes, and we are not sure that your proposal or your

suggestion would protect the American public. It might harm them.

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Mr. STUPAK. Well, let me just read you here. This was an article

handed out earlier today. This is the San Francisco Chronicle, I

think it was, the article. It says on paragraph, column four, first

paragraph: ‘‘But this episode suggests that they’’—being the FDA—

‘‘reject the precautionary principle in favor of the idea that no drug

is dangerous unless it is proven to be so.’’

Mr. WALDEN. I believe that is the British Journal.

Mr. STUPAK. The British Journal? Okay. So in other words,

shouldn’t you err on the side of caution when you are talking about

increased possibility of suicidal behavior in young people, especially

when the drugs thus far has not shown to be effective in the treatment of depression?

Mr. TEMPLE. Well, like the Advisory Committee, I believe we

have to think about a whole bunch of things. There are—I don’t

want to make more of this than they deserve, but it is very clear

that the suicide rate in adolescents has been declining for the last

10 years, the period in which these drugs were started.

Mr. STUPAK. But you can’t give the anti-depressants credit for

that, because you have said that they are not effective in that.

Mr. TEMPLE. No. I have not said that they are not effective, and

it is very important to recognize the distinction.

Mr. STUPAK. Wait a minute. You’re saying now they are effective

in treating depression in young people?

Mr. TEMPLE. No. What I said is that they have not been shown

to our satisfaction to be effective. That is, they haven’t been shown

in well controlled studies to do the things that you are supposed

to do to be considered effective. But we know from depression trials

in adults that lots of drugs that work can’t show that they are effective every time.

In fact, more than 50 percent of all trials in adults fail. Why they

seem to fail so much in children, we don’t know. It could be they

really don’t work.

Mr. STUPAK. You don’t know.

Mr. TEMPLE. We don’t know.

Mr. STUPAK. For all indications right now, we know they don’t

work. We know they increase suicide behavior. Then why don’t you

not allow the drugs be prescribed to children under 18 until you

do know—until you do know? Isn’t it more harm to these people

who may be of fragile mind, suffering from depression, to give them

something like Paxil, which is supposed to make them feel better,

and it really doesn’t? Isn’t the mind then saying, geez, I had a little

hope here; you gave me this prescription, and I would be better. It

doesn’t work. In fact, it is not being effective. Aren’t you really putting that person at risk, at a greater risk with a false hope that

you are giving them?

Mr. TEMPLE. Having untreated depression is risky, too, and we

don’t know——

Mr. STUPAK. Absolutely.

Mr. TEMPLE. We can’t know. You can’t do mortality studies here.

No one will let you do them. We don’t know whether you would be

worse off or better off. The Advisory Committee was quite convinced, but I am not going to tell you they had data to work from.

They didn’t. They were quite convinced that there are many people

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who are suicidal because of their disease who would be made worse

off.

I am not telling you that they know that to be true. I am not

telling you that is evidence. I am not telling you that should lead

to a claim in labeling. But I don’t dismiss it out of hand either.

Mr. WALDEN. If I could interrupt just a second, Mr. Stupak. Are

you able to come back after the votes?

Mr. STUPAK. Sure.

Mr. WALDEN. In which case I would extend you another 5 minutes after the votes. We are probably down to about 7 minutes or

so to go over to vote. What I would like to do is recess the committee, return, and then I will return to you for further questions,

if that is appropriate.

The committee will stand in recess, and we would request our

witnesses to stay here as well. Thanks.

[Brief recess.]

Mr. WALDEN. If I could have our witnesses return to the table,

we will get started here in just a moment. I am going to call the

Committee on Oversight and Investigations back to order.

When we left for the vote, Congressman Stupak had the floor,

and we are extending you another 5 minutes for your continuing

line of questions. So the Chair would recognize the gentleman from

Michigan.

Mr. STUPAK. Thank you, Mr. Chairman.

Dr. Temple, in response to one of the questions by someone up

here, they were asking about the studies, and you said there were

some studies you could not publish concerning the anti-depressants.

Mr. TEMPLE. I said we can’t force people to publish things.

Mr. STUPAK. But can you publish them?

Mr. TEMPLE. Well, let me describe what we can and can’t do.

When we approve a new drug or a supplement to a new drug, our

reviews and things like that are all made public. They are put on

our website. If we do not approve——

Mr. STUPAK. Your reviews, but not the studies?

Mr. TEMPLE. Our reviews, not the studies. But our reviews are

quite detailed. I would modestly say there are at least as informative as a publication in a journal, as a rule.

Mr. STUPAK. Okay. So these are all approved. All these anti-depressants are approved drugs. If another study comes out, do you

get that study? Do you receive that study?

Mr. TEMPLE. Like if they do another study, they must be reported in annual reports, but unless they show something bad, they

don’t have to be—not much has to be done with them. If they show

something dangerous, then they have to be reported to us promptly.

Mr. STUPAK. So they are found in what is called the Annual

Progress Report or another one they call it is the Investigative

Drug Brochure. Correct?

Mr. TEMPLE. Well, that is for a drug that——

Mr. STUPAK. That is for an IND. Right?

Mr. TEMPLE. Yes.

Mr. STUPAK. Okay. In the Annual Progress Report—that is just

a summary of what they did. Right? A summary of these studies,

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the drug companies send it to you: Here’s what we have done in

the past year; here is where reference to our pill has showed up

in a medical journal, or something like that.

Mr. TEMPLE. They may actually put the reprints, but I wouldn’t

want to boast too much about how useful those documents are to

us.

Mr. STUPAK. What if the company fails to leave out part of the

critical point that you are looking for, that something would be

dangerous, such as causing suicide or affecting the central nervous

system. They don’t put it in their annual report.

Mr. TEMPLE. Well, if we somehow become aware of it, we can

bring various legal actions against them. You have to tell us about

things like that. There are examples where delays in reporting to

us have resulted in criminal penalties of various kinds.

Mr. STUPAK. Okay.

Mr. TEMPLE. Of course, we do have to find out about it.

Mr. STUPAK. Sure. Let me ask you this question. Is it true that

the FDA published its Public Health Advisory with a recommended

label change about worsening depression and suicidality in patients

treated with anti-depressants on March 22, 2004?

Mr. TEMPLE. Yes.

Mr. STUPAK. Okay. And who wrote the text of that label change?

Mr. TEMPLE. Wow. Let me ask Dr. Laughren, because he and his

people would have had a major role in that.

Mr. LAUGHREN. The initial draft of the label change came out of

the Division, but there were a number of other groups within the

agency who had input into that, including people in Office of Drug

Safety, Office of Pediatrics and Counterterrorism.

Mr. STUPAK. Well, let me ask you this then. Who would have

been the person to sign off? Who gives it final signature? I know

you have these initial drafts.

Mr. TEMPLE. I mean, something like that goes through parts of

the Commissioner’s office for final sign-off.

Mr. STUPAK. Okay. So Dr. Crawford would be the guy who would

sign off on it eventually then?

Mr. TEMPLE. I can’t say that, but someone in the Commissioner’s

office would.

Mr. STUPAK. If you compare the text that the FDA approved for

the labels of anti-depressants on March 22, 2004, and what is on

the labels of the anti-depressants today, would they be the same?

Mr. TEMPLE. It depends on how the Public Health Advisory is

written. Sometimes they are written before——

Mr. STUPAK. I am talking about the March 22, 2004 Public

Health Advisory. Look at Tab 44. That might help a little bit here.

Mr. TEMPLE. They wouldn’t necessarily be the same. You are

writing in a different way. You are trying to communicate a little

more in the Public Health Advisory.

Mr. STUPAK. Well, explain this to me. Look at Tab 44.

Mr. TEMPLE. They shouldn’t be in major——

Mr. STUPAK. March 22, 2004, says, and I am quoting: ‘‘Health

care providers should carefully monitor patients receiving anti-depressants for possible worsening of depression and suicidality, especially at the beginning of therapy or when the dose either increases or decreases. Although FDA has not yet concluded that

107

these drugs cause worsening depression or suicidality, health care

providers should be aware that worsening of symptoms could be

due to the underlying disease or might be a result of drug therapy.’’

But now the actual labels say this—that is approved by the FDA.

It says, ‘‘Patients with major depressive disorder, both adult and

pediatric, may experience worsening of the depression and/or the

emergence of suicidal ideation and behavior (suicidality), whether

or not they are taking anti-depressants medications, and this risk

may persist until significant remission occurs. Although there has

been a longstanding concern that anti-depressants may have a role

in inducing worsening of depression and the emergence of

suicidality in certain patients, a causal role for anti-depressants inducing such behaviors has not been established. Nevertheless, patients being treated with the anti-depressants should be observed

closely for clinical worsening and suicidality, especially at the beginning of the course of drug therapy or at a time the dose

changes.’’

This is just one example of how March 22, 2004, labeling warning label text is different from the labels we see on the drugs today,

and there is actually another one. My question is, why is the

March 22 language published on your website not good enough to

make it to the labels for the doctors? If you have already weakened

your March 22 recommendation—I believe you have—how can we

trust that you won’t have strong, clearly worded labels on the package that demonstrate the lack of efficacy and the increase of risk

with these drugs?

