U.S. GOVERNMENT PRINTING OFFICE

73–924 DTP WASHINGTON : 2001

ACCUTANE—IS THIS ACNE DRUG TREATMENT

LINKED TO DEPRESSION AND SUICIDE?

HEARING

BEFORE THE

COMMITTEE ON

GOVERNMENT REFORM

HOUSE OF REPRESENTATIVES

ONE HUNDRED SIXTH CONGRESS

SECOND SESSION

DECEMBER 5, 2000

Serial No. 106–248

Printed for the use of the Committee on Government Reform

(

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

http://www.house.gov/reform

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COMMITTEE ON GOVERNMENT REFORM

DAN BURTON, Indiana, Chairman

BENJAMIN A. GILMAN, New York

CONSTANCE A. MORELLA, Maryland

CHRISTOPHER SHAYS, Connecticut

ILEANA ROS-LEHTINEN, Florida

JOHN M. MCHUGH, New York

STEPHEN HORN, California

JOHN L. MICA, Florida

THOMAS M. DAVIS, Virginia

DAVID M. MCINTOSH, Indiana

MARK E. SOUDER, Indiana

JOE SCARBOROUGH, Florida

STEVEN C. LATOURETTE, Ohio

MARSHALL ‘‘MARK’’ SANFORD, South

Carolina

BOB BARR, Georgia

DAN MILLER, Florida

ASA HUTCHINSON, Arkansas

LEE TERRY, Nebraska

JUDY BIGGERT, Illinois

GREG WALDEN, Oregon

DOUG OSE, California

PAUL RYAN, Wisconsin

HELEN CHENOWETH-HAGE, Idaho

DAVID VITTER, Louisiana

HENRY A. WAXMAN, California

TOM LANTOS, California

ROBERT E. WISE, JR., West Virginia

MAJOR R. OWENS, New York

EDOLPHUS TOWNS, New York

PAUL E. KANJORSKI, Pennsylvania

PATSY T. MINK, Hawaii

CAROLYN B. MALONEY, New York

ELEANOR HOLMES NORTON, Washington,

DC

CHAKA FATTAH, Pennsylvania

ELIJAH E. CUMMINGS, Maryland

DENNIS J. KUCINICH, Ohio

ROD R. BLAGOJEVICH, Illinois

DANNY K. DAVIS, Illinois

JOHN F. TIERNEY, Massachusetts

JIM TURNER, Texas

THOMAS H. ALLEN, Maine

HAROLD E. FORD, JR., Tennessee

JANICE D. SCHAKOWSKY, Illinois

———

BERNARD SANDERS, Vermont

(Independent)

KEVIN BINGER, Staff Director

DANIEL R. MOLL, Deputy Staff Director

JAMES C. WILSON, Chief Counsel

ROBERT A. BRIGGS, Clerk

PHIL SCHILIRO, Minority Staff Director

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C O N T E N T S

Page

Hearing held on December 5, 2000 ........................................................................ 1

Statement of:

Callais, Lori and Amanda, Denham Springs, LA; Stacy and Mike

Baumann, Mundelein, IL; and Charles H. Jackson, Jr., Lubbock, TX ..... 6

Pariser, David M., M.D., FACP, American Academy of Dermatology,

Pariser dermatology specialist, Ltd., Virginia Clinical Research, Inc.,

Norfolk, VA; Douglas Jacobs, M.D., Roche consultant, associate clinical

professor of psychiatry, Harvard Medical School, Wellesley, MA; James

T. O’Donnell, PHARMD., M.S., assistant professor of pharmacology,

Rush Medical School, Pallentine, IL; and Jonca Bull, M.D., Food and

Drug Administration, accompanied by Phyllis Huene, M.D. .................... 44

Letters, statements, etc., submitted for the record by:

Baumann, Mike, Mundelein, IL, prepared statement of ............................... 19

Baumann, Stacy, Mundelein, IL, prepared statement of .............................. 24

Bull, Jonca, M.D., Food and Drug Administration, prepared statement

of ..................................................................................................................... 100

Callais, Amanda, Denham Springs, LA, prepared statement of .................. 14

Callais, Lori, Denham Springs, LA, prepared statement of .......................... 9

Jackson, Charles H., Jr., Lubbock, TX, prepared statement of .................... 32

Jacobs, Douglas, M.D., Roche consultant, associate clinical professor of

psychiatry, Harvard Medical School, Wellesley, MA, prepared statement of ........................................................................................................... 61

O’Donnell, James T., PHARMD., M.S., assistant professor of pharmacology, Rush Medical School, Pallentine, IL, prepared statement of ............ 73

Pariser, David M., M.D., FACP, American Academy of Dermatology,

Pariser dermatology specialist, Ltd., Virginia Clinical Research, Inc.,

Norfolk, VA, prepared statement of ............................................................ 49

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ACCUTANE—IS THIS ACNE DRUG TREATMENT

LINKED TO DEPRESSION AND SUICIDE?

TUESDAY, DECEMBER 5, 2000

HOUSE OF REPRESENTATIVES, COMMITTEE ON GOVERNMENT REFORM, Washington, DC.

The committee met, pursuant to notice, at 1 p.m., in room 2154,

Rayburn House Office Building, Hon. Dan Burton (chairman of the

committee) presiding.

Present: Representatives Burton, Morella, Horn, Mica, Waxman,

Norton, and Kucinich.

Staff present: Kevin Binger, staff director; Daniel R. Moll, deputy

staff director; James C. Wilson, chief counsel; David A. Kass, deputy counsel and parliamentarian; Sean Spicer, director of communications; S. Elizabeth Clay and Nicole Petrosino, professional staff

members; Robert A. Briggs, chief clerk; Michael Canty and Toni

Lightle, legislative assistants; Josie Duckett, deputy communications director; Leneal Scott, computer systems manager; John Sare,

deputy chief clerk, Corinne Zaccagnini, systems administrator; Phil

Schiliro, minority staff director; Kristin Amerling, minority deputy

chief counsel; Kate Anderson and Sarah Despres, minority counsels; Ellen Rayner, minority chief clerk; and Jean Gosa and Earley

Green, minority assistant clerks.

Mr. BURTON. Good afternoon. A quorum being present, the Committee on Government Reform will come to order.

I ask unanimous consent that all Members’ and witnesses’ written opening statements be included in the record. Without objection, so ordered.

I ask unanimous consent that all articles, exhibits, and extraneous or tabular material referred to be included in the record.

Without objection, so ordered.

We are here today to talk about the acne medication Accutane

and concerns that the drug is linked to depression and suicide.

Accutane was licensed by the Food and Drug Administration in

1982 as an oral prescription drug for the treatment of severe acne.

Current recommendations indicate that the drug should only be

used when a patient has not responded to other treatments including antibiotics.

During the course of our investigation, we were told by the dermatologists that while the drug has many severe side effects, that

there is no other treatment available. However, we also learned

that many individuals have been prescribed this drug for less severe forms of acne. I am attaching for the record an article outlining natural treatments for acne.

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The most well-known adverse effect attributed to Accutane is

birth defects of the children born to women who take the drug during pregnancy. However, we will focus today’s hearing on the mental health issues. Did the Department of Health and Human Services fulfill its public safety obligation in making the public aware

of the potential for depression and suicide related to this drug?

A significant number of psychiatric events, mostly severe depression, have been reported through post-marketing surveillance. The

FDA has received reports of 66 suicides and 1,373 psychiatric adverse events other than suicide related to Accutane.

According to Roche Pharmaceuticals, the manufacturer of

Accutane, the number of domestic and foreign reports of serious adverse events in the post-marketing adverse events data base for

Accutane as of April 30 was 5,665. The largest percentage of these

reports were psychiatric problems. Almost 19 percent of the adverse events reported to Roche were psychiatric.

Also, the most recent Periodic Adverse Drug Event Report for

Accutane includes, for a 12-month period, over 750 new psychiatric

adverse event reports, both foreign and domestic, including 200

that were coded as serious events, 9 reports of suicide attempts,

and 6 reports of suicides.

Four questions arose during the course of this investigation.

When did the issue of depression and suicide first arise regarding

Accutane?

What actions did Roche and the FDA take to determine if there

was a causal link?

When and how was the public notified?

And, fourth, was the public notification adequate?

According to Roche, there is no evidence of increased risk of depression or suicide related to Accutane. Instead, they believe that

the events reflect the multiple risk factors in the population of adolescents and young adults afflicted with the disfiguring disease of

acne.

While the package insert for the Accutane contains language that

warns of depression and suicide, this information is not typically

provided to patients by either the physician or the pharmacist. Extensive patient education is required regarding pregnancy prevention while on Accutane because of the risk of birth defects. However, there is no system in place to educate patients and families

about depression and, potentially, suicide.

We learned through our investigation that reports of depression

and suicide are not new. The first report of depression in patients

taking Accutane occurred in September 1982. Two patients in a

clinical trial with 523 patients reported depression. Roche received

five adverse experience reports of depression in 1983. In November

1983, Roche received its first report of attempted suicide. In November 1984, Roche received its first report of suicide. In May

1986, Roche received reports of five or six positive rechallenges in

patients who experienced depression during Accutane therapy. In

these patients, the depression went away when they stopped taking

Accutane and began again after starting Accutane therapy over

again. Positive rechallenge is a significant indicator of a causal link

between a drug and the adverse event.

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As early as November 1984, Roche began including information

on the package insert about reports of depression. Even though

French authorities required a label change to include ‘‘suicide attempt’’ in March 1997, the FDA did not require Roche to make a

label change until February 1998. FDA also required that Roche

notify physicians who were likely to prescribe Accutane.

In February 1998, the FDA issued a ‘‘Talk Paper’’ advising consumers of and health care providers of new safety information regarding Accutane; and the paper stated as follows.

Although the Accutane label already included information regarding depression as

a possible adverse reaction, the agency felt health care providers and others needed

additional information as a result of adverse events the agency has received. FDA

and the drug manufacturer are strengthening this label warning, even though it is

difficult to identify the exact cause of these problems. Patients who reported depression also reported that the depression subsided when they stopped taking the drug

and came back when they resumed taking it.

What is disturbing to me is that the FDA published an article

in their own consumer magazine entitled, ‘‘On the Teen Scene:

Acne Agony’’ in July 1999. Thirty percent of the article focuses on

Accutane. It goes into great detail about the pregnancy prevention

because of birth defects, but it fails to make any mention of depression and suicide. This article appeared 16 months after FDA’s advisory. Why did the FDA not use its own consumer magazine to notify the public of this concern?

Today we will hear from three families.

Amanda Callais was prescribed Accutane as a 14-year-old in September 1997. By November, she was seriously depressed and attempted suicide. The psychiatrist treating her for depression was

not aware of the connection between Accutane and depression and

did not suspend her use of the drug after her suicide attempt. She

remained seriously depressed. In February 1998, Amanda’s mother,

Lori, learned of the FDA’s warning and stopped Amanda’s treatment. Amanda quickly made a full recovery. Mother and daughter

are here today to share their experience.

Stacy and Mike Baumann of Mundelein, IL, lost their son Daniel

to suicide in December 1999. Daniel began Accutane treatment in

July 1999. He suffered many adverse effects: chapped lips, dry skin

and itching, joint and muscle pain, headaches, nausea, loss of appetite, mood swings and insomnia. The physician thought this depression was school-related and never mentioned the FDA warning.

Mr. Charles Jackson of Lubbock, TX, lost his 17-year-old son

Clay in January 2000. Clay had been on Accutane for about 3

months. The family was provided no information by the physician

regarding the FDA warning.

Of course, we have one of our colleagues in the Congress who lost

his son. Bart Stupak’s son was lost to suicide not too long ago, and

he believes it was Accutane-related as well.

Accutane is only supposed to be prescribed for severe recalcitrant

nodular acne after every other treatment option has failed. Dr.

David Pariser of Norfolk, VA, will be testifying on behalf of the

American Academy of Dermatology and providing an overview of

the types of acne and when Accutane is recommended.

Dr. Douglas Jacobs, on faculty at Harvard and a Roche consultant, will present his evaluation of the adverse drug events regarding psychosis, depression and suicide and Accutane.

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Dr. James O’Donnell, assistant professor of pharmacology at

Rush Medical School, will present information regarding the connection between Accutane and other vitamin A derivatives and depression and suicide.

Dr. Junco Bull will testify on behalf of the FDA.

I realize that this issue will be difficult for some of you to discuss. To those families who have lost loved ones because of this or

because we believe that is what caused it, our heart goes out to

each and every one of you. I know it is going to be a difficult time

for you today, and we really appreciate you being here. I do hope

that this hearing can help resolve some of the unanswered questions so that these tragedies will be avoided in the future.

The hearing record will remain open until December 18.

I am happy to recognize my colleague from California, Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman.

Mr. Chairman, today’s hearing addresses an issue of great importance, and I want to begin by commending the work of Congressman Bart Stupak in this area. His tireless efforts to raise public

awareness about the risks of Accutane have, I am sure, already

helped many families. His efforts have also been instrumental in

encouraging Hoffman-La Roche and the FDA to do more to learn

about the risks of Accutane and to inform patients and families

about those risks.

Accutane is a powerful and effective drug for the treatment of severe recalcitrant acne. For many acne sufferers, it is the only drug

that can cure them of an otherwise scarring disease. Because of

this drug’s benefits, it is imperative that we understand all of its

risks and fully inform patients and their families.

We already know a great deal about Accutane’s risks of severe

birth defects. That knowledge has provided the basis for patient

education targeting women of child-bearing age. But the same is

not true of the risk of psychiatric disorders, and that must be

changed.

I am troubled by how little we know about the link between

Accutane and psychiatric disorders. No study has proven conclusively that Accutane causes psychiatric disorders, but a great deal

of evidence suggests that there may be a link. A recent FDA analysis of voluntary reports, so-called adverse event reports, found that

147 cases of suicide and hospitalized depression have been associated with Accutane since it was first introduced in 1982. Even

more disturbing, evidence shows that many patients feel depressed

while taking Accutane, stop feeling depressed after treatment

ceases, and then feel depressed again when treatment is resumed.

Officials at FDA state that such cases ‘‘provide the best evidence

to support a relationship between Accutane and psychiatric disorders.’’ But this is not conclusive proof, and it is unacceptable that

such an important question has gone unanswered for so long.

I am also troubled by the lack of information provided to patients

and their families. As we will hear today, and as was the case for

Congressman Stupak, many families are completely unaware that

depression and suicide have been associated with Accutane. While

the risk of depression has been a part of the label since 1985, the

risk of suicide was not added to the label until 1998, and patients

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and their families simply did not have reliable and valuable access

to this information until Hoffman-La Roche changed the Accutane

box in only May of this year. But this new warning is still not

reaching all users, because many old boxes without the warning remain in circulation. With a risk as detrimental and tragic as suicide, it is unacceptable that patients, including many minors, and

their families are not informed about it. A box warning is insufficient. Until a pamphlet specifically geared for patients is issued

under the MedGuide program, they will not be fully informed.

I am heartened by some positive developments. Hoffman-La

Roche has agreed to work with FDA on a patient informed consent

form and the immediate guide pamphlet to warn of the risks of

psychiatric disorders. Both will clearly discuss the risk of depression and suicide and will do a great deal to inform patients and

their families of these grave risks. I call on FDA and Roche to implement the immediate guide and patient consent forms quickly.

Most important of all, Roche has finally agreed to fund research

into the link between Accutane and psychiatric disorders. Roche

will be working with both NIH and FDA on the design of this research. I want to emphasize that this research must be independent, comprehensive, and extensive enough to answer the very serious questions about the psychiatric risks of this drug. This research is crucial and long overdue. I look forward to hearing from

our witnesses and exploring how to improve the information and

improve our understanding about Accutane.