See what I am saying. March 22 you had pretty strong warning.

That is on your website. Now what we see on the package is completely different.

Mr. TEMPLE. I guess I think the labeling language is of similar

strength, although the words are somewhat different. They both

emphasize monitoring. They both emphasize that you can get

much——

Mr. STUPAK. See, here’s our problem. Most of us up here aren’t

doctors. We looked at it. We read it, and we can’t—we think it is

less. We think it is weaker, and then you tell us you are going to

do this black box warning, which the patients and families aren’t

going to get, and the first notice they are going to get about they

are not being effective and may actually increase suicidal behavior

is when they open up their package, because in there is going to

be a Med Guide.

Isn’t that a little bit too late? They have already had their prescription. They already had it filled. They are already there. They

got it. They’ve spent the money. Now after all this, now you are

going to tell them, hey, wait a minute, before you do this you ought

to know this.

That is our concern up here. Sounds like we got the horse before

the cart, the cart before the horse, whatever you want to call it.

Ain’t right.

Mr. TEMPLE. That’s a different question. That is why we made

sure that the Committee discussed the question of whether there

ought to be some attempt to give something out beforehand. The

difficulty with those, and we do do it sometimes, mostly in relation

to fetal abnormalities where the urgency seems maximal, is that

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how you structure that, how you get these into the office, how you

get them discussed adequately, given the current situation on how

long people spend, is not so clear.

Mr. STUPAK. Right. When you discuss these, it is between the

FDA and the drug company. Is anyone there representing the people, the patients, a public citizen or anyone like that at these discussions that you are having on black box and all that?

Mr. TEMPLE. Well, these discussions aren’t being held with the

drug companies either. We are going to propose labeling. Then

maybe after that——

Mr. STUPAK. And then you go back and forth?

Mr. TEMPLE. Maybe, but——

Mr. STUPAK. No, no, you do, every one of them. I have never seen

a drug company yet accept a first recommendation you made on labeling.

Mr. TEMPLE. Well, we didn’t—I mean, Tom would know best, but

I don’t know how much difficulty we had with the one in March.

Mr. STUPAK. Let’s go back to my original question. See, the confusion with your March 22, what you have on the website, people

get it after they purchase drug. Why don’t we just go to an informed consent? I would strongly urge you go to informed consent

before you ever even get this, when you start treating with these

doctors, that clearly spells out like a Med Guide would that here

is what we find. And if it changes, we can change that informed

consent.

I don’t want a voluntary one, because half the doctors don’t give

it. We want a mandatory informed consent, especially when dealing

with young kids.

Mr. TEMPLE. To do that, you also have to have a completely separate distribution system. It has to be shipped directly to the doctor

or something like that. It is——

Mr. STUPAK. I know doctors are busy, but if you tell them it is

a mandatory informed consent and then they are practicing improperly, they would do it.

Mr. TEMPLE. May be. I think what the people on the committee

thought was that the burdensomeness of it would interfere more

than they wanted with the appropriate use of the drugs. That

doesn’t mean we can’t consider this further, but that is what they

thought. They did talk about this a fair amount.

Mr. STUPAK. I would encourage you to do the informed consent,

and thank you for the extra time.

Mr. WALDEN. You are welcome. Thank you for your participation.

Dr. Knudsen, if you would turn to Tab 73, please, sir. Do you recall ever getting this response from Pfizer? I note it says a desk

copy to you on the bottom of the second page, I believe.

Mr. KNUDSEN. I did not—I don’t recall getting the response from

Pfizer that addressed that request that I had of them to provide

additional information. Once again, just because I don’t recall

doesn’t—let’s see.

Mr. WALDEN. Had you gotten an official company response to the

question about suicidality, what would have been your protocol in

reviewing that response?

Mr. KNUDSEN. Yes. I would have read it and ascertained whether

or not they answered the questions posed to them, whether or not

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they answered the questions adequately, and often indicated what

we—well, NAI, no action indicated, signed my name.

I am not saying I did it for this one, because I do not recall anything from them.

Mr. WALDEN. Right. I understand.

Mr. KNUDSEN. But that is how I have done it in the past.

Mr. WALDEN. Were you able to find any memo in the Zoloft files

you looked at, at the agency or in your own files, evidencing that

you or anyone else within the agency actually reviewed Pfizer’s response?

Mr. KNUDSEN. No.

Mr. WALDEN. Had you been satisfied with Pfizer’s response,

would you have most likely written a memo to that effect, had you

been satisfied with their response?

Mr. KNUDSEN. It is conceivable.

Mr. WALDEN. I think your mike got turned off there, sir.

Mr. KNUDSEN. I may have put a No Action Intended—indicated,

excuse me. But, yes, I——

Mr. WALDEN. I mean, you would have written some response.

Mr. KNUDSEN. Yes. Yes.

Mr. WALDEN. So would you have let your supervisor know that

you had reviewed and received the company’s response to a safety

question you posed? Is that standard operating procedure?

Mr. KNUDSEN. I would have put my response in the box, yes.

Mr. WALDEN. The box?

Mr. KNUDSEN. Well, the mailbox for my supervisor.

Mr. WALDEN. Okay. Thank you. Who was your supervisor at the

time?

Mr. KNUDSEN. Dr. Laughren.

Mr. WALDEN. Okay. Dr. Laughren, do you recall ever reviewing

Pfizer’s response on this issue of suicidality in kids?

Mr. LAUGHREN. Not at that time. I have looked at it subsequently.

Mr. WALDEN. And that was because of the hearing coming up

here?

Mr. LAUGHREN. I just learned about it as a result of document

exchanges and what-not. We did not have the letter that Dr. Knudsen sent to Pfizer in our files. I believe we had to get that from

Pfizer.

Mr. WALDEN. That is our understanding. But we are talking

about Pfizer’s response to that letter.

Mr. LAUGHREN. Right, right.

Mr. WALDEN. But you didn’t have either one, is what you are

saying. Is that in part because you don’t have a record retention

policy? Dr. Temple, what is your policy for saving documents like

this?

Mr. TEMPLE. Materials that are—go ahead.

Mr. LAUGHREN. We did have the May—was it May 28, the date

of the receipt?

Mr. WALDEN. Yes, May 28, 1996.

Mr. LAUGHREN. We did have that in our files. What we did not

have is the letter that Dr. Knudsen sent back in March. We didn’t

have a copy of that letter in our files.

Mr. WALDEN. Oh, I see. But you did have Pfizer’s response?

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Mr. LAUGHREN. It was in our files. But there was no indication

that it had been reviewed.

Mr. WALDEN. I see. And you hadn’t reviewed it prior to the committee bringing this to your attention?

Mr. LAUGHREN. There wouldn’t have been any reason for it to

have come to me, ordinarily.

Mr. WALDEN. Unless he had referenced it to you.

Mr. LAUGHREN. Unless he had given it to me. Right.

Mr. WALDEN. All right, and there is no record of that. Okay. But

I guess the question is: Now you have reviewed it, do you think it

raises serious safety concerns?

Mr. LAUGHREN. No. It basically provides additional information

that supports the view that I expressed in my October—I think it

was October 25, 1996, memo where I commented on the issue that

Dr. Knudsen raised in his March review. It basically supports that

view.

Mr. WALDEN. And what he raised at that time was a serious

safety concern, wasn’t it?

Mr. LAUGHREN. Well, he raised a concern that there might be a

signal of increased risk of suicidality in pediatric patients relative

to adults, but if you have seen my October 25 memo, I believe I

fully addressed that. I mean, there were a couple of issues there.

No. 1, he was comparing risk of suicidality in adult patients who

had been scrupulously screened out for not having depression with

a group of children, many of whom had primary depression. So it

was not, in my view, a reasonable comparison.

Mr. WALDEN. all right. If you would turn to Tab 75, we will send

the book of tabs back your way. This is a memo that you authored

on October 25, 1996. Subject line is: You note that ‘‘a concern about

the possibility of a signal of emergent suicidality, suicide attempts,

gestures or ideation association with Certraline used in pediatric

patients was raised by Dr. Knudsen in his 3/28/96 safety review.’’

In your memo you did not mention the fact that Dr. Knudsen requested and received additional information from the company.

Why is that? You had no idea?

Mr. LAUGHREN. Because, obviously, I didn’t know about it.

Mr. WALDEN. Okay. As you know, the company’s response was

May 1996, and so over 4 months before you write this memo. So

this memo gets written. This is in the file somewhere in theory, because it is there today, and nobody reviewed it?

Mr. LAUGHREN. Well, again I said, now that I became aware of

it very recently, I have reviewed it; and as I say, it supports—

sorry?

Mr. WALDEN. It doesn’t raise serious——

Mr. LAUGHREN. Well, it answers the questions that Dr. Knudsen

raised in his letter to the company. It provides additional data and,

having looked at those data, it supports the conclusion that I am

reaching in my memo, that there is no signal.

I mean, really, the only data in that final safety update that Dr.

Knudsen reviewed back in 1996 that is relevant are the controlled

trials data for that one study in pediatric OCD. That was roughly—

that was the study that we have subsequently reviewed, roughly

100 patients in drug, 100 patients in placebo. There is one

suicidality event. That occurs in a placebo patient.

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That is really the only data there that are directly pertinent to

the question.

Mr. WALDEN. Let me just read the final paragraph of this memo.

It is Tab 75. This is the one that you wrote to file. It says: ‘‘In summary, I don’t consider these data to represent a signal of risk for

suicidality for either adults or children. Supplements are planned

for both depression and OCD in pediatric patients, and when we

have more complete data, including Ham-D data, we can look more

critically at this issue using the now standard approach of comparing the proportions of drug and placebo exposed patients who

show worsening on Item 3, suicidality item of the Ham-D during

treatment. At the present time, current labeling simply notes Zoloft

has not been adequately evaluated for safety and effectiveness in

pediatric patients.’’

So you are saying that you are going to look at additional studies. Right?

Mr. LAUGHREN. Well, basically, what I am saying here is that we

would likely look at the Ham-D item. Every one of these depression

rating scales that is used in evaluating—they are often used in

OCD trials as well. They have a standard suicide item. In the case

of the Ham-D it is the Item 3.

Dr. Hammad as part of his review of these pediatric suicidality

data did look at the item scores. He looked at two measures of the

item scores, both——

Mr. WALDEN. But that was when?

Mr. LAUGHREN. Well, that was recently.

Mr. WALDEN. Right. What happened between 1996 and recently?

Did the agency look more critically at this issue? Did you put this

in the pediatric trials for anti-depressants for kids, the written request?

Mr. TEMPLE. No. They all do that, though. They all do a HamD.

Mr. WALDEN. Well, that is not my question. My question——

Mr. TEMPLE. No, no. It did——

Mr. WALDEN. Now wait a minute. Dr. Temple, did the FDA specifically in your written request ask for exploration of this question,

suicidality?

Mr. TEMPLE. The answer is we did not. But again——

Mr. WALDEN. Why?

Mr. TEMPLE. At the time we issued—prepared and issued the

written request, obviously, it was not an issue that was prominent

in our thinking. Again, keep in mind, up until this point we had

never seen a signal for suicidality in the adult data.

Mr. WALDEN. But doesn’t this memo indicate that this is something you needed to look at?

Mr. LAUGHREN. I did consider, and again, as I am saying, looking

at the data that were available in this safety update, there was no

signal for suicidality in children. The signal that emerged for Zoloft

in pediatric patients came later. It came in the depression trials.

There was one study here, only one study,an OCD trial. There

was no signal in that trial.

Mr. WALDEN. All right. But your memo says, when we have more

complete data, including Ham-D data, we can look more critically

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at this issue. How did you look more critically at the issue? How

did you go about getting more data?

Mr. LAUGHREN. We have looked more critically very recently,

looking——

Mr. WALDEN. Very recently?

Mr. LAUGHREN. Very recently.

Mr. WALDEN. See, I am looking at this gap between 1996-97

when some of these issues began to be raised by various people in

FDA.

Mr. LAUGHREN. Well, raised but also addressed. There is no signal in these data.

Mr. TEMPLE. The first real signal came when Dr. Mosholder evaluated the Paxil data.

Mr. WALDEN. And when was that?

Mr. LAUGHREN. That supplement came in, in probably the spring

of 2002, and he finished his review in the fall of 2002, and that is

when we——

Mr. WALDEN. Didn’t we already go through this with Mr.

Mosholder on a 1997 memo where this was also raised as an issue?

Mr. LAUGHREN. Not suicidality. That was agitation and, by the

way, that information got into labeling. That is included in the labeling for Luvox. There was no issue of suicidality raised in Dr.

Mosholder’s review.

Mr. WALDEN. So from 1997 to 2002, how did the agency look

more critically at the data?

Mr. LAUGHREN. We had no—again, up until the time that Dr.

Mosholder reviewed the Paxil pediatric supplement in 2002, we

had no reason to do anything more. There was no signal.

Mr. TEMPLE. Can I also repeat a distinction I made earlier? We

thought at the time—and you can see that in Dr. Laughren’s

memo—that looking at the suicide item on a Ham-D or the equivalent in a pediatric score would be the way to find suicidality. That

is plainly not true, because you don’t see, as Dr. Hammad’s review

showed—you don’t see any increase in that item even in the trials

that show the increased suicidality.

What turned out to be the place to look, which we didn’t know,

was in the adverse reaction reports, and I would say we don’t know

why that is. Why, if you are not feeling more suicidal, do you have

more suicidal events? I don’t think we know the answer to that.

But it is very clear now that the way to look for suicidal ideation

is to, in a more structured and better way that we have probably

done up to now, look at those events that may represent suicidal

behavior or thinking, and that the——

Mr. WALDEN. There is a March 1991 article, a case study called

Emergence of Self-Destructive Phenomena in Children and Adolescents During Fluoxetine Treatment.

Mr. LAUGHREN. Is that the King article?

Mr. WALDEN. I am sorry?

Mr. LAUGHREN. I am sorry. Is that the King article?

Mr. WALDEN. I believe it is, yes, sir.

Mr. LAUGHREN. Right, and that is reporting on individual cases.

Those are not controlled trials data.

Mr. WALDEN. Is this a peer reviewed study? Is this in Journal

of American Academy of Child and Adolescent Psychiatry?

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Mr. LAUGHREN. It very likely is. It came out around the same

time as the Teicher article reporting on a series of, I believe, six

adults being treated with fluoxetine. Again, it is a suggestion that

there might be something, but it is far from, in any sense, definitive.

Again, we had been systematically looking at the adult data for

almost that entire decade, you know, looking at both suicide item

scores, looking at event data, and more recently had begun to accumulate the completed suicides in adults, had not seen a signal. So

there was no particular reason why that issue should have been on

our radar screen.

Mr. WALDEN. Okay. So, basically, you had no reason in these

trials to even look for it, is what you are telling us? When you put

out the written request——

Mr. LAUGHREN. They were looked at in the routine ways. Adverse events were reported, and the item data were collected.

Again, a signal did emerge in the Zoloft data later on with the two

pediatric trials in depression, but even that wasn’t recognized

until—actually, Dr. Mosholder was the medical officer who reviewed that supplement initially. He did not observe a signal for

suicidality. it is only when he went back during the summer of

2003 and looked at—relooked at the same data that a weak signal

emerged.

Mr. WALDEN. Dr. Temple, did you have the authority to ask the

companies to look at this, to keep better data so you could, in your

written request to them?

Mr. TEMPLE. Let me be clear. You always measure the standard

suicide scores, and we have the capacity to look at those. That is

what you do in all these studies. It is how you measure improvement.

So every time you do these studies, you get a suicidality score,

and we look at it. There isn’t anything the company has to do except give us the data. What we could have thought—what we conceivably could have asked but didn’t know to ask was a better,

more structured, more careful look at events that might or might

not represented suicidality, but we didn’t know to do that.

Mr. WALDEN. But didn’t Dr. Laughren say that in the depression

trials you should look more critically?

Mr. TEMPLE. We were looking at the items in the Ham-D score,

and nobody saw anything. It shouldn’t surprise us that we didn’t

see it, because in the very data that have created the signal we are

worried about now, you don’t see any increase in the pediatric

version of a Ham-D. That is not where it shows up, for some reason.

Mr. WALDEN. I guess, as I have listened to this, and I have sat

through these hearings a long time, the picture that begins to

emerge in my mind isn’t a pretty one, because it is one that says

you are worried less about suicidality than in continuing to allow

physicians to prescribe a drug that most studies show at best has

no effect in treating depression in kids and adults.

Mr. TEMPLE. I don’t agree that that is our conclusion. We spent

tremendous resources and devoted tremendous effort to evaluate

the suicidality question.

114

Mr. WALDEN. Well, when Dr. Mosholder does the review and says

I am spotting something here that is very troubling, when you are

dealing with drugs in kids that virtually every trial shows have no

effect and Dr. Mosholder is finding some link to suicide, you—well,

it seems to me, my opinion is you ended up on the side of let them

prescribe it, because they might be okay; we don’t necessarily agree

Mosholder has got this right; we are going to go run it out somewhere else and see, and take that risk.

Mr. TEMPLE. We didn’t think we were letting them prescribe it

or not letting them prescribe it. The question we were trying to

face was do we have enough information to say there is increased

suicidality in children given these drugs. That is what we were

grappling with.

Mr. WALDEN. You have said earlier today that you didn’t want

to discourage the prescribing of these off-label, because they may

work in some people.

Mr. TEMPLE. That is a different question. We thought that it was

very important to get the right answer on this question. That is

correct.

Mr. WALDEN. Well, I will tell you, I guess that is where we are

just going to agree to disagree maybe, but if I had to err and I saw

a sign from one of my top scientists that I handpicked to take a

look at this and who I have a great respect for, and he came back

and said I have looked at the data and I am seeing a link to suicide

in kids, I’d say we better err on the side of caution here. And

maybe you got to go peer review it, but meanwhile since most of

these drugs don’t show any efficacy in kids, let’s err on the side of

against suicide.