Mr. Chairman, should there be further hearings on this subject,

I would like to work with you. I think we ought to hear from the

Hoffman-La Roche company representatives themselves, because

there are questions that I think they ought to answer. But I am

pleased that you have called this hearing. I think you have witnesses that can help us understand the problem and give us a good

guide as to what public policy recommendations we need to make

as representatives of the people. Thank you very much.

Mr. BURTON. Thank you, Mr. Waxman.

Mrs. Morella.

Mrs. MORELLA. Thank you, Mr. Chairman.

Just briefly, I want to thank you for holding this hearing on this

issue. There is nothing that we can do in this committee that is

more important than ensuring that the medication given to individuals, particularly children, is safe and effective. I can’t imagine any

pain that is more grievous than finding that the medication prescribed for your child or family member actually caused them significant pain or, in some instances, even led to their death.

Today’s hearing will hopefully enlighten all of us on the efficacy

of Accutane, whether its side effects lead to depression and suicide.

I know the witnesses that come before us will elucidate both the

positive and the negative outcomes of Accutane. I do want to thank

the first panel for their courage in coming before us.

This drug, Accutane, which has helped thousands of individuals

who have serious acne problems, may also have dangerous psychological side effects. It is essential that we look at all facets of the

issue before any decision is rendered. Preventing others from benefiting from Accutane without ample evidence to the contrary could

be considered pernicious, just as continuing to prescribe the drug

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if we know it is dangerous. In the end, our objective today must

be to ensure that all available information is passed on to families

and patients about all possible side effects.

I look forward to hearing the testimony today and discerning an

appropriate role for our committee.

I yield back the balance of my time.

Mr. BURTON. Thank you, Mrs. Morella.

Mr. Horn.

Mr. HORN. Thank you, Mr. Chairman.

This is a very important hearing. When you look at what seems

to be an absolute flood of suicides in many of the high schools of

America, I would hope someone in these two panels would tell us

if there is any medical data as to whether Accutane has resulted

in a type of suicide that hasn’t been with other types of suicide.

That is the question I would like to know: What else besides

Accutane?

Mr. BURTON. Thank you, Mr. Horn.

I will now turn to our witnesses. Would you all rise, please.

[Witnesses sworn.]

Mr. BURTON. I think we will start right down here at the left,

Mrs. Callais, and we will then have you and your daughter both

make your statements. If you could try to confine your statements

to 5 minutes, that will be fine. If you go a little bit over, we will

be lenient, but we would like for you to stick to that as closely as

possible.

STATEMENTS OF LORI AND AMANDA CALLAIS, DENHAM

SPRINGS, LA; STACY AND MIKE BAUMANN, MUNDELEIN, IL;

AND CHARLES H. JACKSON, JR., LUBBOCK, TX

Mrs. LORI CALLAIS. In August 1997, my 14-year-old daughter,

Amanda, was a normal teenager. She liked school and made

straight A’s. She liked talking on the phone for hours at a time.

She had a new boyfriend, and she liked life. But that quickly

changed.

On September 23, 1997, Amanda started taking the acne medication Accutane. She was excited about taking Accutane because the

dermatologist said that the acne Amanda had been undergoing

treatment for since the 6th grade would be cleared up.

During the visit to the dermatologist, Amanda and her father,

who accompanied her, were given an explanation about the physical side effects, a warning about pregnancy and a pamphlet to

read at home. So together Amanda and I carefully read that pamphlet and the release form her father had signed.

I remember the warning about pregnancy and the many physical

side effects, but I do not remember seeing the word ‘‘depression’’ in

that pamphlet. It definitely was not on the release form, and I

know the word ‘‘suicide’’ was never mentioned anywhere. However,

by November, Amanda had fallen into such a depression that she

wanted to die. On November 15, my daughter took 40 pills in an

attempt to kill herself; and she came within hours of succeeding.

After her suicide attempt, we continued to follow the doctors’ orders, only now psychiatrists and therapists were involved. On the

advice of those doctors, we admitted her to an adolescent facility;

and she started taking anti-depressant medication along with the

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Accutane. By the way, the Accutane was continued with a psychiatrist’s approval.

As Amanda’s depression worsened, despite the therapy and medication, the only thing we could visibly see working was the

Accutane. Her lips dried out, cracked and bled; her joints ached;

and she was always thirsty. But the dermatologist told us that that

was just the effect of Accutane, nothing to be worried about, just

don’t get pregnant.

Finally, after 3 months of treatment, in February 1998, even the

psychiatrist could not understand why Amanda was getting worse.

By now, she had lost 15 pounds, she slept through her classes, she

never talked on the phone, she would not take a bath, she cut her

hands with razor blades, and she generally hated the world, and

my daughter hated herself. My husband and I watched our daughter die before our eyes, and now even the expert was telling us they

could not help Amanda, and she did not understand why she was

so depressed. I cannot begin to describe the hopelessness and the

terror we felt as parents. We did not know how to help our own

child, and we were trying.

Then, on February 26, 1998, I found out from a friend about the

FDA’s warning about the possible depressive effects of Accutane.

She happened to see it on television. You know, I never did see

that information. I had to get a copy of the warning from the Internet. As a matter of fact, I gave that information to both the psychiatrist and the dermatologist, because you see, they knew nothing about the new warning.

I threw the pills away, and within days I watched my daughter

make a miraculous recovery. Within 1 month, her psychiatrist, who

knew and had approved of Amanda taking Accutane all of those

months before, could not believe the change in my daughter. Thank

God, we have gotten our normal, at times aggravating, but definitely normal, teenaged daughter back; and, yes, she still talks for

hours on the phone.

Amanda stopped taking the drug, but we have not stopped telling people about the effects of this drug, and I have not stopped

hearing about the devastating effect it has on teenagers. We have

done news articles in our local paper, we have appeared on news

shows, we have done whatever it takes to get the word out. But

should I have to do this? Is it my job to tell the world that this

drug is dangerous and needs to be studied and controlled?

I know that Roche Pharmaceuticals would tell you that Accutane

does not affect teens, that teenagers are depressed anyway, especially teens with acne. After 16 years of teaching teenagers every

day, and I am an English teacher, I can tell you that, while teens’

emotions are very volatile, very few are clinically depressed and

even fewer are suicidal. Shame on Roche for not giving our children

a fair chance and just casually dismissing their lives as a trivial

matter. It is time to find out the truth about this drug. Therefore,

I demand that the FDA take action. The FDA must require Roche

to produce their worldwide data base of adverse psychiatric reactions to this drug. The FDA must hold Roche Pharmaceuticals accountable.

The FDA must also require Roche to explain why the French

changed their warning in March 1998, but the FDA was not aware

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of the change until a year later. Claiming ignorance about the

warning in France is not an excuse or an explanation, it is a coverup, because, you see, Roche’s parent company is in Europe.

Finally, I demand, ask, plead and beg as a mother that the FDA

require an independent study to be conducted on Accutane to look

into and determine if and how Accutane and the United States and

Roaccutane in the rest of the world causes depression. We need to

see an unbiased study done to investigate this matter.

I know that recently Roche issued a strong warning label, but at

this point warning labels are not enough. Our children are dying

because a drug company makes lots of money from this drug. This

is the same company cited for once advertising that Accutane

helped depression, this just 1 month after the FDA required the

warning about suicide. Is the almighty dollar and corporate bottom

line worth more than our children?

We would never allow our children to play Russian Roulette with

a gun, but we allow that to happen every time a prescription for

Accutane is given. If you do not act and act promptly, you have just

pulled the trigger. I just hope it is not your child, and I hope and

pray that the chamber of that gun isn’t loaded. Thank you.

Mr. BURTON. Thank you, Mrs. Callais.

[The prepared statement of Mrs. Lori Callais follows:]

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10

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Mr. BURTON. Amanda, would you like to make a couple of comments?

Ms. AMANDA CALLAIS. At some point in everyone’s life, they are

faced with the decision to grow up. Most of the time, this is not

a conscious decision, it is just a natural part of life. Unfortunately,

I didn’t have that choice. At 14, I was forced to leave my childhood

behind because of the monster under the bed, Accutane.

The summer after my eighth grade year, I talked on the phone

with my friends and boyfriend, I went to the movies, and I planned

for high school in the fall. I also worried a little bit about my face

because, although I had been undergoing treatment for acne for

several years, my face and back were still broken out. But lately

the dermatologist had been talking about Accutane, so I knew that

there was hope.

Before I knew it, school was here; and high school was great. I

joined some new clubs, I made the volleyball team, and I was elected freshman class reporter. This year was definitely turning into

one of the best years of my life. And then on September 17 my dermatologist prescribed Accutane for my face. We talked about the

physical side effects of the drug, and she warned me about pregnancy. She then sent me home with a pamphlet to read.

Of course, my appearance became worse before it got better. My

lips chapped and bled, and my skin dried out. But my dermatologist and I had discussed all of these physical side effects of

Accutane, so I didn’t care, because it just proved that the drug was

working.

My downfall started from the moment that I took the first pill.

After 2 weeks, my happy mood began to slowly dissolve. I found

myself feeling sad, and I often cried for no reason. I began to slack

off on my school work because I was just too tired to care about

my grades. I frequently argued with my parents and friends. In

fact, I often provoked arguments until I was in a screaming fit with

the other person.

In 6 short weeks, everything about the best year of my life had

become nonexistent. I just didn’t care any more; and on November

14, 1997, I took 40 pills and went to sleep, never expecting to wake

up. However, at 3 o’clock that morning, I did wake up, and I was

sick. My parents found me, took me to the hospital where my stomach was pumped.

I was then taken to an adolescent facility where I stayed for a

week under the care of a psychiatrist, and I began taking Prozac.

However, even the Prozac didn’t help. No matter how hard I tried

to feel better and be normal, and believe me I did try very hard,

I just sank deeper into depression. I began to restrict my food and

lost over 15 pounds. My grades dropped, and I went from being a

4.0 student to making C’s and D’s. I wanted to sleep all of the time.

I hated myself more and more each day and began to cut my hands

with razor blades. Ironically, the only good thing in my life was my

clear skin because of the Accutane.

During that time, I watched a monster live in my body and control my actions. I wanted to feel better and be happy, but I

couldn’t, no matter how hard I tried. No matter how much therapy

I attended, and no matter how much medication I took, I was miserable. I had no control over my life. A monster was in charge.

13

Fortunately, that changed at the end of February when my mom

heard about the warnings for Accutane. Do you remember that little drug? It was going to help make this year the best year of my

life, right? I had been taking it all along. I had even taken it at

the adolescent center with the psychiatrist’s approval.

After that report, Mom took me off of Accutane; and within 2

weeks I began to feel normal again. I started eating and quit cutting myself. I began to study again and stayed awake in my classes. By the end of March, the Accutane was out of my system, and

I was working hard to catch up, but I was in control. No monster

in sight. By April, my psychiatrist released me from her care, saying that I had made a full recovery. All of my doctors agreed that

they had never seen a turnaround like this, and my depression

must surely have been caused by the Accutane.

That year became a defining moment in my life when I was

forced to grow up. I just find it sad that I was never given the

chance to choose, to hold on to my innocence and keep my childhood for a little bit longer.

I have had to pay the price and face the consequences for a

choice that I didn’t voluntarily make. I think the people who make

Accutane should have to face the consequences for stolen innocence

and lost lives because of the choices they make to hide the devastating effects of this drug. I know that Accutane causes depression, no matter what the so-called experts say. I have lived to tell

my story. There were two girls that year: me and me on Accutane.

Today, I am grateful just to be alive. I am a senior in high school

and plan to go to college next year. I was lucky. I survived

Accutane. But I will live with the memories of that year every time

I gaze in a mirror.

You must do something about this drug, because so many people

do not survive. You see, the monster under the bed is supposed to

be imaginary, not a pill you take to clear up your skin.

Mr. BURTON. Thank you very much, Amanda.

[The prepared statement of Ms. Amanda Callais follows:]

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Mr. BURTON. Mr. Baumann.

Mr. BAUMANN. Can I take 7 minutes?

Mr. BURTON. Sure.

Mr. BAUMANN. May I say that, listening to Amanda for the first

time, I can see exactly what happened to my son. It was the same

thing.

I am coming to Washington today not in anger, but with some

hope. I am not angry at the school system that called us in unexpectedly and with no previous communication to sit down in a

small room in front of two administrators and three armed police

officers to be told our son, Dan, was to be home-schooled as a result

of the Columbine tragedy simply because he wore black. They were

afraid, and I understand that.

I am not angry at the dermatologist who diagnosed the cause of

Daniel’s acne as being stress-related and even pinpointed the day

of the meeting as its beginning, but then prescribed Accutane as

an initial remedy rather than a last resort with no patient/parent

counseling as to the possible consequences. I am not sure if he was

not aware or just thought that the risk was not worth mentioning

in light of the great results that could be obtained.

I am not angry at the pharmacy that distributed this expensive

drug for not counseling us in any way as to the potential side effects. I recently went to the same pharmacist for a prescription for

antibiotics, and he spent 5 minutes talking with me, including talking to me about the side effects, which included nothing at that

time more serious than possible stomach ache if not taken with a

meal. I know he cares.

I am not angry with the company that labels the drug, even

though the labeling did not include the dangerous potential side effects of suicide, although I am not sure why it did not.

I am not angry with the drug company that makes Accutane, because I believe that, for many, it is a Godsend.

I am not angry at the therapist in Lincoln, NE, last Thanksgiving, who, when told that Dan had scored high on a Suicide Risk

Inventory test, elected to interview him over the phone from home

and clear him from all risk. Dan committed suicide 2 weeks later.

Mostly, I am not angry with myself or my wife, Stacy, for thinking that our son’s behavior was just that of a normal, healthy, independent-thinking teenager who was going through a phase in life.

I do not know if our dermatologist giving up his practice had

anything to do with our son’s death or not, but I do know that he

is now teaching at Loyola University. I can only hope that he

teaches his students that the use of these drugs, even for dermatology, should not be taken lightly.

I met a friend from high school not long ago in a Sam’s Club. It

turns out she was there to pick up a prescription for her son of

Accutane. When I asked if she was aware of the potential risk, she

looked at me like I was crazy. I asked if she was counseled by her

dermatologist who is different from ours. She said she was not. I

asked her if this drug was prescribed when other remedies had

failed and found out that it had been prescribed first before any

other remedies had been tried. I then asked to look at the labeling

and letter that came with her prescription and found that it made

no mention of depression or suicide, and the pharmacist made no

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mention of suicide for sure, and the pharmacist said nothing about

these potential dangers to her. The pharmacy and the labeling

company were both different than ours. I then tried to reiterate my

concern and was dismissed with, ‘‘My son is very well-liked, outgoing and happy,’’ much like my Dan, as though nothing could happen to her son.

I don’t think hearing the potential risks from me meant anything

to her. I believe that people do have the right to determine the

amount of risk that they are willing to assume for themselves, but

they do not have the right to impose that risk on others unbeknownst to them.

I fly small airplanes for a living and on occasion take people from

one place to another in bad weather. If there is a thunderstorm in

my path, I let them know the possible consequences and that it will

be safe. However, it may be very uncomfortable. Even if the situation changes, we may have to divert and delay or possibly not be

able to get to the intended destination. I believe the choice is

theirs, and if I lose a few trips as a result, so be it.