Mr. TEMPLE. But we put out several public announcements saying that you should be careful and that we are worried about this.

We didn’t change the label, though. That is correct.

Mr. WALDEN. I have way overrun my time. Thanks for your patience. I yield to the ranking member, Mr. Deutsch.

Mr. DEUTSCH. Dr. Temple, in an earlier point there was a discussion regarding this issue of different sort of contraindications for

children versus adults, and you are saying that it applies to both—

you know, no separation of warning. At what point is a recommendation that there be a separate warning? Are there separate

warnings—I mean, how atypical is this? Is this the process? Is this

the procedure? Are there cases where you do have separate warnings?

Mr. TEMPLE. Well, the warning language that will describe the

now documented increased—now we believe it is documented.

Maybe someone else thought it was documented before. What we

now believe is the documented increase in suicidality in children.

That will be a separate statement, because we don’t think such

a——

Mr. DEUTSCH. What tips it to make that difference, the separation?

Mr. TEMPLE. Well, it isn’t so much the separation, but we

now——

Mr. DEUTSCH. Well, the dual warning.

Mr. TEMPLE. Well, we now believe—we have not seen such a

thing in adults. As I mentioned before, Dr. Mosholder presented an

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analysis on Paxil that quite clearly does not show that finding in

an adult population, using the same methods that showed it in pediatrics.

So you need a special warning on that subject for children, because they are the ones who get that reaction. The warning in

March was about pay attention to people when you are starting

therapy. That is still a good warning for everybody. That still applies to everybody.

Mr. DEUTSCH. I guess the question I am trying to get at is at

what point do you tip the balance and then say a separation for

children?

Mr. TEMPLE. I don’t think it is a balance. I think, as soon as you

have information that says children are different, you do it.

Mr. DEUTSCH. And are you looking for that information or is it

just——

Mr. TEMPLE. Well, one of the points of doing studies in children

is that very point, to see if they respond differently.

Mr. DEUTSCH. Right, but is that only done in terms of, you know,

the incentives that we have put on in terms of increased exclusivity

based upon that issue?

Mr. TEMPLE. The usual request for data, written request for

data, includes a request for studies of effectiveness, pharmacokinetic studies because that can be something, and a safety study

. That is what they usually consist of.

Mr. DEUTSCH. Right, but generally those safety studies don’t

break out children. So that——

Mr. TEMPLE. Sorry. This is for a written request on gaining pediatric exclusivity.

Mr. DEUTSCH. Right.

Mr. TEMPLE. So that is only children.

Mr. DEUTSCH. Right. Right, but if it is a pediatric exclusivity,

then you would have that. But outside of that, a pediatric exclusivity, then you would have no information.

Mr. TEMPLE. Outside of that, it is extremely hard to get any

studies in children. That is why we have the Best Pharmaceuticals

for Children Act, because children—well, it is extremely unusual,

and most people would say it is not appropriate, to start studies

of children before you have the drug properly worked up in adults.

There’s a lot of nervousness about, you know, children can’t give

consent and so on.

So it has always been true, whether we have the Best Pharmaceuticals for Children Act or before, that we expected the pediatric

studies to be done afterward.

Mr. DEUTSCH. If I can switch to Dr. Seligman, I have a series of

questions, but I want at least to open it up and give you an opportunity, because my understanding, this has not been brought up at

this point, which is the investigation regarding—I guess in response to the San Francisco Chronicle article detailing the FDA’s

decision to remove Dr. Mosholder’s presentation.

If you can at least give us your perspective of why that investigation began and the appropriateness of that investigation.

Mr. SELIGMAN. Certainly. Both prior to and subsequent to the

publication of two articles in the San Francisco Chronicle, a number of staff in the Office of Drug Safety approached me raising a

116

concern of the possibility that there may have been an inappropriate disclosure of confidential information to the reporter at the

San Francisco Chronicle.

Upon receipt of that information, as you have in your book, I forwarded those concerns on to the Office of Internal Affairs at the

FDA.

Mr. DEUTSCH. Did you result in finding who had leaked the information?

Mr. SELIGMAN. I’m sorry?

Mr. DEUTSCH. Did you find out who leaked the information?

Mr. SELIGMAN. No, I did not.

Mr. DEUTSCH. If you can turn to Tab 65, an e-mail dated February 20, 2004, from yourself to Horace Coleman and Thomas

Doyle at the Office of Internal Affairs in which you outline your

reasons for initiating this investigation. You attached an article,

the San Francisco Chronicle article.

I assume you are familiar with the article. Is that correct?

Mr. SELIGMAN. Yes, I am.

Mr. DEUTSCH. Your e-mail states that a member or members of

the staff of the Office of Drug Safety may have inappropriately disclosed information of a sensitive matter.

Were staff members of the Office of Drug Safety the only people

with access to the information contained within the newspaper article?

Mr. SELIGMAN. No, they were not.

Mr. DEUTSCH. But you were only concerned with the activities of

your staff?

Mr. SELIGMAN. No, I was not.

Mr. DEUTSCH. Then why is the memo only talking about the staff

of the Office of Drug Safety?

Mr. SELIGMAN. Only members of the Office of Drug Safety raised

the concern to me that such information had been improperly disclosed.

Mr. DEUTSCH. Why would that be?

Mr. SELIGMAN. Because I am their direct supervisor.

Mr. DEUTSCH. Right, but if you are asking Internal Affairs to be

looking for a leak in your office—I mean, the leak would only be

within that particular group of people?

Mr. SELIGMAN. I don’t believe I stated that I thought the—that

is correct. I did say that I am concerned that a member or members of the staff of the Office of Drug Safety may have inappropriately disclosed information. I did state that, although in my interview with the Office of Internal Affairs, I did point out that there

were clearly others who had access to such information as well.

Mr. DEUTSCH. If you turn back to Tab 66, the report of the investigation, on page of that report it notes that you named five employees of the ODS who had been called at home by Waters. How

did you know that these five individuals had been called at home?

Mr. SELIGMAN. They either came to me or they reported such to

my deputy, Dr. Anne Trontell, who informed me of that information.

Mr. DEUTSCH. And apparently another ODS employee, David

Bram, merely because he had been very vocal in the past regarding

the scientists’ findings being suppressed—did you call—again, is

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that—we are trying to understand why—I mean, were you suspicious of people within your own group for any particular reason

because of actions like that?

Mr. SELIGMAN. As I indicated in the interview, the investigator

asked me whether there were people of whom I had particular concern in the office, and I indicated as such, that there were such individuals.

Mr. DEUTSCH. If you turn to the conclusions on page 6, you will

note the initial conclusion was that no evidence was found that

classified or proprietary information from the FDA was released. In

fact, the release of the classified or proprietary information is the

only basis to initiate an investigation into a leak. Is that correct?

Mr. SELIGMAN. That is correct.

Mr. DEUTSCH. So let me just again follow up on Tab 69. The

fourth page of that exhibit is headed by the date 5/7/04. This is a

document which Horace Coleman of the Office of Investigation noticed that he is closing the case, and further noticed that he had

to ask you to contact Dr. Mosholder to assure him that he was not

a specific target of this investigation, that OIA found no evidence

to indicate that classified or proprietary information had been released and that OIA was closing the investigation.

Why did Mr. Coleman need to have you assure Dr. Mosholder

that he had not been the target of this investigation?

Mr. SELIGMAN. I don’t know the answer to that question, but I

did reassure Dr. Mosholder of that fact.

Mr. DEUTSCH. On that same page, Dr. Coleman notes that he

had advised you that he would also contact the CDR Director

Galson to advise him of the above information. Since Galson had

left the office to attend an awards ceremony, he would be requesting his director, Terry Vermelion, to reach out and debrief Director

Galson.

This raises several questions. What was the urgency to get this

information to Galson?

Mr. SELIGMAN. I have no—I don’t know the answer to that question.

Mr. DEUTSCH. And what about the propriety to initiating an investigation? Whom did you talk to in CDER and what were their

opinions about your proposed actions?

Mr. SELIGMAN. I took these actions independently. I informed Dr.

Galson, who is indeed my supervisor, that I was considering such

action, but received no direction from him, one way or the other,

as to whether I should take it. He was the only person with whom

I discussed these matters.

Mr. DEUTSCH. Who did you keep informed regarding the progress

of the investigation?

Mr. SELIGMAN. The only time I received any information about

the progress of the investigation was at the conclusion of the investigation on May 10 when I met with Agent Coleman and Kurisky

who provided me the report and debriefed me on the investigation.

Mr. DEUTSCH. One final question. This summary report, also Dr.

Hammad’s reanalysis and its comparison to Dr. Mosholder’s original work was widely reported in the press before FDA released any

of the information publicly.

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My understanding is you did not initiate an investigation into

these leaks and, if not, why not?

Mr. SELIGMAN. I did not report those allegations to the—I did

not—that is correct. I didn’t mention that to the Office of Internal

Affairs.

Mr. DEUTSCH. Why was that different than the earlier release?

Mr. SELIGMAN. Probably no different than the earlier release.

Mr. DEUTSCH. I mean, there is no basis for the difference? The

original investigation is technically considered a criminal investigation. I mean, is it just by whim that we start criminal investigations? I mean, is there some basis of differentiating?

Mr. SELIGMAN. This is not treated as a whim. I take, and I imagine everyone at the agency takes the protection of proprietary information and trade secret information very seriously. When allegations of such are brought to my attention, I——

Mr. DEUTSCH. Let’s be very specific, though. The Mosholder thing

didn’t involve proprietary information.

Mr. SELIGMAN. As it turned out, that is correct.

Mr. DEUTSCH. Right, but even the allegation, even the report

wasn’t proprietary.

Mr. SELIGMAN. The allegation had to do with inappropriate disclosure of——

Mr. DEUTSCH. Yes, but not proprietary.

Mr. SELIGMAN. That is correct. Inappropriate disclosure of confidential information. That is correct.

Mr. DEUTSCH. I mean, I am just going to ask one more time and

give you a chance to maybe try to be clearer or think again. But

why were these two leaks treated differently?

Mr. SELIGMAN. I can’t explain why they were treated differently.

Mr. DEUTSCH. And it was your decision to treat them differently.

Mr. SELIGMAN. It was probably my oversight in the latter circumstance to treat it differently, yes.

Mr. DEUTSCH. Thank you.

Mr. WALDEN. Dr. Seligman, can we go to this affidavit again.

Mr. SELIGMAN. Certainly. What tab was that?

Mr. WALDEN. This is troubling just in—this is the one that I

think is Tab 57, I believe, sir. Now walk me through again. What

was the reason for, and who would have suggested that Mr.

Mosholder modify this?

Mr. SELIGMAN. I wasn’t involved in that at all.

Mr. WALDEN. Who was?

Mr. SELIGMAN. I would have to turn to Dr. Mosholder for that.

I wasn’t involved in the discussion or consideration of this affidavit.

Mr. WALDEN. Okay, but this is an affidavit that was provided to

you. Right? The original affidavit?

Mr. SELIGMAN. The affidavit did appear in the May 10 report.

That is the first time that I saw it.

Mr. WALDEN. All right. So it was an official affidavit. It comes

to your—it is part of your investigation. Right?

Mr. SELIGMAN. It was part of the Office of Internal Affairs investigation Mr. WALDEN. I’m sorry. All right, part of the Office of Internal Affairs.

Mr. SELIGMAN. I did not conduct any such investigation.

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Mr. WALDEN. All right. So I guess what I am trying to figure out

with this affidavit is what was the need to—who can answer why

this affidavit would need to be altered to be presented to somebody

else?

Mr. TEMPLE. I don’t think anyone at the table can. It was my understanding that a letter or something like that has been sent to

the committee explaining all that. Am I mistaken?

Mr. WALDEN. All right. If there is nobody here that can address

that, I believe we do have a letter. I just remain concerned about

it is all. I was hoping to dive in a little deeper on it, because it is

sort of——

Mr. TEMPLE. I am sure, if after looking at our response the committee has more questions, we will be glad to answer them.

Mr. WALDEN. I appreciate that, Dr. Temple. Dr. Hammad, would

you agree that, with only 400 or so person years of exposure that

FDA cannot rule out that there is a risk of suicidal behavior of one

out of 100? I’ll make you a deal. You turn your mike on, and I will

repeat the question. There we go.

Would you agree that, with only 400 or so—we are talking about

the pediatric clinical trials. Would you agree with only 400 or so

person years of exposure that FDA cannot rule out the possibility

there is a risk of suicidal behavior of one out of 100?

Mr. HAMMAD. Actually, I did not deal with the person years. I

used the individuals as the unit of analysis. So I can’t answer the

question, because I did not analyze it.

Mr. WALDEN. Dr. Mosholder, would you mind returning, and perhaps you could help us on this question. I appreciate your long day

here, sir.

Here’s the deal. You have 10 million prescriptions for anti-depressants written on an annual basis for children in the United

States, and so how many person years of exposure would you estimate this prescription volume represents?

Mr. MOSHOLDER. Well, 10 million prescriptions, just a very rough

rule of thumb, one would figure a month per prescription is usual

practice. So that would be 10 million months divided by 12. So I

guess that is something like 800,000 person years, if my arithmetic

is correct.

I think you may be referring to a calculation that was in my

March consult report, if I may. If that is in this binder, perhaps

I can refer to it.

Mr. WALDEN. Yes, sure. I think it was in your presentation, too,

the PowerPoint presentation that is dated September 13, 2004. It

is one of the slides there. Reference is 406.9 patient years.

Mr. MOSHOLDER. Oh, yes, that is correct. Having observed no actual suicides in that amount of person time, there is a way to calculate sort of the upper limit of what a true number of suicides

might be expected, which I did in my March consult. If it is in the

binder, I can probably find that.

Mr. WALDEN. We are going to see if we can’t find it in the binder.

It looks like there are 74 sponsored defined suicide related events,

54 serious, it says on your slide. But again we are trying to find

the right tab in our binder of documents. Tab 53, I am told.

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Mr. MOSHOLDER. Oh, yes. These are my slides from last week.

The calculation I was referring to, I think I can find in the March

consult document, which I think may address your question.

Mr. WALDEN. Well, I’ll tell you. Why don’t we go to this question,

the one that is more recent, dealing with the 400. I guess the question is: Would you agree that with only 400 or so person years of

exposure that FDA cannot rule out there is a risk of suicidal behavior of 1 out of 100?

Mr. MOSHOLDER. I am not sure I——

Mr. TEMPLE. You don’t mean suicidal behavior. You mean suicide.

Mr. MOSHOLDER. Do you mean—yes, that was my question.

Mr. TEMPLE. Suicidal behavior, we know, occurs at 2 percent in

the control group and about 4 percent in the treated group. So as

Dr. Hammad showed, there is a 2 to 3 percent frequency of that.

I think you must be referring to how sure can you be that there

are no suicides, and the answer is, with that exposure, you don’t

have much information on that.

Mr. MOSHOLDER. Yes. If I can refer to my March consult, which

is Tab 29, page 20 at the top paragraph, this is a calculation I did

based on some statistical assumptions. The upper one-sided 95 percent confidence limit for the actual rate given in observation——

Mr. WALDEN. Dr. Mosholder, can I interrupt you a second, sir.

What page in that document are you referring to?

Mr. MOSHOLDER. Page 20.

Mr. WALDEN. Page 20. Thank you. Okay, and where are you on

that page?

Mr. MOSHOLDER. The top paragraph on that page, I think, is

maybe pertinent to your question.

Mr. WALDEN. Okay. Go ahead and read that for us, would you.

Mr. MOSHOLDER. Yes. What it says is that the upper 95 percent

confidence limit, as we say, for an actual rate in the population

given an observation of zero suicides out of 407 patient years of exposure is 1 in approximately 136 patient years, the point being not

the numbers so much, but just to illustrate that 407 patient years,

as we reckon these things, doesn’t—it only goes so far in reassuring

about whether or not there is a risk of actual suicide as opposed

to suicidal behavior, which we have already established is increased.

Mr. WALDEN. So, basically, 400 patient years is not a very long

time for the kind of research you need or the data you need?

Mr. MOSHOLDER. Well, the real question here, one of the limitations of all this is that the real issue is whether there is an impact

on suicide, not just suicidal behaviors, and we don’t have enough

information to really address that as adequately as one would like.

Mr. WALDEN. But there could be a risk of death?

Mr. MOSHOLDER. There could be——

Mr. WALDEN. You can’t rule that out either.

Mr. MOSHOLDER. There could be. The clinical trials aren’t long

enough in exposure to give us a precise risk estimate.

Mr. WALDEN. But you do know from the data we have that there

is a higher risk of suicidality. Correct?

Mr. MOSHOLDER. That is true.

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Mr. WALDEN. Okay. All right. Dr. Temple, on page 4 of your testimony you state, the pediatric suicide rate, ‘‘has fallen about 25

percent over the last decade, the period in which the use of antidepressants has grown steadily. This association does not prove

that the increasing use of anti-depressants is the cause of the decline in suicide, but it at least is suggestive.’’ However, according

to the slide presentation by Dr. Diane Wiskausky of FDA’s Office

of Drug Safety before the September 2004 Advisory Committee

meeting, the increasing use of anti-depressants and decreasing suicide may simply co-exist and may not relate at all to each other.

Her slide states that correlation does necessarily imply causality,

and that numerous factors may be coincidental, not causal.

Dr. Temple, did you ever have a discussion on ecological association with Dr. Wiskausky?

Mr. TEMPLE. Well, we talked a little at meetings about this. I

don’t think I had a particular discussion, and I don’t disagree with

the assertion that these kind of data are hard to interpret. There

could be other factors. But these were presented to us at an Advisory Committee by people who thought that there weren’t any obvious other explanations, and it is something to be considered.