I have found that this drug can be very dangerous to pregnant

women and is associated with various birth defects and that there

is no circumstance under which it should be prescribed. According

to the Physicians’ Desk Reference, women should sign a form stating that they will not get pregnant while on Accutane.

I have seen a television commercial, which is animated, of kids

sitting around a computer. Then the computer screen is shown

with a picture of a boy’s face with dots on it, representing acne.

The child at the computer presses a button and the dots disappear.

Call Roche for more info. I don’t think it is as easy as pressing a

button on your computer and getting rid of your acne.

I saw a doctor on TV saying there is no link between this drug

and suicide but later found that the drug company itself funded his

research. In my mind this is a conflict of interest and, at the very

least, gives the appearance of impropriety. In the PDR, Roche itself

lists depression and suicide in bold, which means highlighted, as

possible adverse reactions.

I believe that this is a powerful drug and have no doubt that it

can clear up or at least improve even the most severe acne, which

my son did have. I realize that the drug company is in the business

to make money, and I am sure that a widely prescribed expensive

drug like Accutane does just that. But my question would be, at

what cost?

My suggestions: I do not necessarily think that this drug should

be pulled from the market, but I think its distribution should be

handled differently and additional research conducted by an independent source as to potential hazards. I wonder if my son’s suicide

was ever reported to the FDA and how many others might be out

there. Wouldn’t it be OK if we let people know that there may be

a danger and let them decide for themselves if it is an acceptable

risk? So what if the drug company makes a little less money? After

all, I believe most people think that smoking is harmful, but many

still do it, and the cigarette companies are still in business.

None of us as individuals has the time or resources to fight for

all of the causes that are important in life, but if by coming here

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today we are able to find a stronger, more powerful voice to carry

on this investigation and education, we have done our job.

In conclusion, I would like to thank you for letting me come here

and speak my piece. If sharing my experience helps even one person, the trip will have been worth it. I believe that life should always be held with a higher regard than money, and that fear,

greed, and ignorance, all things I think that can be overcome with

compassion, understanding and education, all played a part in my

son’s death.

Last, my greatest hope is that by coming here, in some small

way, my son’s life will be given meaning and his death dignity.

Thank you.

Mr. BURTON. Thank you, Mr. Baumann.

[The prepared statement of Mr. Baumann follows:]

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Mr. BURTON. Mrs. Baumann.

Mrs. BAUMANN. Daniel began Accutane therapy on June 25,

1999, 3 days after his first visit to the dermatologist. On June 22,

Daniel’s dermatologist told us that the breakout was a result of

high school stress and even pinpointed the week the stress may

have begun. The dermatologist sent Daniel home with a prescription for Prednisone, Erythromycin, a shopping list that included

Purpose Bar, Colladerm Fluid/Jell, Presun Ultra Gel and vitamin

B5.

In addition, we received two brochures that we were to read before starting Accutane therapy: Important Information Concerning

Your Treatment With Accutane and What Young Men Need to

Know About Acne and Its Treatment With Accutane. Daniel and I

read both brochures and felt that it was something that we needed

to do and were looking forward to the promising results. This was

a very big decision for us, considering we didn’t have insurance and

was going to be self-paid throughout the Accutane therapy, monthly dermatologist visits, and blood tests.

It wasn’t long before the side effects started: chapped lips, dry

skin and itching, joint and muscle pains, headaches, nausea, loss

of appetite, mood swings, and insomnia. This was a very difficult

summer for Daniel. He didn’t even want to leave the house anymore and just wanted to stay in his room all day.

On the first day of school, Daniel cried as we were driving there.

He was 15 at the time, going to be a sophomore. He didn’t know

why he was crying. He said he just felt weird. School was very difficult for Daniel this term, and he had a very hard time concentrating.

Daniel and I went to the dermatologist every month, and we

were told that this was all very normal and to be expected. He assured us that the mood swings were normal and would be going

away as soon as the Accutane therapy ended.

On December 11, 1999, Daniel committed suicide.

I called the dermatologist 2 days after Daniel’s death and talked

to him directly and let him know what had happened and that we

wouldn’t be making our next appointment. He offered his deepest

condolences.

At the time of Daniel’s death, we knew nothing about Accutane

and its adverse reactions linked to depression and suicide. It wasn’t

until 2 months later, on February 9, that I discovered that

Accutane might have played a role in Daniel’s suicide. I was having

lunch with some friends and a concerned friend mentioned that she

had heard that Prednisone may be linked to depression and she

knew Daniel was taking this for his acne. As soon as I came home

that afternoon, I looked for Daniel’s entire prescription receipts and

started reading everything I could. I got on line and used the two

key words: Accutane and suicide, and found the FDA’s Med Watch

News dated February 26, 1998: ‘‘important new safety information

about Accutane.’’ I was home alone at the time and just couldn’t

believe what I was hearing and learning for the very first time.

In addition, I also discovered that the brochures Daniel’s dermatologist gave us were copyrighted in 1996 and 1997, respectively. The brochures had no adverse reactions reporting depression, psychosis, suicidal ideations, suicide attempts and suicide. I

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was finding it very hard to believe that Daniel’s dermatologist had

no idea or updated information to hand out to his patients.

I have since visited the pharmacy where Daniel’s prescriptions

were filled and asked the pharmacist if she knew any of the adverse reactions associated with Accutane. She was not aware of depression and suicide. She immediately grabbed the 40 milligram

package from the shelf and was surprised to find out that the depression and suicide warning was not present on the packaging.

I find it interesting that 5 months after Daniel’s death his dermatologist unexpectedly announces to his patients by the way of a

postcard that he was closing down his practice to teach at Loyola

University.

In addition to everything that continues to point that Accutane

played a role in Daniel’s suicide is a picture that I received from

a friend on the day after Thanksgiving this year. Looking at this

picture brought tears to my eyes. His beautiful smile of hopes,

dreams and promises had been taken away before Accutane therapy. I realize that we have pictures of Daniel before Accutane all

smiling and pictures of Daniel on Accutane, no smiles.

As you can imagine, this past year has been very painful for our

family, and the more we research, the more we realize that somehow or another our precious son’s life fell through the cracks. I am

not looking for an out. I do know this for a fact: The dermatologist

provided us with outdated information. The pharmacist didn’t provide any patient counseling. Renlar Systems and First Data Bank

package insert did not include the most current adverse reaction,

suicide. Roche’s labeling did not include in the warning depression

and rarely suicidal thoughts, suicide attempts and suicide.

The FDA has allowed Roche to continue to profit from this drug

for far too long without taking any responsibility for the damage

it continues to do to our children. Mistakes were made by many,

and now we are all suffering because this could have all been prevented if everybody did their jobs.

I hope that this limited information I have provided today will

somehow make a positive difference in our children’s future. Thank

you for giving me an opportunity to share Daniel’s story with you.

[The prepared statement of Mrs. Baumann follows:]

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Mr. BURTON. Mr. Jackson.

Mr. JACKSON. Mr. Chairman, thank you for inviting me to come

here and testify before this committee today. This is going to be extremely difficult for me to talk about. However, it is extremely important for me to be here so we can hopefully prevent just one parent from having to experience the pain and grief that my family

has had to endure, so that maybe all of this will be worthwhile.

On January 13, 2000, my 17-year-old son and my best friend,

Clay, died from a self-inflicted gunshot in our home. Around 4 p.m.

that day, imagine my wife and my 10-year-old son coming home to

find his lifeless body dead in his bedroom. I will never be able to

remove what they saw that day from their memory. This is going

to stay with them for the rest of their lives.

Clay began going to a dermatologist at the age of 14 for normal

teenage acne. In October 1999, at the age of 16, his treating physician decided to put Clay on Accutane for his mild acne. There was

never any mention of suicide as a side effect. The information that

Clay brought home from the dermatologist was a brochure dated

1994 and made no mention of suicide. The only thing that concerned the dermatologist was our ability to pay for the drug. The

package insert that came with the prescription made no mention

of suicide as a side effect. The pharmacist where we had all of

Clay’s prescriptions filled never mentioned suicide as a side effect.

The first time that we were ever made aware of any relationship

between Accutane and suicide was when we heard the news stories

about Congressman Stupak’s loss of his son and the information

that he uncovered. Looking back, I have to assume that neither the

dermatologist nor the pharmacist knew anything about the link between Accutane and suicide.

We are given so much freedom in this country to make choices

for ourselves because we have so many checks and balances built

into the system to protect the citizens sometimes we make those

choices blindly. That trust has been violated. I am not sure who is

to blame. I do not have those answers. I just know that that trust

and faith that I once had has been greatly diminished.

Also, in looking back, I wish that I had taken seriously that

young investigating officer who investigated Clay’s death when he

asked me the question back in January, was Clay taking Accutane

and did I think that this attributed to his death. Oh, how I wish

I had taken him seriously then, and maybe Congressman Stupak’s

son would be here with us today.

I would be happy to answer any questions you might have, Mr.

Chairman.

[The prepared statement of Mr. Jackson follows:]

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Mr. BURTON. First of all, on behalf of the committee, I want to

thank you all for being here, and I want to once again express our

condolences for the tragedies that you have had to encounter and

will continue to live with.

Let me start with you, Mr. and Mrs. Baumann. You found out

after your son was gone that, prior to his death, on the Internet

there was information that showed that there was depression and

possible suicide if they took Accutane.

Mrs. BAUMANN. That is correct.

Mr. BURTON. So this information was on the Internet before this

tragedy occurred, but you had never been told that by a pharmacist

or a dermatologist or the company itself?

Mrs. BAUMANN. That is correct. The information that the dermatologist gave me are brochures that are made by La Roche that

were copyrighted in 1996 and in 1997.

Mr. BURTON. But the point I want to make is that had you been

aware of the problem when it was first put on the Internet, if it

had been properly given to you by the company or the pharmacist

or the dermatologist, this whole tragedy very well might have been

avoided?

Mrs. BAUMANN. I agree.

Mr. BURTON. How about you, Mr. Jackson?

Mr. JACKSON. Yes, sir. The same situation. This was 9, 10

months after Clay died before we even suspected anything like this,

and we saw the news story, went to Congressman Stupak’s Web

site and saw the information that he had.

I think what got our attention was that, even though it was 9,

10 months later, we heard the little news story on the 10 o’clock

local news and we saw like the last 3 seconds, and my wife and

I both reacted because there was something about Accutane, something about suicide, but we didn’t catch the whole story. And that

was—that put us back to January when this investigating officer

asked us this. You know, at the time we thought it to be absolutely

ridiculous, and now we hear this story, we find Congressman

Stupak’s Web site, we see all of this mountain of information that

has obviously been available for as much as 2 years prior to Clay’s

death.

Mr. BURTON. So had you been able to have that information before, you would have seen the signs and it very well may have been

avoided.

Mr. JACKSON. There would have been absolutely no way that

young man would have ever been on that drug. Because the other

thing we learned was that it was a drug of last resort and for very

severe cases of acne. Clay did not have those traits. In my opinion,

he had no reason to be on this drug. He had a normal, 16 yearold face that—it just did not—it was not the severe case that this

drug is licensed to be prescribed for.

Mr. BURTON. Mrs. Callais and Amanda, had you known what

was available prior to Amanda going on Accutane, you probably

wouldn’t have had her on that, or at least you would have noticed

the signs.

Mrs. LORI CALLAIS. I think that we possibly would have started

it. You don’t know until you are on this drug how you are going

to react. But I know had we had the information—I can only tell

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you what happened when we walked into the emergency room and

my husband looked at the emergency room physician and he said,

do you think Accutane could cause this, because it was the only

drug she was taking, and his response was, no, that is an acne

drug. So, had we known, we would have taken it away from her

immediately, but we didn’t have that option, so she continued it.

Mr. BURTON. But the point is the physician at the hospital when

you went had no knowledge whatsoever about the side effects of

Accutane, even though it had been reported much earlier and was

on the Internet.

Mrs. LORI CALLAIS. I don’t know that at that time, because this

was back in 1997, it was on the Internet. Apparently, it was in the

PDR, buried, the possible depression, but we didn’t know that, and

apparently neither did the physicians. Because had we known any

of that and had it been available to us, we definitely would have

taken her off Accutane.

Mr. BURTON. OK. Thank you.

Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman.

Thank you all for your testimony. I know how difficult it must

be to come before a committee of the Congress and share your pain,

and we certainly want to extend our sympathies to you. I think

your being here is very important as we explore this issue and we

learn what we can.

You have all said, as I understand it, that if you had known

about this risk, if there was some information about a risk of suicide versus clearing up some acne, none of you would have put

your children at that kind of risk. Is that a fair statement from all

of you?

Mrs. BAUMANN. Yes.

Mr. JACKSON. Yes.

Mrs. LORI CALLAIS. Yes.

Mr. WAXMAN. And you didn’t know until very late that the problem in the case of suicides might have been related to using

Accutane. Once you learned, or at any point, did you ever let the

company know that you think there was a problem related to the

drug or let the FDA or your doctor know about it?

Mr. JACKSON. We notified the FDA. We filled out an adverse

event report form and sent it to the FDA. I found it strange that

that was a voluntary reporting system that we were supposed to

do, but we were not aware that it is even out there. And a dermatologist for sure isn’t going to be sending in that type of a report.

Mr. WAXMAN. And this was how many months after your son’s

death?

Mr. JACKSON. This was in—it is October or November of this

year when we sent the report in.

Mr. WAXMAN. So it was after you heard about Congressman

Stupak’s son and you started making this connection and then you

took it upon yourself to let the FDA know.

Mr. JACKSON. Right.

Mr. WAXMAN. Did you let your doctor know?

Mr. JACKSON. No. You know, it is extremely hard to go back in

that office, and because of everybody is so scared of getting sued

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and nobody wants to say anything, so nobody will talk to you. I

don’t want to put that attitude out there, but I was interested in

knowing what was in Clay’s medical file. And I called over there

and I asked to have a copy of all of his medical records and they

said, no problem, would you like to come by and pick those up. Yes,

that would be fine. So I went by later that day and signed the release and picked up a copy of his file and left, and it was just business as usual. There was no, how are you doing or—you know what

I mean? It was really strange. And I go back out in the car and

I sit in the parking lot, and what I could read of his handwriting,

you know, there is absolutely nothing in that file. It is just the

dates of the appointments.

Mr. WAXMAN. As far as you know, the doctor didn’t even know

about the association of Accutane with suicide.

Mr. JACKSON. No. And this is a highly respected dermatology

clinic in our community. This isn’t some rookie—I mean, this is a

prominent, very well respected dermatology clinic in our community, and the brochure that we come home with is dated 1994, and

when he was put on the drug was in 1999, 5 years later.

Mr. WAXMAN. Mr. and Mrs. Baumann, I am asking the question,

were you contacted by the doctor or the company or the FDA? Not

in any way to be critical, but just to know if you did; and if you

didn’t, I can understand you not doing it. But what would be your

answer?

Mrs. BAUMANN. I contacted the doctor 2 days after Dan’s death

to let him know that Dan had passed away and that we wouldn’t

be making his next appointment that week, and this was before I

even knew that there may be a potential link between Accutane

and depression and suicide. I don’t know if the doctor reported it

to the FDA. I can guess he didn’t, because I would assume that

someone would have contacted me; and, like I said, I do know that,

5 months after Dan’s death, the doctor is now not in practice and

teaching at Loyola University.

Mr. WAXMAN. Well, Congressman Stupak recommended further

studies about the links between Accutane and psychiatric disorders, as well as for increasing the information for patients and

for families to receive that information about those risks. I assume

all of you think, at the minimum, we ought to know more about

this problem and people ought to be advised about the risks that

they never even would have dreamed that they are subjecting their

children to.