I would never allege that that is proof. It is not a controlled trial.

You can’t do controlled trials of that, but it is what you got. And

it also doesn’t seem to be going up, which is not a trivial matter

either, because the drug use has been going through the roof, as

people have pointed out.

Mr. WALDEN. If that is all the case then, why would the Europeans suddenly find there are problems?

Mr. TEMPLE. Well, I don’t think the Europeans found anything

that we didn’t find also. In fact, they used our data. The question

is what to do about it. What they decided to do about it was tell

everybody to start with Prozac and, if that doesn’t work, only experts should use the other drugs.

You know, it depends on the arrangements you have, whether

experts are available, and a lot of other things. That determines

what you do.

One of the major concerns of our advisors was that people who

aren’t really knowledgeable about these drugs are using them, and

that is one of the reasons, you know, all these warnings go in

there. One of the hopes—there is sort of pro and con here. One of

the hopes is that it will scare people who aren’t very qualified into

sending people to doctors who are.

Nonetheless, the same figures, I understand, are seen in Europe,

too, that the rate is declining.

Mr. WALDEN. But they prescribe a far lower percentage, do they

not, among this class?

Mr. TEMPLE. Yes, they do. That is correct.

Mr. WALDEN. Do you know the difference?

Mr. TEMPLE. No, I wouldn’t have those figures.

Mr. WALDEN. I thought I had heard it was like 1/6 of what we

do in young people.

Mr. TEMPLE. That could certainly be.

Mr. WALDEN. That would tend to lend some credence to Dr.

Wiskausky, her comment that it may not be causal.

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Mr. TEMPLE. Well, or it could mean they are better at picking the

people who really can benefit.

Mr. WALDEN. I see.

Mr. TEMPLE. One of the concerns that was expressed. There isn’t

any doubt that people—almost everybody thinks the drugs are used

casually for people who really probably don’t need it, and if there

is a risk of making people worse, there may be no compensating

benefit in those people. So that is a legitimate worry.

Mr. WALDEN. Just seems like, when these concerns have been

raised, again it seems like effort by the FDA hasn’t been to put

that word out. You’ve really erred on the side of caution in terms

of putting any word out there that there may increased rates of

suicidality, and yet when the studies are there that show these

may be no more effective than sugar pills, that doesn’t seem to be

something that gets put out there much. I just—I don’t get it.

The Chair recognizes the gentleman from Michigan, Mr. Stupak.

Mr. STUPAK. Thank you, Mr. Chairman. On the last document

you just showed from Diane Wiskausky—this was shown at last

week’s Advisory Committee hearing—underneath there it mentions

a patient level controlled observation study, the Jick, et al., study.

Is that Dr. Jick from Saskatchewan, Canada? Do you know?

Mr. TEMPLE. No. I think he operates out of Seattle.

Mr. STUPAK. Okay. I was interested in your conversation when

you were going back and forth with the Chair on, you call it,

suicidality scores or signals, and you were saying, not that Dr.

Mosholder was wrong, but you were looking at different signals,

and there’s different signals to look at, and you mentioned the

Hamilton-D scale, Hamilton depression scale, Ham-D you called it.

Okay? Remember that?

Mr. TEMPLE. Yes.

Mr. STUPAK. Earlier today when Dr. Mosholder was testifying, I

had a couple of exhibits there. One was pharmacology/toxicology

consultation from September 2001, and that was on Accutane, but

they related to an SSRI. Remember that discussion?

Mr. TEMPLE. Yes.

Mr. STUPAK. Then I had the PET scan which, again with

Accutane at 4 months, showed a decrease in the brain in the frontal orbital lobe. You remember that?

Mr. TEMPLE. I remember that. Not that I know how to read

those.

Mr. STUPAK. I’m not asking you to read it. But that study showed

that the 17-year-old was noted by her family and clinician to have

behavioral disturbances and dropped out of school. She did not,

however, have a clinically significant increase in depression as

measured by the Hamilton depression scale. Even though we can

see a physical change in the brain, the Hamilton-D scale did not

pick it up, but the PET scan picked up.

Are we maybe looking at the signals?

Mr. TEMPLE. Maybe Tom knows the answer to this. I don’t know

how well any particular brain lesion or finding has been correlated

with depression. The world is full of people who are trying to do

that, to try to pick out who is going to be a responder and things

like that. But I don’t know that literature. So I don’t know whether

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there is a credible PET scan that indicates depression or anything

like that.

Mr. LAUGHREN. I am not an expert in that area, but from what

I know, most experts agree that we don’t understand—we really

don’t understand the pathophysiology of depression or any other

psychiatric illness. But what I wanted to come back to is this issue

of whether or not the Ham-D, as it is currently used, or any other

depression rating scale, is an adequate instrument for assessing

suicidality.

I think that is one of the things that we have learned here, and

one future direction in which we are moving and trying to greatly

improve our ability to do ascertain it for suicidality. This is one of

the things that we hope to come out of this collaboration with Columbia University.

The one thing that they have done is help us in classifying more

appropriately and rationally events, but the other thing that was

apparent in these trials is that it appeared patients were not asked

all the right questions.

Mr. STUPAK. Well, isn’t the questions on the Hamilton-D scale

the same?

Mr. LAUGHREN. No, no. Again, there is no clear instruction on

these instruments as to what sort of follow-up questions should be

asked if a patient responds positively. That is something that Columbia is working on, developing an instrument that gives clinicians very clear instructions about how to follow up if there——

Mr. STUPAK. Sure, but the point here is the patient, whether you

want to believe the PET scan or not, had social behavior, like dropping out of school and behavioral disturbances, but one of the

scales you used, the Hamilton-D scale, to judge depression didn’t

pick it up, which would indicate—which would indicate either the

person didn’t tell the truth when they did the testing on the Hamilton-D scale and is good enough to fool the clinician and everything, or does it really beg to another question that maybe there

really is something going on here in the brain with these SSRIs

that we are not picking up and we never thought of before.

That’s the only question. I am putting forth another possibility

here, because the jury is still out, as you keep saying, and if the

jury is still out, I think you ought to start looking at other factors,

because obviously you guys are missing something.

I think Dr. Mosholder, more or less, said that. You didn’t want

to believe his stuff. So you went to a different set of signals, and

those set of signals, at least according to the little bit I have seen

from this one study, can be fooled.

Have you ever thought about bringing in outside experts other

than just the FDA, like a workshop to bring in other experts and

see what is happening with the orbital frontal cortex, which is an

area we know mediates depression, or the hippocampus with

retinoids and all these other things, and the SSRIs. Have you

thought about bringing in outside experts, outside the FDA, to take

a look at this data and ask them their suggestions on how do we

get to this problem, which we don’t seem to have a good answer

for?

Mr. LAUGHREN. It is undoubtedly true that our understanding of

depression and other psychiatric illnesses is in its infancy. We realVerDate 11-MAY-2000 09:23 Jan 03, 2005 Jkt 000000 PO 00000 Frm 00131 Fmt 6633 Sfmt 6602 96099.TXT HCOM1 PsN: HCOM1
124

ly do not understand them at a biological level. There is a lot of

work going on. You know, it is something that we would hope in

the future to have a better understanding of.

There is a lot of work going on, trying to identify various genetic

markers and other things that might help us make distinctions

among people who clinically all look the same.

I mean, that is one of the problems, is that you have a number

of people who all have the same—roughly the same clinical state,

but they may have different underlying pathophysiologies, and that

may explain why some respond to drugs differently than others,

both in a positive sense and in a negative sense. We just don’t understand this.

Mr. STUPAK. Absolutely. So that is why I am asking, have you

brought in different people for a workshop or a study to look at this

anti-depressant, this SSRI, to see what are we missing here? Do we

have different ideas on how best to explore it, to measure it, test

it, to do some studies?

Mr. TEMPLE. Tom is going to know this better. There are just

constant workshops on these very questions, some of them devoted

to——

Mr. STUPAK. Okay. But I am asking about SSRIs. Have you done

that, like you have done for Accutane and some of these others?

Have you done that? That’s what I am asking.

Mr. TEMPLE. You mean to see if there is something about the effects on the brain of SSRIs that would tell you something? Is that

the specific question?

Mr. STUPAK. No. The question was: On SSRIs have you brought

in to do a workshop to try to figure out maybe what else—are we

just missing something, just kick it around with the experts,

whether it is the talk about SSRIs, the effect on hippocampus

where we know there is depression, the frontal orbital cortex where

we know it mediates depression, different ideas other than—you

know, we all, even Members of Congress, believe it or not, get rigid

in our thinking, and sometimes we don’t think outside the area and

bring i n other experts to help us out.

Have you done that in this problem which has confronted you on

these anti-depressants? That’s all the question is. No trick, just a

simple question.

Mr. TEMPLE. I’m sure Tom would know better. There are constant workshops on every neurologic disease and every psychiatric

disease you can name on these very subjects. They must, by definition, deal with the question of whether the drugs work differently

and things like that.

I mean, I don’t go to those workshops, but the people in the Division regularly would. The interest in those things is partly because

people, as Tom said, hope to find out who is a responder and who

is not, who gets toxic and who doesn’t, and it is partly because people hope to be able to choose drugs to develop better on the basis

of the effects on some of these markers.

So there is a tremendous amount of interest in it. But I can’t

speak to SSRIs particularly.

Mr. STUPAK. Okay. Let me ask you this, Dr. Temple, just a couple of quick questions here. My time is almost up. I want to ask

a couple of series of questions on the pediatric exclusivity.

125

As I understand it, there’s 293 written requests that have been

written by the FDA for products to be studied in children. Of these

393, studies have been submitted on over 110 products. How many

of these studies were efficacy studies?

Mr. TEMPLE. I am just not going to know the answer to that. In

neurology——

Mr. STUPAK. Do you require efficacy studies on all drugs? Do you

require efficacy study? No?

Mr. TEMPLE. Not necessarily.

Mr. STUPAK. Why not?

Mr. TEMPLE. There are some kinds of drugs where the pediatric

request is based on what you call a pharmacologic effect. For example, if you wanted to see whether a beta blocker works in children,

you might look at heart rate, if that was thought to be relevant,

for example, for protection against arrhythmias. That is a judgment call.

In psychiatric disease, there is no marker like that. So I am quite

positive that everyone of them called for efficacy studies.

It is worth noting that the written requests in depression always

called for at least two studies, because we know it is so hard to do.

The written request in other things, like obsessive compulsive disease, sometimes have only called for a single study.

Mr. STUPAK. So you don’t know how many efficacy studies were

done of these 293 studies. Right?

Mr. TEMPLE. I don’t. I may have some notes on it. I will keep

looking.

Mr. STUPAK. We will put it in writing to you, because we would

really like to know that.

Mr. TEMPLE. Okay, that’s fine.

Mr. STUPAK. Of those for which efficacy studies were done, how

many showed they were not effective, that there was no efficacy?

Mr. TEMPLE. Yes. I’m not going to know that either, but we can

get you the answer.

Mr. STUPAK. It would be interesting, because we are working on

some legislation on pediatric exclusivity.

If efficacy is shown, is this then added to the label of the drug

in pediatrics?

Mr. TEMPLE. At least usually, and we can get you numbers on

how many have had——

Mr. STUPAK. And if efficacy is not shown in a pediatric study, is

that added to the label?

Mr. TEMPLE. Well, we are in the process of changing our view on

that. Historically——

Mr. STUPAK. Up until today, before you change you mind, was efficacy—if efficacy was not established, was that put on the label?

Mr. TEMPLE. Usually not.

Mr. STUPAK. So we give them the good news but not the bad

news.

Mr. TEMPLE. Well, the reason, which you have heard me say before, is that failing to show something in a trial doesn’t mean that

it doesn’t work. This is not related to the pediatric setting particularly.

Mr. STUPAK. Sure.

126

Mr. TEMPLE. However, in reconsidering this, what we have come

to think is that, really, the whole point of the Best Pharmaceuticals

for Children Act is to find out if what you know—mostly—mostly—

is to find out if what you think you know about—what you know

about adults is applicable to children, and it is more relevant than

usual to say, hmm, I didn’t see anything in children. We are intending to put——

Mr. STUPAK. When you are talking about adults and children,

dosage has a lot to do with that, too, does it not?

Have you done any dosage studies on the SSRIs ?

Mr. TEMPLE. No. The substitute for dosage studies—and it is not

an adequate substitute—is to look at the pharmacokinetics and at

least try to get close on the blood levels. Dose response information

in a disease that is hard to study at all is murderously difficult to

get.

Mr. LAUGHREN. Actually, I have one comment on the question of

SSRIs and dose and exposure. Actually, the written request for the

Luvox application was specifically focused on looking at pharmacokinetics, because what we found—the company had already done

the efficacy trial even in advance of the written request. They had

done the one study that we actually talked about earlier.

What they had shown is that the drug appeared to work in children, but there were also adolescents in that trial. It did not work.

So we asked them as part of the written request to go back and

look at exposure, and that helped us to understand possibly why

that trial had failed to show efficacy in adolescents.

Mr. STUPAK. Well, our concern is, being the policymakers and

writing the Best Pharmaceuticals—I didn’t write it, thank God. But

in 1997 when we did it, and again in 2001, the Best Pharmaceutical Act, we were told efficacy would be labeled. Now you are

telling us, up until today, it has not been labeled.

That was one of the big contentions on this committee. If you are

going to give people the good news, you also have to give them the

bad news.

Mr. TEMPLE. Just let me be sure I understand. You were told

that, if the studies were negative, that would go in?

Mr. STUPAK. That would go in?

Mr. TEMPLE. That would go into the labeling.

Mr. STUPAK. Of course, you shouldn’t label before you give the

patent extension, so people know what the heck is going on. But

we don’t do that either.

Mr. TEMPLE. We have pretty much decided to do that. So it is

a little late, but we are going to do that.

Mr. STUPAK. We are not a little late. FDA is a little late, since

1997.

Mr. TEMPLE. That is what I said. We are a little late.

Mr. STUPAK. Okay. I thought you said it is a little late now. All

right. Probably got time to vote.

Chairman BARTON. Is the gentleman through? Okay. The Chair

would recognize himself for what he hopes to be the last 10 minutes. I’m sure you all are glad to hear that.

We want to thank you all for being here this afternoon. It has

been a long day, and I appreciate your patience. I have just 2 or

3 questions, and then a wrap-up.

127

I am going to direct some of these questions to Dr. Knudsen—

Is it Knudsen or K-nudsen? Knudsen? Sure. Okay. You’ve got to

push that little button there.

Now I know that some of this ground has been plowed before,

but I wasn’t here when it was plowed. So I apologize if we have

gone over this.

You are aware that your letter of March 19, 1996, was not in the

FDA file. I think you are also aware now that there are two

versions of the letter that wasn’t in the file, one apparently a typographically incorrect that was sent at 10:18 on March 19, 1996.

The other was sent at 12:10.

I believe you told the staff that you have no recollection of these

letters. Is that correct or incorrect?

Mr. KNUDSEN. That is correct.

Chairman BARTON. So once you saw the letters, did that revive

any memories of them?

Mr. KNUDSEN. No.

Chairman BARTON. What were you involved in, in March 1996,

that would have caused you send these letters to the Pfizer Corporation?

Mr. KNUDSEN. I was involved in the review of the OCD NDA

Supplement for Certraline.

Chairman BARTON. Which is an anti-depressant?

Mr. KNUDSEN. That is correct.

Chairman BARTON. And they were attempting to have it approved for use in adults or in adolescents?

Mr. KNUDSEN. Treatment of OCD in adults, I believe.

Chairman BARTON. And you—were you the reviewer of that application or were just asked to comment on it by somebody that

was reviewing the application?

Mr. KNUDSEN. I was the reviewer of the supplement or the OCD

supplement submitted by Pfizer—for Certraline by Pfizer.

Chairman BARTON. Taking aside the point that the letter wasn’t

in the file, and apparently you didn’t have a copy in your personal

files, the substance of the letter is that it appears—and I will read

the last paragraph: ‘‘We note’’—These are your words: ‘‘We note

that there appears to be an increased frequency of reports of

suicidality in the pediatric/adolescent patients exposed to

Certraline compared to either placebo or Certraline treated with

adult OCD patients. If this in fact the case, what would be a plausible explanation?’’

So even though you have no recollection, you apparently were

looking at some data that caused you to think that, if this particular drug was used, it would increase suicidality in the pediatric

population, which is a serious concern. Would you agree with that?

Mr. KNUDSEN. Yes.

Chairman BARTON. Now once you sent the letter, apparently you

and everybody at FDA forgot about it. Is that true or not true?

Mr. KNUDSEN. I want to back up a second. I commented upon the

fact that I did not recall at the time—since it was 1996 this letter

was generated, I personally do not recall information back that

length of time. Even with looking at the letter, you asked if I generated the letter or if I recall generating the letter. In fact, as I

said, I do not recall writing the letter.

128

It does not mean that I did not. I simply do not recall. I understand. But 1996, for me—even yesterday is a little difficult to remember sometimes. But 1996, quite frankly, as I told the subcommittee folks who called me in Maine, much to my chagrin, I

simply do not recall writing that letter. I may have.

Chairman BARTON. You do recall that you were involved in the

review of an application for the drug.

Mr. KNUDSEN. That is correct, although that is a bit different

than generating and writing a letter and not—I just——

Chairman BARTON. Well, but this isn’t a run of the mill application. Your last paragraph is pretty important. ‘‘There appears to be

an increased frequency of reports of suicidality in the pediatric/adolescent patient exposed to Certraline compared to either the placebo or the Certraline treated with adult OCD patients.’’

That is a pretty important finding or pretty important question.

Yet once you sent the letter off, which nobody at the FDA kept any

copies of, everybody forgets about it until 8 years later or 6 years

later.

Mr. KNUDSEN. Well, in fact——

Chairman BARTON. You can’t even remember writing the letter.