Mrs. Callais, did you ever contact anybody about your experience

with Accutane and the relationship you started to think was there?

Mrs. LORI CALLAIS. Actually, I did. The next day, the day that

I found out, after I found out about the warning, when it first came

out from the FDA, I called Roche Pharmaceuticals, because their

number was on there, because it said, report it, and I called. And

I remember something that the person that I talked to said that

just struck me as horrible. She said, you know, we have had a lot

of calls about those things today. And I thought, my God. And I

said, how many kids have died? And she said, hmm, I don’t know.

I also talked to them again a couple of months later, because they

were supposed to call back in 30 days to see how Amanda was.

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They didn’t bother. As you can understand, I was furious by this

time.

I have talked to my daughter’s dermatologist, and I talk frequently now. I still use that dermatologist. It took a lot to go back,

but I trusted that she didn’t know, and she didn’t know. And since

that time, she and I have talked. She always wants to know that

I am doing it, because we talk all the time. I go everywhere I can

to tell about this drug. And she has said that, since Amanda’s case,

she has pulled three patients off of the drug, and she now asks

them about how they are doing, if they are depressed. But she is

the only dermatologist that I know of in our entire area that even

bothers to ask, and she only asks because she knows about Amanda. So I don’t know that anybody else ever even checks. I mean,

who tells their dermatologist they are depressed? You go to your

doctor. You don’t go to your dermatologist.

Mr. BAUMANN. I know that Stacy has talked to the pharmacy

about it on a couple of occasions and I think even recently the

pharmacist said that they have done some of their own investigating as well.

Mr. WAXMAN. Mr. Chairman, if you will allow me, we do know

that even before any of you had your experiences with Accutane

that the company knew that there was some association with the

use of Accutane, and the FDA had knowledge about it as well. In

Europe, they are taking stronger action. My feeling is that they are

the ones who should be telling you, not you telling them, so that

we can avoid these problems.

Mr. BAUMANN. The word that came to my mind when I did find

out is I felt bushwhacked.

Mr. BURTON. Mrs. Morella.

Mrs. MORELLA. Thank you. I want to add my voice to those who

have said that we thank you very much for coming and telling your

story. As a parent myself, and I think all of us on this panel are,

we can empathize with what you have been going through, as

much as one can who hasn’t experienced it.

It seems to me, from what you have said, Accutane has almost

an immediate reaction. I mean, we are talking about things that

have happened within several months; is that correct?

Mrs. BAUMANN. Probably several weeks.

Mr. BAUMANN. From listening to Amanda in the back give a report to a news—it is exactly the same thing that happened with

Daniel, too, and I can’t remember the question that was asked, but

it was so appropriate. The reaction is immediate, but it is continually worsening. Would you say that is accurate?

Ms. AMANDA CALLAIS. Since I have been on the drug, and I am

the only one on this panel who can state how it feels to be on

Accutane, the physical side effects occur very quickly, but within

days of taking Accutane, my mood began to change. Within a week,

I was crying for absolutely no reason.

I think one of the easiest examples to tell people is my dad

bought me a jacket that I had wanted, I wanted it for a few

months, and when he gave it to me, I looked at it and I burst into

tears, because he hadn’t asked me, and I didn’t understand why I

was so upset. But I was, and I couldn’t stop crying. So it definitely

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takes effect very quickly. Within days, my mood had begun to

change, along with the physical side effects of the drug.

Mrs. MORELLA. I am trying to understand, the warning statement that is contained within the insert with Accutane now warns

against depression and possible suicide; is that correct? It does

now?

Mrs. LORI CALLAIS. It does now, but I caution you about one

thing on this depression. It is not a normal depression. It doesn’t

act like you would normally see. Also, if you don’t know what teenage depression is, or clinical depression, you have no clue.

This doesn’t happen in such a way that you wake up one morning, oh, my child is depressed. It happens each—a little more each

day until finally you wake up 1 day about 6 to 7 weeks later, and

it is generally about 2 months into the treatment, 7 weeks, something is wrong. So it is very, very gradual. So while it may explain

depression or say depression now, you need an explanation of what

depression is.

Mrs. MORELLA. Someone who is on Accutane needs to be

watched, monitored every day, to see whether there are nuances

that can be determined from 1 day to another.

Now, this warning was not on there, though, back in what 1997?

Did it happen in 1998, is that what we are talking about?

Mrs. LORI CALLAIS. February 26, 1998, the warning came out.

Mrs. MORELLA. 1998. And the French did it before we did?

Mrs. LORI CALLAIS. In March 1997. I guess French people are

more receptive to depression than Americans——

Mrs. MORELLA. Or more aware of it, in terms of the sensitivity

of it.

Mrs. LORI CALLAIS [continuing]. But I hope not. But that’s what

happened at the time. I realized that, and I wondered—I thought

that if another country came out with such a warning, that the

FDA would—has requirements that Roche should have immediately told them.

Mrs. MORELLA. FDA has that reputation of making sure that

every precaution is taken well before other countries, generally.

And I think all of you have said that your doctors really were not

aware of the intensity of the consequences of Accutane.

Mr. Baumann.

Mr. BAUMANN. I am not sure if they weren’t aware. One of my

customers is a physician, and he says that he does not routinely

tell everybody all the bad things that can happen as a result of a

drug being administered, because the instances in many cases are

so small of bad things that it is just whether it is not worth it or

what, I don’t know.

Mrs. MORELLA. It seems to me that it should be in great big, bold

print, because I have read aspirin bottles which say, you know, all

kinds of horrible things could happen as a result of taking more

than two aspirin at any one time.

Mr. BAUMANN. I would like to respond to your previous question.

We did meet our friend, who was picking up an Accutane prescription for her son, and I asked her to look at the labeling. I even

asked her to save it for me, but apparently she didn’t think that

it was an important thing that I was asking her, so she didn’t, but

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there was nothing on her labeling. And this was just last summer—this summer.

Mrs. MORELLA. Sometimes even labeling is such small print also;

not only are we not accustomed to looking at warnings, but such

small print.

Again, it almost sounds as though doctors, either they are—they

feel that they are worried about the risk of being sued, whether

that is a problem, liability problem, or whether they just don’t

know. So it seems like in a recommendation that might come from

this committee there should be something with regard to educating

doctors, too. Do you agree?

Mr. BAUMANN. Definitely.

Mrs. MORELLA. I mean, I am trying to figure out what it is we

need to do.

Mrs. BAUMANN. I would say some physician education and patient, potential patient, education. We need to educate the children

and the parents.

Mrs. LORI CALLAIS. One of the things that I noticed about physicians, dermatologists particularly, and what I have heard said over

and over from them—you have to understand I now go and talk,

I ask everybody about it—they will say, well, I have never seen it

before. Or they will say, well, the risk is so minimal that, you

know, I have not seen this; it is not something to worry about.

I don’t think that the dermatologists actually believe that depression is a possibility, and if they don’t see it—and if a child commits

suicide, they will never see them again, and if a child is depressed,

the amazing thing about Accutane is you pull them off, and they

get better. So once they stop the treatment, well, then they are OK,

so then you don’t ever see that part of it. So I don’t think that they

are really aware, or if they are, they just assume it won’t happen

to them.

Mr. BAUMANN. I feel that parent education is most important because it is the parents that monitor their children most of the time.

The physician only sees them on occasion, once a month, and the

parents—had I known what Amanda here had said earlier, it

would be very easy to see the signs as a parent.

Mrs. LORI CALLAIS. May I ask something that I have wanted to

see done ever since then because I realized it? If there was some

way that every time a child went to the dermatologist right now

they could fill out a little—just a little checklist and a parent had

to fill that checklist out of certain symptoms, that would clue you

in as to what is going on; as a physician, you could take it and do

it. I even think there is one in existence today, and that can be

done. It is a profile of some sort, something that lets the parent

and the physician know what is going on with that kid.

Mrs. MORELLA. You mean a profile before?

Mrs. LORI CALLAIS. Every time—you start before, what is your

mood, how many hours a night do you sleep, do you have insomnia

or something, something so you have a base to start, and then once

they start, if every visit that child went to the dermatologist, and

I am saying very selective, not mild or moderate anymore.

Mrs. MORELLA. OK. So you continue to monitor?

Mrs. LORI CALLAIS. You continue the monitoring so that physician has, right in their hands, they can see something going on.

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But you need the parents to do that because I am afraid the kids

would not necessarily tell the truth. They would be afraid they

would be taken off.

Mrs. MORELLA. Exactly.

Mr. BAUMANN. One thing that seems to be a tie here that I heard

Mr. Jackson say also in the back was lean people seem to be—low

body fat seems to make a difference.

Our son was very thin. He stopped eating. He slept all the time.

He didn’t want to go to school. He didn’t care about his grades. He

lost his desire to live, I believe, and he also was very thin at the

end and very depressed. He stopped taking care of our dogs, and

he had done that all of his life. He loved those dogs.

Mrs. MORELLA. It almost seems like there should be a connection

between the mental health groups as well as the physical health

groups in this particular situation. Maybe we can work something

out.

I want to thank you very much for your—did you want to make

another statement?

Mr. MICA. I believe there are some obvious signs. As a parent

now, hearing what I am hearing today, I think there are some obvious signs that can be very easily interpreted, and maybe we can

avoid other people having the problems.

Mrs. MORELLA. And, again, the studies that have been mentioned, I would think we should move ahead fast with those. I

thank you very much.

Thank you, Mr. Chairman.

Mr. BURTON. Thank you, Mrs. Morella.

Mr. Horn.

Mr. HORN. Thank you, Mr. Chairman.

I have been very moved by your studies, and I have known a lot

of children that have had Accutane when my own children were

going to school. Fortunately, we did not have the problems that occurred and led to death, but the dermatologists that I have known

have put it under a very controlled manner of just 6 weeks or that,

and then they haven’t given it anymore.

Now, to what extent they have this knowledge, I think, Mr.

Chairman, there is a nice list of major associations attached to an

article in your opening testimony. We ought to send them all the

files we have got here and copies so that they could understand,

your daughters, your sons, what happened to them. I would think

they ought to be getting increasingly conscious of the effect of this,

and then obviously in the second panel we will get into it. But if

we have to do it on a human side, certainly we could give some of

you the package of testimony we have had, and that might sway

a few doctors into asking the questions you want them to ask that

they apparently, according to your testimony, do not ask.

In my opening statement, I said I would like to know the difference between suicides that have Accutane and the suicides that

don’t, and the degree to which that is likely to happen. Now, maybe

we will hear that on panel two, I don’t know, but that certainly is

a question we ought to ask and try to deal with.

So I thank you and yield back my time.

Mr. BURTON. Thank you, Mr. Horn.

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I want to thank the witnesses for their testimony. I know it has

been very difficult for all of you. Let me just say that we on this

committee and in the Congress will do everything we can to make

sure that the information that you have given us today in your testimony is disseminated as widely as possible so that parents and

children across the country will have as much information as possible so that these tragedies won’t occur in the future. Once again,

thank you very much. Thank you very much for being with us

today.

Our next panel is Dr. Pariser, Dr. Jacobs, Dr. O’Donnell, Dr. Bull

and Dr. Huene.

Dr. Huene.

Mr. MITCHELL. Mr. Chairman, it was the Department’s understanding that Dr. Huene was coming to accompany the witness and

would answer any questions that our witness Dr. Bull might not

be able to answer for you. I thought that was our understanding

with the staff.

Mr. BURTON. That’s fine. Does she prefer not to be at the table;

is that correct?

Mr. MITCHELL. Yes, Mr. Chairman, that is our preference.

Mr. BURTON. OK. Well, if we have questions for her, I presume

she will come forward at the time.

Mr. MITCHELL. Yes, Mr. Chairman, that’s the case.

Mr. BURTON. Would you stand, though, Dr. Huene, along with

the rest of the table.

[Witnesses sworn.]

Mr. BURTON. OK. We will start with Dr. Pariser.

Did I pronounce that correctly?

Dr. PARISER. Yes, sir. Thank you. Dr. David Pariser.

Mr. BURTON. You are a dermatologist; is that correct?

Dr. PARISER. Yes, sir.

STATEMENTS OF DAVID M. PARISER, M.D., FACP, AMERICAN

ACADEMY OF DERMATOLOGY, PARISER DERMATOLOGY SPECIALIST, LTD., VIRGINIA CLINICAL RESEARCH, INC., NORFOLK, VA; DOUGLAS JACOBS, M.D., ROCHE CONSULTANT, ASSOCIATE CLINICAL PROFESSOR OF PSYCHIATRY, HARVARD

MEDICAL SCHOOL, WELLESLEY, MA; JAMES T. O’DONNELL,

PHARMD., M.S., ASSISTANT PROFESSOR OF PHARMACOLOGY,

RUSH MEDICAL SCHOOL, PALLENTINE, IL; AND JONCA

BULL, M.D., FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY PHYLLIS HUENE, M.D.

Dr. PARISER. Good afternoon, Mr. Chairman and members of the

committee. My name is David Pariser. I am a dermatologist in private practice in Norfolk, VA. I am also the chief of dermatology and

a professor of dermatology at the Eastern Virginia Medical School

in Norfolk, and I am on staff in four Norfolk-area hospitals.

For the last 24 years, I have had the opportunity to treat thousands of patients with acne of varying degrees of severity. Furthermore, I also maintain an active practice in clinical research. Over

the last 8 years, I have participated in over 150 research projects

and clinical trials, including numerous acne clinical trials for a variety of pharmaceutical companies, including three trials funded by

Roche Pharmaceuticals.

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I have received indirect funding in the past through the National

Institutes of Health, but not any from that agency in the past year.

In addition to my daily medical duties, I am a member of the

board of directors of the American Academy of Dermatology. I am

here today on behalf of the over 13,000 members of the Academy

and millions of patients, and I wish to express my appreciation for

your invitation to appear before you and discuss the drug

isotretinoin, commonly referred to today as Accutane.

My No. 1 concern when treating patients, and that of the Academy’s, is for patient safety. We are committed to ensuring the safe

use of this drug, and we are also committed to ensuring that

Accutane continues to be available to patients who need it.

Like many of my colleagues, I was drawn to the specialty of dermatology for intellectual as well as personal reasons. As a young

man, I personally suffered from severe cystic acne, and today my

face bears the scars of my battle with this disease.

I have a 20-year-old son who suffers from severe cystic acne, and

I have prescribed Accutane for him. He just finished his second 5-

month course of Accutane at age 20, having taken a previous

course when he was 15.

Acne is not simply a cosmetic problem. This is a disease, and in

some cases a very serious skin disorder. It is the most common

skin disorder of any age group affecting 85 percent of all teenagers,

approximately 20 million Americans. Acne is a disease of the

pilosebaceous unit, the hair follicle, which consists of an oil gland

connected to it, and although found all over the body, these

pilosebaceous units are larger and more numerous on the face, on

the scalp, on the upper back and the chest. There is where acne

is most prevalent.

In normal skin, the oily substance, called sebum, produced by the

sebaceous gland empties onto the skin surface through the opening

of the follicle. So while we do not know exactly what causes acne,

we do know that changes in the lining of this hair follicle occur

that prevent the sebum from passing through the follicle to the

skin surface.

In acne, the cells that line the follicle are shed too quickly and

clump together, and these clumped cells block the follicle so that

the sebum cannot reach the surface of the skin; and then bacteria,

which normally and harmlessly live on the skin surface, begin to

grow in the follicle, and all of these factors together produce the inflammation.

Now, dermatologists will classify the type of acne by the presence

of particular types of lesions. And in the written information that

I have provided for you, there is a detailed description of the different forms of acne lesions.