Mr. KNUDSEN. Well, I mean, how many people in this room, I

would like to ask, can remember writing letters in 1986? This is

purely speculative, and I am not going to speculate. I cannot recall

writing the letter.

The point of fact is it is a very important issue. I may have written it. For simplicity, I will say I did write it, and because I was

very much concerned about this issue when I reviewed the

OCD——

Chairman BARTON. You are missing my point. Nobody is challenging whether you wrote the letter or not. Now if you want to—

you know, you said it looked like your signature, so you probably

did or you did. You will stipulate. I could care less.

What I am concerned about, that we have a drug that is being

used in adolescents to treat depression and, according to whoever

wrote this letter, there appears to be an increase in suicidality.

Now that is an important thing, and nobody at the FDA did anything on it for 6 years. That is pretty important.

Mr. TEMPLE. That is not entirely correct. Dr. Laughren

reviewed——

Chairman BARTON. It is more correct than incorrect.

Mr. TEMPLE. Dr. Laughren reviewed the data that was the basis

for that letter, wrote a memo.

Chairman BARTON. Well, you all didn’t even find a copy, and now

we got two different copies from the drug manufacturer, and we

get—when we asked about document retention policy—you don’t

have access to this, because it didn’t come in until today.

It is an e-mail that was sent today to the young lady to my right,

and it says, ‘‘FDA does not have a specific regulation that governs

the record retention of NDA files and drug master files.’’

It is pure serendipity that the manufacturer kept a copy.

Mr. TEMPLE. I think the problem was that the letter never went

into appropriate channels. That is why it was never seen.

Chairman BARTON. Well, it is not stamped. There is no stamp

that it was.

129

Mr. TEMPLE. It didn’t go to Dr. Laughren. It didn’t get into the

file. That is why nobody knows it was there.

Chairman BARTON. Do you think you should have a document retention policy? Do you think that something like this should have

gone through channels, that somebody at your level or some level

should have checked into it and done something before 6 years

later?

Mr. TEMPLE. Of course.

Chairman BARTON. Yes or no?

Mr. TEMPLE. Of course, it should have gone through channels.

Chairman BARTON. And you think something should have been

followed up on this?

Mr. TEMPLE. Had anybody known about it and seen the result,

yes, of course. But I do want to point out that the basis for that

letter was reviewed by Dr. Laughren a couple of months later, and

his conclusion was that there was no signal there.

Chairman BARTON. Beg your pardon?

Mr. TEMPLE. His conclusion was that there was no signal there,

that the analysis was invalid. I believe the letter never should have

been sent. It doesn’t make any sense.

Chairman BARTON. In spite of all the studies that have been

done since then—and correct me if I am wrong. We have looked at

15 studies. Twelve of the 15 have shown no effect, no efficacy.

Some of those have shown an increase in suicidality, and in spite

of that, you say this letter shouldn’t have been sent?

Mr. TEMPLE. This letter reported that there was an increased

risk of suicidality in children compared to adults.

Chairman BARTON. Let’s be fair. It says there appears to be.

Mr. TEMPLE. Okay.

Chairman BARTON. He is just questioning. Even though he has

developed amnesia, at the time he was doing his job, and he was

saying that somebody needs to check—well, he didn’t say that. He

just says what are your comments on it. Now once he wrote it, he

forgot he wrote it. He didn’t keep a record of it, and it was forgotten about.

Mr. TEMPLE. Right. The——

Chairman BARTON. Now this gentleman to your right, Dr.

Laughren, says that he reviewed this letter?

Mr. TEMPLE. No, not the letter, the review that led to the letter.

Mr. LAUGHREN. I would like to clarify.

Chairman BARTON. All right. So you reviewed the same data.

Mr. LAUGHREN. No, no. Let me explain. Dr. Knudsen wrote a review of March 1996 around the same time that he sent the letter.

He raised the concern in his review, and I responded to that concern in a memo that I wrote to the file later that year.

It is true—I mean, there is no question. This is a failure in our

document flow. However, the response that Pfizer sent in response

to his letter in May of that same year——

Chairman BARTON. The response is in the file. Isn’t that correct?

Mr. LAUGHREN. That response apparently is in our file. I have

since—I agree that it is years later, but I have recently looked at

it. It is completely consistent with the conclusion that I reached in

the memo that I wrote in October of the same year, in October

1996.

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So it is true, you know, this is a document failure. No question

about it.

Chairman BARTON. Well, it is more than document failure.

Mr. LAUGHREN. No, no. There is no signal there. There is just no

signal there. There is no signal in those data.

Mr. TEMPLE. The analysis included three uncontrolled trials and

one controlled trial in excessive compulsive disease. In the OCD

trial there was one suicidality case in the placebo group and none

in the treated group.

The comparisons are entirely invalid. The letter should not have

been sent.

Mr. LAUGHREN. Yesterday I spoke to someone completely independent, an epidemiologist in our Division, the head of the safety

team, about these data just to get another view on this, and she

completely agreed with me, that looking at those data that Dr.

Knudsen looked at back in 1996, there is no signal for pediatric

suicidality. None.

Chairman BARTON. But nobody did that. You all didn’t even look

at the data.

Mr. TEMPLE. No, he did.

Mr. LAUGHREN. I did.

Mr. TEMPLE. He looked at the data that Dr. Knudsen had placed

in his review, not the letter. We didn’t know about the letter.

Chairman BARTON. Well, let me ask another, because I don’t follow the—I am not a medically trained person.

This particular drug—in 1996 was it being prescribed off-label

for adolescents?

Mr. LAUGHREN. I can’t answer that. It probably was.

Chairman BARTON. It probably was?

Mr. LAUGHREN. The point of this——

Mr. TEMPLE. But it is not for depression.

Mr. LAUGHREN. Right. This study was for—sorry.

Mr. TEMPLE. This was for a different condition.

Mr. LAUGHREN. This study was for obsessive compulsive disorder

in kids.

Chairman BARTON. But it leads to an increase in—it could—it

appears that there could be, ‘‘that there appears to be an increased

frequency of reports of suicidality.’’

Mr. TEMPLE. Yes, that is what it says, but——

Chairman BARTON. That was in 1996. This is 2004. It is 8 years

ago. If it was prescribed to 10,000 children and 100 of them committed suicide because they took it, I think something should have

been done.

Mr. TEMPLE. That would be a bad thing. This provides no signal

that that is a risk. There is no signal in those data. In the controlled trial there were more suicidality——

Chairman BARTON. What did—apparently, what the FDA—I’ve

got some other questions, but apparently what the FDA did about

this, this gentleman or others looked at this data and said we don’t

see a problem there. And so you did nothing. You did absolutely

nothing.

Mr. TEMPLE. I don’t understand. There was no signal.

Chairman BARTON. Well, you know what I would have done?

Mr. TEMPLE. What would you have done?

131

Chairman BARTON. I would have gone in and done some more

trials. I might have even told the drug manufacturers not to let it

be—strongly encourage them not to prescribe it off-label. I might

have erred on the side of safety and prudence and said let’s don’t

take a chance. That’s what I would have done.

Mr. TEMPLE. So in response to a study that showed more

suicidality in the placebo group than in the treatment group, you

would have done more studies? I don’t think I understand.

I understand why the words—this looks like it might be a signal—would be distressing, but that was a wrong interpretation of

the data.

Chairman BARTON. Well, even Dr. Laughren said—and again

this is a memorandum. It is Tab 75 dated October 25. This is apparently after he had reviewed the data. He says, ‘‘I don’t consider

these data to represent a signal of risk for suicidality for either

adults or children. Supplements are planned for both depression

and OCD in pediatric patients, and when we have more complete

data, including Ham-D data, we can look more critically at this

issue using the now standard approach of comparing the proportions of drug in placebo exposed patients to show worsening on

Item 3, which is the suicidality item, to the Ham-D during the

treatment.’’ So even he said that there should be something done.

Mr. TEMPLE. Well, those things were done, but we now have exquisite evidence that looking at the Ham-D doesn’t work.

Chairman BARTON. Well, I am going to, unfortunately, have to

run and vote.

Should FDA develop a document retention policy for NDAs and

drug master files? Yes or no? You have none now.

Mr. TEMPLE. Well, I believe we have one, but we will——

Chairman BARTON. Well, your e-mail says you don’t.

Mr. TEMPLE. We don’t have a rule.

Chairman BARTON. If you don’t, should you?

Mr. TEMPLE. Yes.

Chairman BARTON. What did the British see when they pulled

these things off the market that you didn’t see, that FDA didn’t

see?

Mr. TEMPLE. You mean when they wrote their thing contraindicating it?

Chairman BARTON. Yes, sir.

Mr. TEMPLE. It is a different interpretation of the same data. I

don’t know why they reached that conclusion. One reason might be

that they are less inclined to use these drugs in the first place.

Why that is, I can’t say.

Chairman BARTON. All right. I am going to thank you gentlemen.

There will be further questions for the record, and we are going to

adjourn this hearing.

[Whereupon, at 5:46 p.m., the subcommittee was adjourned.]

[Additional material submitted for the record follows:]

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Æ