But in addition to these lesions on the skin, acne has a number

of psychosocial effects. Studies have shown that people with acne

suffer from social withdrawal, decreased self-esteem, poor body

image, embarrassment, feelings of depression, anger, and also higher rates of unemployment.

As a clinician, I often see patients with moderate to severe acne

who have difficulty in making eye contact when speaking, and

many cannot even bear to look at themselves in the mirror.

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Many people believe that acne is a result of poor hygiene. Dirt

or surface skin oils do not cause acne, and believing this myth can

actually make acne worse because vigorous scrubbing and washing

can sometimes actually irritate and interfere with topical therapy.

Acne is not caused by diet. Extensive scientific studies have not

found any meaningful connection between eating things like fried

foods and chocolate with acne, although in some individual patients

there may appear to be a cause-and-effect relationship.

Acne is not caused by stress, although stress can influence acne

and many other medical diseases.

Some people feel their acne is improved by sunlight, and some

patients do get a temporary drying effect from sun exposure. Sun

exposure should not be recommended as a major treatment for acne

since it can lead to the development of skin cancer.

Dermatologists have a number of effective acne treatments at

their disposal, and after appropriate evaluation a dermatologist

may recommend cleansing agents, over-the-counter medications,

topical and systemic drugs to treat acne. And again, in the written

information supplied there is a more detailed discussion of some of

the treatments.

Nonprescription products, such as cleansers, many over-thecounter medications, are, in fact, quite effective for mild cases of

acne. In advanced cases, however, some of the stronger cleansers

can irritate the skin and even further aggravate acne.

Prescription products, such as benzoyl peroxide, topical treatments, work by destroying bacteria that are associated with acne

and works well for mild acne if used continuously.

Another product topically that’s available over the counter without prescription, salicylic acid, does help to correct some of the abnormal shedding of skin cells and unclogging the pores.

If acne fails to respond to some of these intermediate treatments,

this is the place for the oral vitamin A derivative known as

isotretinoin, or Accutane.

Accutane has proven to be our most powerful weapon against recalcitrant cycstic acne and has dramatically changed the way dermatologists manage this terrible disease. Despite its tremendous

benefits, though, this drug is not prescribed casually. It is a serious

medication. Typically, patients with treatment-resistant acne are

placed on a 5-month course of Accutane, and after usually 2 to 3

months, most patients will begin to see a dramatic decline in the

number of nodules and deep cycstic lesions. A few patients, such

as my son, may require a second course of treatment at a later

time, but generally not more than two courses.

Now, before prescribing the drug, I counsel patients about the

many risks that are associated with Accutane. I instruct them not

to take any vitamin supplements containing vitamin A while taking Accutane since there may be some additive toxicity. I tell them

to avoid sun exposure. I test the blood to assess liver function if

needed and always test for level of the triglycerides, fatty substance in the blood, which may be elevated in up to 25 percent of

people who take Accutane.

Of course, women who are pregnant or may become pregnant

during therapy must never take the drug. There is a pregnancy

program that is developed by the manufacturer of the drug which

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I have incorporated into the routine of my office. I speak frankly

to all female patients about the devastating birth defects and discuss the importance of using two forms of contraception.

And all women of child-bearing potential, that is any female old

enough to have a menstrual period and not surgically sterilized

who is prescribed this drug, must have a negative pregnancy test

prior to receiving their first dose and should not begin their

Accutane until the second or third day of the menstruation.

I am aware of the warnings on the label concerning the changes

in mood, depression, and I monitor my patients’ behavior. I have

a personal belief that it is as important to be up front and honest

with patients about their mood changes, potential depression, just

as objectively as I talk to them about the dryness and chapped lips

which they will get or about the potential elevation in the

triglycerides.

I am aware of the reports that have been mentioned already

today about patients who take Accutane who seem to get mood

changes, who go off it and mood changes get better; they go back

on, and the mood changes can recur. I have had one or two patients

myself who have had that.

I am also aware of suicide of patients who have had severe acne

that have not been prescribed Accutane; mostly young men who— where the burden of the taunting of their peers was too heavy to

bear.

Far more commonly, however, far, far more commonly, I have

seen the remarkable positive changes in patients’ mood and demeanor due to the resolution or significant improvement of their

disease. It is as if a great burden has been lifted from these people,

and their faces and their bodies are cleared of acne.

If I have any doubts about the patient or doubt whether a female

will be compliant about using birth control, or if anyone has an underlying mental health concern or previous history of depression, I

may not prescribe this medication; but I would say that there are

people who have clinical depression and who are on antidepressant

medications for whom I have prescribed Accutane when given appropriate psychological followup.

Given the many benefits of this drug, I am concerned about efforts to create a mandatory registry. A mandatory registry may not

be the best method to improve patient safety. Regulation cannot

and must not be substituted for the frank, personal and complete

discourse inherent in the physician/patient relationship.

To this date, it is my understanding that the FDA has mandated

only one mandatory physician/patient pharmacy registry system for

the drug called thalidomide. This drug, there has only been 11,000

patients registered over the last 2 years. Now Accutane, on the

other hand, is prescribed to nearly 500,000 new patients annually;

a tremendous high number compared to thalidomide, mostly by

practitioners in private practice. If there were a registry program

that was instituted, the economic burden and administrative burden of this would be tremendous for patients, for physicians, for

pharmacists, let alone the tremendous increase in the cost of therapy.

Education of all parties, physicians, patients, nursing staff, medical support personnel, pharmacists, is paramount and must be an

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ongoing enterprise. Efforts to educate patients should be and have

been reevaluated and improved, and new knowledge must be incorporated into physician practices.

Continuing medical education and nursing education programs

are and continue to need to be amended to assure that new information is disseminated to all. This is how it should be; and education and not regulation is how we will further reduce the small

number of inadvertent pregnancies and the psychological events

that are occurring.

Thank you again for allowing the American Academy of Dermatology to appear before you today, and I will be glad to answer

any questions at this time.

Mr. BURTON. Thank you.

[The prepared statement of Dr. Pariser follows:]

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Mr. BURTON. Mr. Jacobs.

Dr. JACOBS. Thank you, Mr. Chairman, and good afternoon, and

other members of the committee. I am Douglas Jacobs. I am a psychiatrist on the faculty of Harvard Medical School. I am also executive director of the National Depression Screening Day, which is a

nonprofit organization which does receive several Federal grants.

My interest in suicide began—and I am going to be summarizing

my statement rather than reading it. Excuse me. My interest in

suicide began in 1972 when my first patient who I was caring for

hung himself in a hospital only to be saved by another patient. As

a young physician, psychiatrist in training, that was an overwhelming experience for me, and obviously for my patient. When

I interviewed my patient, he said to me, I have been a bad patient.

I thought to myself, no, I have been a bad doctor.

That experience has stimulated and propelled my entire career.

I have devoted myself to the understanding of suicide. I have

learned a lot. There is still a lot to learn.

In that context, I have examined—I have treated suicidal patients, I have done research, and I have edited several textbooks.

As part of this journey, I have also become very interested in the

problem of depression. Depression in the 1980’s, with studies from

the National Institute of Mental Health, it was determined it was

underdiagnosed and undertreated. And since depression is clearly

linked to suicide, although not a cause of it per se, it was in that

context that I decided to try out a model of screening for depression, and this might answer some of the questions of Mrs. Morella

and Mr. Horn, that could we screen for depression like we screen

for other medical disorders? And it has been an experiment; I think

it is an experiment that has succeeded in the sense that we can

do it. The problem is that there is much more to be done.

For example, of the 20 million Americans who experience depression each year, less than 20 percent are in active treatment. So we

have many Americans, including young people, if we look at young

people, and there are approximately 20 million 15 to 19-year-olds,

their prevalence of depression is about 6 percent, which means

about a million young people that age experience depression each

year, and of that group only 200,000 or so get treatment. Many of

them end up in physicians’ offices. Many of them end up not getting treatment.

In order to answer your question, Mr. Horn, about 2,000 of that

group goes on to commit suicide each year, and I will explain that

the suicides that I have looked at in Accutane work are no different

than the suicides that are occurring throughout America. And it is

in that context that I have also formed a high school depression

screening program and a suicide prevention program called SOS,

Signs of Suicide, in which we are trying to communicate to young

people that it is better to have a mad friend than a dead friend,

because as young people who don’t let their families know, the suicides occur out of the blue, and we see it—we see a suicide occurring.

I was asked by Roche to evaluate the suicide and depression reports and the Medwatch reports. I have been a consultant to them,

but I am here today at your invitation.

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Let me say in order to first understand suicide, to put it in some

perspective demographically, suicide is the eighth leading cause of

death. There are about 30,000 suicides each year. In the young

population, ages 15 to 24, it is the third leading cause of death.

Suicide rose dramatically in that age group from 1950 to 1980,

where it tripled. Since 1980 to now, it has remained about the

third leading cause of death. It is clearly something that we have

to address.

Depression, as I indicated, occurs in about 6 percent of the population. What we know about suicide is that from a clinical perspective, it occurs with severe depression. The majority are not in mental health treatment. The majority have seen a physician within

the last 6 months. The majority are male. The majority commit suicide on their first attempt.

If one looks just at the profiles of the Accutane suicides, just

from a demographic standpoint, that is what we see: The majority

are male, they are not in treatment, it is their first attempt.

If we could show table 1, and I think you all have this, but this

is a graph to illustrate the complexity of suicide. It is a multifactorial event. No 1 factor causes suicide, and there are 12 or 14 factors. I have put this specific to adolescents who do have age-specific

stressors of self-esteem and image related to severe acne, academic

problems, disciplinary crisis, humiliation.

When I was asked by Roche to look at these spontaneous reports,

I said to myself, well, how could Accutane cause suicide? So from

what I know about suicide, I said, well, does it somehow affect suicidal behavior? Does it cause impulsiveness? Does it affect the

neurobiology? And does it cause psychiatric illness?

That’s my orientation since I didn’t see how it could relate to any

of these other factors.

In terms of neurobiology, and, again, what we know about depression, and, again, I will talk specifically about that, we believe

that there is some alteration of the brain messenger chemicals that

affect our mood centers. We do not believe that isotretinoin,

Accutane, affects the neurotransmitter system causing some alteration that would lead to a depressive illness.

Impulsiveness, again, is related to neurobiology. There is no evidence that there is any neurobiologic substrate causing impulsiveness.

In terms of suicidal behavior, and this really relates to what we

see in the spontaneous reports, and there is not a one-to-one relationship between suicidal ideation, suicide attempt and suicide, of

the 5 million Americans who have suicidal ideation, less than

30,000 go on to complete suicide. And out of that group, we believe

about 600,000 attempt suicide.

In the Medwatch reports there are categories of suicidal ideation.

The problem in evaluating those is that suicidal ideation from a

clinical standpoint is defined as thoughts of suicide accompanied by

an intent to die, whereas thoughts of death—which has a prevalence of about 2.6 percent. Thoughts of death has a prevalence of

about 28 percent. So what is in the Medwatch—spontaneous reports may or may not be suicidal ideation. The same for suicide attempts.

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Let me just say, and I know it is—it is not a chart that I included, but if one were to simply look at the Accutane series of

events that I believe are on Congressman Stupak’s Web site there

are various numbers listed. If one took the prevalence that I am

reporting to you today, the numbers reported in these events are

much, much smaller. For example, there are a total of 155 cases

of suicidal ideation. In terms of prevalence, just in terms of the

base population, one would anticipate 390,000 cases of suicidal ideation. In terms of hospitalization, there is 475. In terms, again,

prevalence, one would anticipate 13,500.

Now this gets to psychiatric illness. Psychiatric illness is clearly

the No. 1 risk factor for suicide, yet the majority of Americans, fortunately, with psychiatric illness—which is also part of the hope

when I am consulted that just because you have a psychiatric illness, you are not fated to die by suicide—that of the 20 million

Americans who experience depression, less than 20,000 go on to

suicide.

What we have heard today, descriptions of depression, I thought

I would try to define what we mean and what is depression and

what is depressive symptoms, and if we could show the next chart,

the American Psychiatric Association has developed a diagnostic

and statistical manual which has a criteria for depression that

really states that there has to be physical—social and occupational

impairment for a 2-week period of time with five of these nine

symptoms.

What is important here is that there are multiple symptoms; not

only emotional symptoms such as depressed mood and loss of interest, but cognitive, the way one thinks about oneself, their bodily

changes, and then the most serious, thoughts of death or suicide.

When looking at the issue of the spontaneous reports in terms

of depression, the question is, is this depression, or is this the

blues, or are these just moods changes? In the majority of cases,

in my opinion, what we are seeing are mood changes. They do not

satisfy criteria for clinical depression.

There were some comments made earlier about positive challenges and dechallenges. I have looked at all of those cases. Again,

the majority of those cases, the mood symptoms go away without

specific treatment once, quote, the drug is stopped. That would not

be the case if this were clinical depression. Clinical depression has

a time course of 6 to 9 months; where in the values of treatment,

specific psychiatric treatment, is that improves treatment in 1 to

2 months.

Mr. BURTON. Excuse me, Doctor. Could you summarize relatively

soon because we want to make sure we get to everybody.

Dr. JACOBS. In terms then of the specific suicide cases, the spontaneous reports I looked at in terms of gender, the relationship to

on/off Accutane, the issue of concealment of symptoms, and then

the issue of does Accutane exacerbate underlying illness.

It was my conclusion that the gender distribution is the same;

that there was a report of temporal association, that some committed suicide on Accutane, some off Accutane. There is no predominance. A compelling series of cases are a group of cases, and there

are about 10 to 12 of them, who had underlying psychiatric illness.

They were given Accutane from anywhere from 6 months to 18

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months. They didn’t develop any symptoms, no exacerbation of

their pyschopathology. Anywhere from 6 to 10 years later, they

committed suicide. To me, this is as close to a—obviously, it is not

a study per se, but if one were designing a study of saying giving

a drug to an adverse group, that causes suicide, this didn’t happen.

If I could just read the last part. You have asked my thoughts

on the adequacy of a passive adverse event reporting system in this

context. Although I am not an expert in adverse event reporting

mechanisms generally, I believe that in this matter the adverse

event reporting system has performed its function of providing a

signal of a potential issue. In light of the overall incidence of these

conditions, the appropriate focus is on the education of prescribers

and patients as well as further study, scientific study, and analysis.

In conclusion, although the current scientific evidence does not

support a causal link between Accutane, depression and suicide,

given the clinical population in dermatology and in all medicine in

terms of where I am committed in terms of my career, it is still

important for health professionals to be aware of psychiatric risk

factors. Monitoring patients for depression, depressive systems and

suicidal ideation can help identify any patients who may be at risk

and improve patient care by facilitating appropriate diagnosis and

treatment of patients experiencing clinical depression.

It is my understanding that enhancements are being implemented in the communication of psychiatric information to

Accutane prescribers and patients. I welcome these efforts, and I

believe they will have a beneficial impact on the dermatologic patient population as a whole.

Thank you for this opportunity.

Mr. BURTON. Thank you, Dr. Jacobs.

[The prepared statement of Dr. Jacobs follows:]

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Mr. BURTON. Dr. O’Donnell.

Mr. O’DONNELL. Mr. Chairman, members of the committee,

thank you for the invitation to share my comments with you regarding an overview of existing research and information linking

acne, depression, psychosis and suicide with other drugs like

Accutane and other drugs used to treat acne.

I am an assistant professor of pharmacology at the Rush Medical

College in Chicago. I am also a licensed pharmacist and a certified

nutritionist. I do not hold any Federal grants, although I have testified as an expert witness in matters against Roche.

I would like to project my one slide and leave it projected for the

course of my comments. My review has included the basic pharmacology and toxicology of vitamin A, and if we could focus just on

the top three chemical formulae there, from the audience you won’t

be able to see that, but please take my word that the three molecules of retinol, tretrinoin and isotretinoin are practically identical. There is only an extremely minor change on the far right end

aliphatic group between an OH and a COOH. That won’t mean

anything to you as a layperson, but as a chemist and a pharmacologist, looking at these three chemicals, not knowing anything

different, you would predict the same actions, including the same

toxicities.

This is part of the basic pharmacology and toxicology of vitamin

A and retinoids. This was considered as part of the Accutane clinical research data base, and it is also referred to in published literature describing hypervitaminosis A, a condition which is caused

by too much retinol, too much vitamin A.

Now vitamin A and retinoids have been used to treat skin conditions for 50 years, and we now have almost 20 years’ experience

with Accutane, and clearly Accutane is a very effective drug. I am

certainly not encouraging anyone to remove it from the therapeutic

armamentarium to treat severe acne.

I do question if 1.5 million prescriptions are written for 500,000

patients per year, how many of those patients qualify according to

the prescribing indications approved by the FDA for severe recalcitrant acne? I would direct that question to the gentleman from

the Academy of Dermatology because he did not include that information in his remarks.

The mechanism of action as to how Accutane improves or cures

acne, from my reading, is unknown. We also don’t know why

Accutane and vitamin A substances cause psychiatric conditions.

Perhaps I am using the word ‘‘cause’’ very casually, and I should

correct myself. Clearly, there are associated reports of psychiatric

conditions that have been reported for the last 150 years with vitamin A. Polar explorers used to eat anything they would find on the

icecaps, and they ate polar bears, and they favored the livers. Some

of them became psychotic, and they reported conditions since then,

since 1856, of neurotoxicities, toxic psychosis, schizophrenia-like

symptoms. These have been published throughout the literature

since that time.

Similar toxicities to vitamin A toxicity have been reported in the

literature as well as case reports for Accutane. In fact, the investigational brochure for Accutane in 1978 stated, and I quote, adverse reactions seen with the use of orally administered Accutane

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are essentially those of hypervitaminosis A. So, in other words,

you’re expected as a pharmacologist, as a chemist, when you are

using a drug, you have to look at history and learn from history.

We have a long history of psychiatric toxicity associated with vitamin A. It is not surprising that we have similar reports of similar

psychiatric toxicity associated with Accutane.

I am not going to comment on Dr. Jacobs’ or Roche’s analysis. I

think he made a very succinct and accurate presentation of that

data. Nor will I comment on the FDA’s analysis because they are

here to speak for themselves.

I would like to mention an analysis that was undertaken in Ireland by a scientist who did a pharmacoepidemiological analysis of

psychiatric side effects associated or reported with Accutane and

five other drugs, five other oral treatments used to treat acne. The

other drugs were primarily tetracycline antibiotics, which is a common first-line treatment for acne, and also some hormones which

some dermatologists and other physicians use to treat acne.

Dr. Middlekoop’s findings were that there were more reports for

psychiatric adverse events and suicide worldwide from isotretinoin

than from the use of the five other acne therapies combined, and

her statistics describe a several hundredfold increase in risk of psychiatric side effects with acne.

Now, since we don’t know the mechanism of action as how acne

works—excuse me, how Accutane works on acne, we also heard we

don’t know the mechanism of action of why vitamin A retinols and

Accutane cause these toxicities. No one questions that they do. Fortunately, we do now have warnings that say because of these reports, this may be associated with suicides, suicide ideation and so

forth.

The case reports are suggestive of an association. Clearly, we

don’t have solid scientific information proving the cause, but this

is a neurobiological issue. Sometimes we can’t get into the brains

to actually prove what works. We heard from Dr. Jacobs that we

don’t believe that the neurotransmitters are affected, and

neurotransmitters certainly are responsible for depression and

other psychoses—excuse me, and psychoses. But there is literature

that does suggest that retinols are associated with schizophrenia

and retinols are associated with genes that transcribe the

neurotransmitters in the brain.

I am going to stop, because my time is over, with a comment that

I am pleased to hear that an informed consent form will be provided. I would also state that since historically we know that vitamin A is accepted to cause these toxicities, that instead of saying

we need to prove that—that Accutane actually does this, I would

turn the tables and say, let’s prove that it doesn’t, and until we do,

take precautions and especially warn patients and their families,

because otherwise they are the ones who are really the ones who

have to monitor it and prevent—make a choice whether they want

to take that risk, and if they do, then recognize and be able to

avoid a tragedy. I thank you.

Mr. BURTON. Thank you, Dr. O’Donnell.

[The prepared statement of Mr. O’Donnell follows:]

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Mr. BURTON. Dr. Bull.

Dr. BULL. I would first like to thank the families for being here.

I think the human face that they place on this is far more compelling than any Medwatch form that I have ever viewed in this area.

Mr. Chairman, members of the committee, I am Jonca Bull. I am

Deputy Director of the Office of Drug Evaluation V of the Center

for Drug Evaluation and Research of the Food and Drug Administration.

I appreciate the opportunity to discuss the committee’s concerns

regarding the drug Accutane. Helping to ensure the safe and effective use of Accutane has involved difficult scientific and ethical

issues for FDA. We have taken our regulatory responsibilities concerning this drug very seriously.

FDA approved Accutane in 1982 for use in the treatment of severe recalcitrant cystic acne that is unresponsive to conventional

therapy, including antibiotics. Accutane is uniquely effective in

treating patients with this disease, but is associated with serious

adverse events, including birth defects. For this reason, it continues to be one of FDA’s most difficult challenges in the area of postapproval risk management.

FDA must constantly balance the public need for access to effective therapies with the risks associated with their use. FDA has

been proactive in addressing the issue of risk management. We recognize, however, that FDA is but one of many players that can and

must have an impact on the safety of health care in the United

States.

Because Accutane is the only product that can potentially cure

cystic acne, FDA permitted the continued marketing of the product

in spite of the known risk of birth defects and other serious reactions. FDA has proceeded to periodically reassess the risk-benefit

equation.

From 1983 through 1990, FDA and the manufacturers stepped

up efforts to communicate the significant risk to women of childbearing age. The original clinical trials for market approval for

Accutane did not contain significant reports of depression or mood

disorders. However, in the mid-1980’s, due to postmarketing reports of depression, a label revision was done to include changes

in mood and depression as part of the adverse reaction section.

FDA began a reevaluation of the psychiatric illness reports in

1996 when a physician in the Reviewing Division noted two cases

of suicide in a routine listing of recent adverse events associated

with Accutane. Reports such as this does not necessarily mean that

the event has any relationship to the drug. Accutane, however, had

previously been associated with depression as already noted in the

Accutane labeling.

Because suicide is the most serious consequence of depression,

the FDA Reviewing Division enlisted the help of specialists in the

FDA Epidemiology Division to try to determine whether the cases

could possibly be related to Accutane use.

The divisions undertook a systematic analysis of the published

literature, previously reported cases entered into data bases and incoming safety reports. These reports were not numerous relative to

the rate of depression and suicide expected to be seen in the population likely to receive Accutane, teens and young adults. Some of

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the reports, however, included important details that did suggest

the possible involvement of Accutane.

Therefore, in May 1997, the FDA began working with the manufacturer to fully evaluate the data and determine appropriate next

steps. In February 1998, a labeling change moved psychiatric adverse events in the professional labeling to the warning section.

While Accutane labeling had previously included depression in the

adverse reaction section, it was hoped that the addition of wording

that calls attention to possible suicidal behavior would help further

ensure that prescribers would take appropriate actions if patients

developed mood changes. Even though a causal relationship between Accutane and suicidal behavior had not been scientifically

established, this action was thought prudent, given the available

information.

In addition, a letter was sent to doctors who might prescribe

Accutane, as well as those likely to see patients who develop psychiatric disturbance. FDA also posted a special notice about

Accutane on its public Web site and released a talk paper to the

press to further ensure wide attention and dissemination of this

warning. There was also an update placed on the FDA consumer

Web site. FDA also instructed the manufacturer to discontinue promotional claims regarding the psychosocial benefits of Accutane

treatment for acne.

Patient information is intended to remind the patient about important things they discussed about their treatment with their prescriber. It is not often—it is often not identical to the wording of

professional labeling. Prior to the 1998 change in the professional

labeling, there were five signs of potentially serious problems listed

as bullets for patients, with all capital letter instructions to stop

Accutane and call their doctor immediately.

All of these bullets, except mood changes, reflected serious adverse events in the warning section of the professional labeling.

Thus, when psychiatric problems were moved in 1998 to the warning section of the professional labeling, it was already in the proper

list in the patient information.

As with other symptoms of possible serious or fatal problems, the

patient information on mood changes did not include specific information about the possible outcome, that is, suicide, instead being

followed by the advice to stop the drug and call the doctor immediately due to the possibilities of serious consequence.

After the 1998 labeling change about psychiatric disorders, FDA

embarked on a very comprehensive reassessment of the overall labeling and risk management for Accutane. The revised patient information resulting from this work was implemented on an interim

basis, with a commitment by the manufacturer to conduct patient

comprehension testing and to pursue further revision. The interim

revision implemented in the summer of 2000 captures the possible

outcome for mood disorder; that is, suicide. The need for research

to determine if the linkage was causal began soon after the labeling change. The manufacturer undertook multiple epidemiologic

studies. Results reported thus far have been inconclusive.

Epidemiologic studies by FDA of the dechallenge/rechallenge

cases, also analyzed by Roche study, are suggestive of the critical

need for further research. It is very likely that a controlled mass

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clinical study would not be feasible for ethical and technical reasons. Therefore, an important goal of seeking outside expert advice

was to explore other approaches.

In September 2000, the Dermatologic and Ophthalmic Drugs Advisory Committee again discussed Accutane. The two major topics

were prevention of fetal exposure and risk management strategies

for the uncertain risks of psychiatric effects associated with the use

of Accutane.

On the issue of psychiatric events, the committee unanimously

agreed that there was sufficient concern about Accutane to justify

exploring additional risk management strategies, even though the

risk was uncertain. The committee recommended that the manufacturer add the information about the adverse events to the informed

consent documents signed by patients and their parents or guardians prior to receipt of Accutane; that they develop and distribute

an enhanced prescriber educational program about the psychiatric

events; that a medication guide be developed and implemented for

Accutane.

The committee was also asked whether further studies to help

clarify the relationship between Accutane use and psychiatric

events were needed, and, if so, what kinds of studies. The committee discussed the many ethical and technical problems with controlled clinical trials in this instance and offered ideas for other

types of studies with an emphasis on basic science research, particularly focused on the adolescent central nervous system, as well

as epidemiologic studies in addition to those already under way.

The agency is working with the manufacturer as well as the National Institutes of Health to implement the committee’s recommendations.

In conclusion, Accutane continues to be one of the more challenging products that FDA regulates. We think the record demonstrates the agency’s continued concern regarding this product

and our efforts to manage the associated risks. We are hopeful that

research will establish whether or not the psychiatric events associated with the use of Accutane are truly caused by the drug. We will

continue to work with the manufacturer to keep health professionals and consumers aware of the risks associated with Accutane

and the circumstances under which it should be used and prescribed.

Thank you for the opportunity to discuss this important matter.

[The prepared statement of Dr. Bull follows:]

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Mr. BURTON. I presume that Dr. Huene does not want to make

an opening statement; is that correct?

Dr. BULL. No.

Mr. BURTON. OK.

We will probably have a couple of rounds of questions, questions

at least as far as I am concerned. So bear with us. We are going

on 5-minute rounds, and then we will come around with a second

round for those who want to ask more questions.

Dr. Jacobs, are you aware that a month after the ‘‘dear doctor’’

letter was sent out warning doctors about the concern about

Accutane being linked to depression, that the FDA sent a warning

letter to Roche Laboratories about advertising that made false or

misleading statements and promoted Accutane for an unapproved

use?

According to the warning letter, ‘‘Roche’s promotional materials

state or suggest that Accutane is safe and effective in the treatment of what Roche describes as the psychosocial trauma and emotional suffering associated with acne, including negative psychosocial effects such as depression and poor self-image.’’ This claim

is particularly troublesome in light of information recently presented in a ‘‘dear doctor’’ letter that Accutane may cause depression, psychosis and rarely suicidal ideation, suicide attempts and

suicide.

As someone who is an expert in suicide, how would you respond

to a company promoting a drug with reported suicides for a treatment for psychosocial trauma?

Dr. JACOBS. Well, first of all, I am not aware of any communications between Roche and FDA. I mean, you are bringing that to my

attention. I have not seen that.

The issue for me, as an expert, is that suicide and depression can

occur in the Accutane-treated population. On the other hand, we

know that persons who have severe acne, as was indicated by Dr.

Pariser, can have psychiatric symptoms, including depressive

symptoms, anxiety symptoms. The Accutane can be helpful.

Clearly, the need to communicate accurate information I certainly support. I was aware of that label change. From a scientific

standpoint, I do not see that Accutane causes depression or causes

suicide. The issue is should a physician be aware of mood changes

in their patients? Should a physician be aware of suicidal ideation?

Part of the project I am involved in, National Depression Screening Day, and to answer Mrs. Morella, we have a primary care outreach, and part of what we do is we educate physicians about what

the signs and symptoms of depression are and how to ask about

suicide.

So I think it is important. Should it be specific for Accutane, I

think it should be for all physicians, including dermatologists.

Mr. BURTON. You are not aware? That was my question, you

were not aware that the FDA wrote a letter to—or contacted Roche

saying that they were giving questionable information?

Dr. JACOBS. No, and maybe it is important to clear up. My relationship to Roche, I have served as a consultant, specifically from

a scientific standpoint looking at the data in the spontaneous reports; and that’s the nature of my consultation.

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Mr. BURTON. What drugs are you aware of that can cause depression and suicide?

Dr. JACOBS. Well, that’s also a very interesting question. In my

opinion, there is no one drug out there that causes depression or

suicide.

In the PDR, and I have researched this, there are about 100

drugs listed that, ‘‘cause depression.’’ However, that is not a—because it is in the PDR, that is not a scientific study. What this is

is these are drugs that cause depressive symptoms. I think it is

important—— Mr. BURTON. OK.

Dr. JACOBS. The issue of beta blockers, which many people are

familiar with, cause lethargy, lack of energy, and physicians are

aware it, ‘‘can cause depression,’’ but it is not depression per se; it

is depressive symptoms. And none of those drugs are associated

with suicide.

If you are asking about drug-induced, quote, depression, it is

symptoms of depression that don’t satisfy the criteria that I indicated earlier, but there is no study that shows that that type of,

‘‘depression is associated with suicide.’’ Mr. BURTON. Well, you are a consultant to Roche. Are you still

a consultant with Roche?

Dr. JACOBS. Yes, I am.

Mr. BURTON. OK. Have you done similar reviews of suicide and

possible drug causal link for any of these drugs you are talking

about?

Dr. JACOBS. In terms of looking at—I have looked at some of the

issues of fluoxetine, or Prozac. In the context of my consultation

with Roche, I reviewed the entire literature on drug-induced depression, and I mentioned about beta blockers. I didn’t do the research.

Mr. BURTON. But you found no causal link?

Dr. JACOBS. I found no causal link.

Mr. BURTON. OK. That answers my question.

Dr. JACOBS. OK.

Mr. BURTON. Mr. Waxman.

Mr. WAXMAN. Thank you very much, Mr. Chairman.

Let me start off with you, Dr. Pariser. I have heard estimates

that as many as 80 percent of patients for whom Accutane is prescribed have only moderate or mild acne, not the severe cystic acne

for which Accutane is approved. This is undoubtedly why Accutane

had over $485 million in sales in the United States last year. This

overprescribing exposes significantly more people to the very serious and, as we have discussed, unknown risks of Accutane. How

much does the Academy believe that Accutane is overprescribed,

and what is your position on what should be done to limit it?

Dr. PARISER. Thanks for the question.

Well, I don’t know that we have any systematic information on

exactly how much acne may be prescribed, technically speaking, off

label.

Mr. WAXMAN. Accutane?

Dr. PARISER. I am sorry. How much Accutane is prescribed for

acne which is not in nodular, cystic, recalcitrant and unresponsive

to other therapies.

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I think that it is a clinical dilemma that many of us who treat

acne all the time face. I will commonly see a patient who has acne

which may be recalcitrant, which may be nonresponsive to other

therapies, but which may not be cystic acne; and yes, I have prescribed Accutane in those situations. There are no statistics that I

am aware of.

Mr. WAXMAN. Do you believe that there is an overprescribing of

Accutane?

Dr. PARISER. Well, I would have to know what the numbers were

first. Accutane is prescribed for many off-label indications.

Mr. WAXMAN. Off-label means not for—— Dr. PARISER. For acne which is recalcitrant, which is nonresponsive.

Mr. WAXMAN. There could be dermatologists who are prescribing

it for acne cases for which the FDA never envisioned this particular

drug to be prescribed?

Dr. PARISER. I think that is a correct statement, but it is in the

context of many drugs that we prescribe in ways that are not directly labeled.

Mr. WAXMAN. What is the Academy doing to ensure that members are better informed about these risks?

Dr. PARISER. Well, every year at our annual meeting, which is attended by, last year, over 90 percent of our membership, we have

seminars on acne among many other factors; we have various continuing medical education efforts that are going on, and those are

the major efforts of education that the Academy sponsors. There

are other venues from which our members get information.

Mr. WAXMAN. Our earlier witness, Amanda and her mother, testified that their dermatologist and other treating physicians did not

know about the possible relationship between Accutane and depression. How do you explain the ignorance of her dermatologist and

other psychiatrists and treating physicians about the relationship?

Are they not informed by the Academy? Are they not informed by

FDA? Are they not informed by Roche?

Dr. PARISER. Well, I think all of the above would be applicable.

I am personally heart-saddened by the fact that many of my colleagues seem to be less informed on this than they should be, and

I have no defense for that. I think it is something which we all

have to work harder to do. Education has got to happen.

Mr. WAXMAN. Dr. Jacobs, I want to begin by asking a few questions about your background.

Have you served as an expert witness or been deposed on behalf

of defendants in cases involving patient suicides?

Dr. JACOBS. Yes, I have.

Mr. WAXMAN. And have the defendants been practicing drug

companies or drug companies like Roche?

Dr. JACOBS. The defendants have primarily been physicians or

health care providers. There have been very few cases in which I

have actually testified on behalf of pharmaceutical companies in a

medical legal matter.

Mr. WAXMAN. How many cases have you been involved with, and

what percentage of your income comes from these cases?

Dr. JACOBS. Well, I have been doing this work since about 1980,

and I have been involved in approximately 300 medical legal matVerDate 11-MAY-2000 11:22 Aug 22, 2001 Jkt 000000 PO 00000 Frm 00124 Fmt 6633 Sfmt 6633 C:\DOCS\73924.TXT HGOVREF1 PsN: HGOVREF1
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ters, and in terms of my income, approximately 70 percent of my

income comes from my consultation in medical legal matters.

Mr. WAXMAN. You represented Roche before the FDA when the

agency decided in 1998 to strengthen the warning on psychiatric

disorders; isn’t that correct?

Dr. JACOBS. I was asked to serve as a consultant. I don’t know

if I would officially say I represented Roche. I was a consultant for

them certainly.

Mr. WAXMAN. For Roche, and then you testified——

Dr. JACOBS. At the FDA hearing; that is correct.

Mr. WAXMAN. Do you think the FDA was wrong to strengthen

their warning and do you think the French and the British Governments were also wrong to have similar warnings on Accutane?

Dr. JACOBS. I certainly don’t think they were wrong. From the

data I saw, if I were asked is that accurate, is that an accurate

statement that Accutane—and I think the label reads Accutane,

and I don’t know whether it is ‘‘may cause’’ or Accutane ‘‘causes depression, psychosis, and in rare cases suicide attempts and suicide.’’ As a scientist, I did not see that. From a public health standpoint to alert patients that—to alert families and physicians that

the Accutane-treated population are at risk just as other populations are at risk for depression and suicide, as a physician dedicated to informing the public about suicide, you know, I don’t think

that is wrong at all.

Mr. WAXMAN. Just on this one point, I know my time has expired, but FDA requires Roche to add the following new boldface

warning to Accutane’s package insert—FDA is still unaware of the

new French warning—‘‘Warning: Psychiatric disorders; Accutane

may cause depression, psychosis and, rarely, suicidal ideations, suicide attempts, and suicide. Discontinuation of Accutane therapy

may be insufficient. Further evaluation may be necessary. No

mechanism of action has been established for these events.’’

Then there is ‘‘Adverse Reactions. In the postmarketing period,

a number of patients treated with Accutane have reported depression, psychosis and, rarely, suicidal ideations, suicide attempts, and

suicide. Of the patients reporting depression, some reported that

the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.’’

My question to you, with that warning label, were you testifying

in support of that warning label or were you testifying in opposition? And if you were asked your opinion, would you have urged

FDA to have that warning label?

Dr. JACOBS. I wasn’t testifying for or against labels. That is not

my area. I was asked to testify on my scientific analysis of the

spontaneous reports. It is up to the FDA to make their conclusions

based upon my testimony.

As I indicated before, because there is not a scientific rationale

for that label, I am certainly not in opposition to that label. It is

certainly conservative. There are certainly some patients, as we

have heard today, who have had unfortunate experiences while on

Accutane. And to the degree that physician awareness and family

awareness that depression can occur in young people, that suicide

can occur, and if this is a way to alert people, I am all for it.

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Mr. WAXMAN. Thank you. Was Roche advocating this, or was

Roche urging, to your knowledge, that they not go with this label?

Dr. JACOBS. I was unaware—that is not the level that I get involved in. I know that there were discussions after my presentation

between Roche and the FDA, and then I heard—I only heard the

outcome. I wasn’t involved in the process.

Mr. WAXMAN. Thank you. I will wait for another round.

Mr. BURTON. Mrs. Morella.

Mrs. MORELLA. Thank you, Mr. Chairman. I will try to ask each

of you quickly a question so I can get to all of you.

First of all, Dr. Pariser, you mentioned that it is not prescribed

casually, and I am wondering—and yet it seems as though there

is no system in place to educate parents and families.

With your extensive experience in dermatology, do you feel that

physicians prescribing Accutane are doing enough to educate parents and families of the possible dangers of the drug?

Dr. PARISER. Well, there are many venues and many modalities

of education. There is pamphlets, there is consent forms, there is

education.

Mrs. MORELLA. Is there something that you feel is particularly

good?

Dr. PARISER. But the main responsibility and the main place to

educate is when the physician and the patient are together in the

treatment room, with all other outside influences outside the closed

door. I think it is the physician’s responsibility to do that. If the

physician chooses to use some of these educational aids to help

that, I think that is fine, but it is the responsibility of the physician

to do that. I spend more time in my practice talking to somebody

about Accutane than I do—it takes me longer to do that than to

take off a skin cancer or to do many other procedural services.

Mrs. MORELLA. So what you are saying is it should be done, it

is the responsibility of the physician, but you don’t have any guarantee it is being done.

Dr. PARISER. That is correct.

Mrs. MORELLA. Exactly. You also talk about the fact that you

would see the symptoms develop—or actually, let me put it this

way. Accutane is prescribed for like a 5-month period and then

maybe it is prescribed again, and yet hearing from our previous

panel, they seem to see adverse symptoms almost immediately and

certainly within a couple of months, but they even said during the

first week. So is there a disconnect there?

Dr. PARISER. The clinical studies that were done of Accutane that

derived the data on its efficacy were done with defined courses of

16—usually 16 to 20 weeks of treatment as a defined period of time

usually once, and sometimes that 16- to 20-week period can be repeated again later if adequate treatment did not occur prior to

that, but usually, not more than that. I don’t think Accutane

should be or is casually prescribed in the situation of take a little

bit now and a little bit later. I think that is a misuse of the drug.

Mrs. MORELLA. Except it gets to what I am pointing out that we

heard from previous testimony, that that is a very long period of

time for a course of action, because we can detect adverse consequences sooner than that.

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But let me go on then to Dr. Bull. Picking up on what Mr.

Pariser has said in his testimony, he discusses the difficulties of

the creation of a registry, a mandatory registry for Accutane and

uses Thalidomide as an example and says that there will be a lot

more that would be required.

Is FDA considering a registry of that nature, and do you see

some similar problems besetting the Thalidomide registry?

Dr. BULL. I would add that the Thalidomide experience with the

registry certainly informs how the registry is approached. There is

also another drug, RU–486, that does have a patient registry in

place.

With regard to Accutane—and I think actions that ensure the

safe use of the drug, particularly for a potent drug with the risk

profile that Accutane has, I think really compels that we investigate other options in terms of the sufficiency of our current risk

management structure, and we are working with the manufacturer

in terms of instituting the registry. So that will—— Mrs. MORELLA. Is there a time line that you could offer at this

time?

Dr. BULL. We hear from the sponsor at this point in time as

early as next summer, the summer of 2001.

I would like to add as well with regard to the MedGuide and the

enhanced informed consent, we expect to have those out by the

first of the year, sometime in January 2001. So Roche has gotten

in a draft to the agency, we have responded, and we are optimistic

that it is in its final stages to be distributed and available to patients.

Mrs. MORELLA. I feel that the chairman would probably want to

have the committee notified of what is happening in that regard.

Then finally, for Dr. Jacobs and Dr. O’Donnell, just briefly, if you

think the dangers of Accutane were made clear to patients and

their families, do you think there is a connection that that would

lessen the chances of depression and suicide? Has there been any

evidence to show that patients who knew about the dangers of the

drug were less likely to experience depression or attempt suicide?

Dr. JACOBS. I am not aware of any—— Mrs. MORELLA. I know this is a difficult thing to say, cause and

effect, at this point.

Dr. JACOBS. I am not aware of any studies that has looked at

that. Certainly, making families aware of signs of depression, signs

of suicide, as I indicated before, would not only be helpful in the

Accutane-treated population, but in all families in suicide, that the

suicide rate unfortunately has remained about the same. Most people are not aware that depression can occur in young people, about

6 percent, that suicides do occur, and what the warning signs are.

So education clearly would be helpful.

Mrs. MORELLA. My time has elapsed. Thank you, Mr. Chairman.

Mrs. MORELLA. Sorry. I didn’t give you a chance to answer, Dr.

O’Donnell. Thank you.

Mr. BURTON. Go ahead.

Mr. O’DONNELL. I think your first question was if you tell them

about it, would it decrease the occurrence? It is not going to decrease it. But as you heard from Amanda, that had they known,

they would have recognized the association and stopped it. And

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that is a basic premise in any drug treatment. That is why it is

important to put warnings and package inserts in so that if it occurs, the doctor can look and say oh, yes, this is associated. If not,

they are not going to make the connection.

I do believe that for the patient who goes and demands to their

mother or father to go to the dermatologist and demand Accutane

because they have one pimple, that if they learn about the risks,

they are going to realize that maybe we shouldn’t take this risk.

For those who need it because it is severe acne or it is maybe not

so severe, but it is disturbing to them, they recognize the risk and

they can avoid tragedy by educating their child. And I have heard,

I have heard—and I agree, this is not clinical depression according

to DSM4. Maybe it is Accutane depression. We have Accutane, we

have an Accutane-induced birth defect which has its own diagnosis.

Children say—they don’t say I am depressed, they say I feel weird,

or they just spend more time in their room. And having raised

teenagers, you don’t always know what they are thinking. But if

you know that they are put at risk or they may be at risk, and

since we hear from the psychiatrists they are at risk already because they are in that age group, do we want to give them another

possible risk factor without doing whatever we can to recognize it

and avoid the tragedy?

Mrs. MORELLA. It seems that we are looking for a balancing act

too, the fact that maybe a physician should not prescribe it if someone comes in and says I want it, even though you are saying it is

not prescribed casually. Maybe we also need a registry and maybe

we want to make sure that the physicians educate the parents and

the families.

Thank you, Mr. Chairman.

Mr. BURTON. Mr. Horn.

Mr. HORN. Thank you, Mr. Chairman. I am curious; what are the

major magazines, professional magazines that dermatologists generally receive and that you receive? Would you say it is 5 or 10 or

20?

Dr. PARISER. A smaller number specifically related to dermatology. The Academy publishes a journal, the Journal of the American

Academy of Dermatology, which is the premier educational journal

for dermatologists. The Journal routinely carries articles about

acne, about Accutane; the guidelines of care, for example, is published in that journal.

The other major clinical journal is the Archives of Dermatology

which is an AMA publication, one of the AMA specialty journals

that is read by most dermatologists, and there are probably 2 or

3 others that most dermatologists would be familiar with in some

way, shape or form. It is not 10, but probably 5.

Mr. HORN. Dr. Jacobs, do you agree with that, or are there other

magazines that would be professionally used by the typical dermatologist?

Dr. JACOBS. Well, I would really have to defer to Dr. Pariser on

that. I mean in terms of psychiatry, generally psychiatrists read

the professional journals of their particular specialty. But now with

the information explosion on the Internet, certainly reviews are accessible to physicians, which actually make the reading of whole

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journals probably less, but particular information is more available

to physicians today.

Mr. HORN. Dr. O’Donnell, would you agree with your two colleagues on that?

Mr. O’DONNELL. Yes, I would. Yes, I could.

Mr. HORN. Dr. Bull, do you generally read the kinds of journals

the professors have noted?

Dr. BULL. I would—Dr. O’Connell, who is with me today, would

you agree with that? The publications that dermatologists generally read, the archives.

Mr. HORN. Well, I am interested in what is the major professional journals for a dermatologist, especially board certified dermatologists.

Dr. BULL. Yes, those are the major ones.

Mr. HORN. The reason I ask that is, aren’t there a number of

pharmaceutical ads that you find in most of these magazines? I

mean the pharmaceutical companies do advertise in magazines,

don’t they?

Dr. PARISER. Yes, they do.

Mr. HORN. And these are professional magazines and they advertise in them; is that correct?

Dr. PARISER. Absolutely.

Dr. JACOBS. Yes.

Mr. HORN. I am just a country boy that wants to sort of figure

out how it works. Have you ever seen a pharmaceutical ad that

says we have a problem regarding clinical depression, suicide,

whatever, and maybe you should be careful about this ad? Have

you ever seen one of those ads?

Dr. JACOBS. I am not an expert on advertising, and I generally

don’t read the ads, but what I do know is that generally when a

pharmaceutical product is advertised, that the whole package insert is there with both the risks and benefits of the medication. I

am not saying that I read that, but it is there.

Mr. HORN. Well, that is part of the problem; people are busy and

they have offices filled with people that they are trying to treat,

and generally they treat very well. But I am just curious when a

pharmaceutical company or the Academy puts an ad in or at least

a warning on one of the professional journal pages, so they could

say now you really should be very careful in prescribing this.

Dr. PARISER. Well, in the case—it is my understanding that all

advertising of any—whether it is in a journal or whatever venue

that any pharmaceutical company undergoes, is reviewed by FDA,

I thought. I know in the case of the Journal of the American Academy of Dermatology, our premier journal, that there is medical

oversight for all of the advertising and nonscientific pages that are

in there such that there is nothing—nothing off the wall gets

through.

Mr. HORN. Well, I guess my impression, and I have looked over

the years at maybe 130 medical journals that were in the university library, and they sort of are usually pretty glowing with flowers in the ads and all the rest of it. And I just wondered, where

does reality come from if it doesn’t come from the profession?

Dr. JACOBS. Well, the issue of where reality comes from, it is a

serious matter; and when I say I don’t read those ads, it is because

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I am aware of the medication indications. It is no different what

is in there than what is in the PDR or what is available. The prescribing of medication is a very serious matter, whether it is

Accutane or any other medication, and that has to be addressed between the physician and the patient and sometimes, if it is a

minor, the family. And the reality has to come from the physician.

I think medical journals have a responsibility to provide information. The issue of economic support, that is a reality, but the reality

of medicine is that it is a practice, and it is something that has to

be taken seriously between the physician and the patient.

Mr. HORN. How many MDs are board certified for dermatology?

Dr. JACOBS. I would have to defer to Dr. Pariser.

Dr. PARISER. There are approximately 8,000 to 9,000 in the

United States. I think that is a close guess.

Mr. HORN. That is the board certified?

Dr. PARISER. Ninety-seven percent or so of those are members of

the American Academy of Dermatology.

Mr. HORN. So how many thousand are not certified?

Dr. PARISER. Few.

Mr. HORN. Because the problems come, if they don’t go to put in

their standing hours or something in order for licensure, why, they

are not going to hear it very much. And often they pick nice places

to go, and I understand that; most professions do that, and it is a

good way to get people in the door. But I just wondered to what

extent, or is there a vigorous effort made by the professional leadership when there is a drug of one sort or the other or a practice

of one sort or the other? It seems to me that would be one of the

main channels, eyeball to eyeball, or send them an e-mail or whatever it is.

Dr. PARISER. Well, at the last annual meeting at the American

Academy of Dermatology we had 17,500 registrants. There were

seminars and symposium on acne as well as on dozens of other topics.

Mr. HORN. Do you think it made an effect?

Dr. PARISER. I think every little incremental change helps some.

I don’t know that there is a way that we measure the details of

that particular kind of educational effort, but certainly a lot of effort goes into it.

Mr. HORN. I am going to have to leave, so may I just ask one

more question?

Mr. BURTON. Sure, sure.

Mr. HORN. Have there ever been major studies of just plain old

vitamin A versus Accutane? What is the effect, if any? Does vitamin A have suicidal tendencies, or what?

Dr. JACOBS. I am not aware of any such study. The only—what

I am aware of about vitamin A, and that is mostly from reviewing

the literature, is that it can cause symptoms that we see in depression, such as irritability, anorexia, loss of energy; it does not, from

my understanding, cause clinical depression, and in that sense I

have not seen it in any association with suicide.

Mr. HORN. Don’t you think it would be worthwhile——

Mr. BURTON. Why don’t you let Mr. O’Donnell answer that? I

think he has information on that too.

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Mr. O’DONNELL. Well, there have been no studies, because old

drugs are not studied to determine what people already believe

about them. And the reports that are in the literature that Dr. Jacobs referred to and I referred to earlier describe patients who are

psychotic, who have schizophrenic-like symptoms, and suicides

have been associated with vitamin A toxicity.

The condition of vitamin A toxicity causes a change in the brain

chemistry. The condition that brings vitamin A toxic patients to the

hospital is a swelling in the brain. When we talk about mental

health, we have to convert that to chemical actions in the brain.

So there is a damaging chemical action in the brain that has been

known, and I don’t know that anybody has done large-scale studies

in rats, but we certainly wouldn’t do that purposely in patients. I

hope that answers your question.

Mr. HORN. No, it is very helpful, and I assume that some of the

pharmacists have to write a dissertation or a thesis of some sort,

and I would think that that is something they ought to really go

after.

Mr. O’DONNELL. Of the vitamins, the first thing in pharmacy or

pharmacology 101, is that fat-soluble vitamins are toxic, can be

toxic, and vitamin A and vitamin D are major fat-soluble vitamins,

and we constantly, and especially with people using—vitaminizing

themselves and herbalizing themselves, we see more and more toxicity from these products that they can go and buy; and of the vitamins, that is where we have the major toxicity.

Mr. BURTON. Thank you, Steve.

Let me ask Dr. Pariser, does Roche Laboratories pay for any of

your Academy’s annual conference? Do they pay any of the fees for

that?

Dr. PARISER. Roche, as well as many other pharmaceutical companies, give unrestricted grants to the Academy of Dermatology for

various educational and other efforts. But they do not sponsor specific Academy—— Mr. BURTON. No, but I mean their money is being used to help

pay for some of these events.

Dr. PARISER. That is correct.

Mr. BURTON. You know, I have been to conferences all of my life,

and when you have a large number of people like 17,000, 18,000,

19,000 people and you have different meetings to inform those people, usually a very small number go to any one meeting because

there are so many other things going on at the same time, including extracurricular activities such as golf and tennis and other

things like that. You know what I am talking about.

Dr. PARISER. Yes, sir, I——

Mr. BURTON. I am sure you do, but let me just go on. There is

no way at a conference like that that you could disseminate the

kind of information on a wide-scale basis that everybody would be

able to understand and digest.

One of the things that troubles me about this hearing today is

we have people whose children committed suicide or were adversely

affected by Accutane, and they had no knowledge whatsoever from

their dermatologist or their pharmacist about this. And, in fact, the

dermatologists didn’t know anything about it, even though it had

already been publicized. The pharmacists knew nothing about it,

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even though it had been publicized. So your conference has not

really gotten the job done as far as informing dermatologists across

the country about the possible dangers psychologically, or suicide,

of Accutane.

What I don’t understand is if you are a member of an organization like that, why can’t you just send out a fax to everybody in

big bold black letters saying, Accutane can cause severe depression

and possibly suicide, as has been said in current warning labels in

France and other parts of the world? Why don’t you do that?

Dr. PARISER. Well, perhaps if our membership hasn’t availed

itself of the other means of education, perhaps they wouldn’t read

that either; I mean, you could argue that. I agree with you that it

is an annual meeting where there are many things going on. It

may not be the best way to reach the masses.

Mr. BURTON. Let me ask you this. Do you think it would offend

LaRoche Laboratories if you sent a fax out to every single one of

your dermatologists around the country informing them of the possible dangers? Do you think it might offend them?

Dr. PARISER. I don’t think it would.

Mr. BURTON. You don’t? You don’t think it would endanger the

money that you get for these conferences?

Dr. PARISER. I don’t think it would endanger the money, and

even if it did, that would not be the mission of our Academy, to

yield to those kinds of economic pressures.

Mr. BURTON. Why don’t you just go ahead and send a fax out to

all of the dermatologists in the country saying, this is a risk and

many dermatologists evidently don’t know about it; there was testimony before the Congress of the United States by people who had

lost children, they knew nothing about it, even though it had been

publicized on the Internet, and so we want to make sure you know

about it. Why don’t you do that?

Dr. PARISER. I will check into that.

Mr. BURTON. Would you do that? If you don’t, do me a favor.

Give me a list of all of your members and I will send the daggone

thing out, OK?

Dr. PARISER. We can do that.

Mr. BURTON. Because I don’t want other people coming before

our committee with their kids being dead because possibly

Accutane caused it.

Now, let me ask you a question, Dr. O’Donnell. You said that the

people who ate polar bear livers in the middle 1880’s that were on

polar expeditions had psychotic events because of the large

amounts of vitamin A they were consuming in the livers of polar

bears; is that correct?

Mr. O’DONNELL. Yes, sir.

Mr. BURTON. Was this just an isolated incident or was this something that happened more than once?

Mr. O’DONNELL. There were several reports, not many were published, but it was common knowledge that people had to avoid excessive use. But similar reports through—since then have published neurotoxicity, toxic psychosis. But the first report I referred

to was a polar expedition in 1856.

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Mr. BURTON. So vitamin A in large quantities definitely causes

the kinds of problems you are talking about, and that is what

Accutane, in main part, is made up of?

Mr. O’DONNELL. Yes, sir.

Mr. BURTON. You know, Dr. Bull, one of the things that I don’t

understand is—and I won’t be able to ask Dr. Huene about this,

I guess—but I would like to know just a little bit about how

Accutane was approved and what kind of testing took place at the

FDA before it was approved. I understand that this was approved

before advisory committees were being utilized, so Dr. Huene and

others evidently did some of the research on that before it was

made—put into the public domain.

Can you tell me what kind of testing was done; and if not, can

Dr. Huene give us that information?

Dr. BULL. Well, I can get it started and certainly if Dr. Huene

wants to add to my statement, that would be certainly suitable.

FDA does not conduct research. We review research conducted by

the manufacturer, so all of the research that we reviewed was done

by Roche Pharmaceuticals.

Mr. BURTON. Let me interrupt you. When you review, when your

advisory committees today—or whatever it was back in those

days—reviews it, they review the scientific data in detail before

they give an advisory opinion to the head of the FDA so that it can

be approved?

Dr. BULL. The process begins with review of the protocol for the

study, and once the studies are completed, review of the actual

data, how well the study adhered to the standards that were set

out for powering the study, the number of patients enrolled in the

study, the parameters that were to be assessed to determine efficacy, what parameters were studied to assess the safety of the

drug, and how well it meets the mark for what it has to have as

its proposed indication.

Mr. BURTON. I have to yield to my colleague, but let me just cut

through this and say what I want to find out is how extensive was

the research, and was it thoroughly examined before they put this

on the market? Did they have any kind of information about adverse impacts, about depression, about possible suicide? Was any

of that looked into before they put this on the market?

Dr. BULL. The typical way that safety is assessed is based on

what is reported. There are adverse events that are anticipated

that studies I think probably bring a higher level of precision in

terms of soliciting comments and direct information from investigators. Then there are others that are—could be considered at the

discretion, and going back almost over 20 years ago when these

studies were conducted may not have had quite as high a level of

stringency applied to them in terms of reporting all things, because

there is so much about a new drug that you don’t know. So in a

sense, every event that a patient may experience is sort of in play.

Mr. BURTON. Well, I have more questions on this. I will yield to

Mr. Waxman right now, but I want to get back to that.

Dr. BULL. Certainly.

Mr. WAXMAN. Thank you very much, Mr. Chairman.

This drug was approved in 1982. This is now the year 2000, and

we have heard more and more about the possible link between

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Accutane and depression and suicide and suicide ideations and all

of that.

In September of this year, there was an advisory committee

meeting, and the FDA found out that as of May 2000, 37 suicides

were associated with Accutane. Is that still the number of suicides

associated with Accutane?

Dr. BULL. Thirty-seven?

Mr. WAXMAN. Yes.

Dr. BULL. In that ballpark. The numbers in terms of ones that

have been assessed for not having duplicate reports in the data

base is in that ballpark. I have to admit the latest number I have

seen is 41, so there may have been some additions to the data base

since September.

Mr. WAXMAN. So there have been more reports of suicide since

September?

Dr. BULL. Yes. And certainly the publicity attendant to Representative Stupak’s Web site and the reports on that have certainly stimulated more reports.

Mr. WAXMAN. FDA has always stated that Medwatch captures

only 1 to 10 percent of actual adverse events. Can we assume that

the number of reported suicides only represent a small fraction of

the actual cases?

Dr. BULL. That is certainly reasonable.

Mr. WAXMAN. In 1997, a year before FDA required Hoffman

LaRoche to place a warning about suicide on its label, French authorities required Roche to add a warning to Accutane about its

risk of suicide. Roche did not inform the FDA of this warning

change, and it was not until FDA required Roche to warn of suicide

that FDA learned of the French regulatory action. Is that correct?

Dr. BULL. Yes, sir.

Mr. WAXMAN. Was Roche under any legal obligation to tell you

of the French regulatory action, and wouldn’t this information have

been helpful to you in requiring new warnings for Accutane?

Dr. BULL. I will answer your second question first, which certainly it would have been helpful to have known. Your first question in terms of whether or not there was a legal responsibility, we

have researched that, it was certainly addressed once we learned

of the French labeling change, and our regulations are unclear as

to whether or not labeling changes must be submitted. The action

the agency is taking to address this is that we have a proposed rule

that will address these kinds of gaps, because certainly that information is quite important.

Mr. WAXMAN. So for the future you will require this information

from the pharmaceutical manufacturers?

Dr. BULL. Yes, sir.

Mr. WAXMAN. You had clear statutory authority for MedGuide in

1997 and 1998 when you were considering changes to Accutane labeling. Why didn’t FDA require issuing a MedGuide with Accutane

at that point, warning of birth defects, suicide and psychiatric disorders?

Dr. BULL. I think part of the decisionmaking at that point had

to do with looking at MedGuide as a forward-looking tool, and I

think initially was anticipated to be put in place for new drugs.

Certainly, I think by all criteria Accutane, in terms of serious and

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significant adverse events, fits the criteria, and it will certainly be

one—it will be a drug that will have a MedGuide attached to it.

I think in terms of why it wasn’t considered in 1997, 1998, in terms

of what our strategies were for implementing the rule, it was considered—I think certainly the continuing reports have compelled us

to say it makes sense to have a MedGuide attached to this drug.

Mr. WAXMAN. Just for people who may be watching on television

on C–SPAN, what is a MedGuide?

Dr. BULL. A Medication Guide is, I like to think of it as a plainlanguage tool to convey serious and significant adverse events to

patients. What is special and unique about a MedGuide is that it

is required to be given to the patient at the time of dispensing at

the pharmacy.

Mr. WAXMAN. Now, a MedGuide is different than information to

the dermatologist or the professional, isn’t it?

Dr. BULL. Yes, sir.

Mr. WAXMAN. And when did information go to dermatologists

first under direction of FDA about the possible association with

Accutane and depression and suicides?

Dr. BULL. To dermatologists?

Mr. WAXMAN. Yes.

Dr. BULL. In February 1998 was a time that letters were sent

out to the Academy of Dermatology members, the family practitioners, and psychiatrists.

Mr. WAXMAN. Has the clinical data about Accutane and psychiatric disorders changed since 1998, and do Roche and FDA know

significantly more about the risks of suicide?

Dr. BULL. I think more work has been done; I think we still, in

terms of data that is conclusive, we don’t know—we don’t have conclusive findings. There has certainly been some fairly large epidemiologic studies that have been undertaken; one was published

in the Archives of Dermatology in October of this year, and I think

certainly there is a need for more work, but the data remains inconclusive. Do we really know more? I think, unfortunately, no.

Mr. WAXMAN. I guess the question I would have to ask you is,

if we don’t know very much more about this whole problem of association with Accutane and depression and suicide than we did in

1998, why shouldn’t the new box label warning, new informed consent form and new MedGuide have been made 2 years ago?

Dr. BULL. Because we don’t—in terms of tools, and I think—one

thing that FDA is learning is that our traditional tools for constraining safety information do not work as effectively as we would

like to see them work. I think as we are learning more, with the

overall changing paradigm of health care, given that we are realizing as well that the physician is the intermediary to the patient for

information, that that linkage is not working as effectively as it

used to. We really are having to look much more critically at what

other mechanisms we can engage to make sure that consumers are

fully informed about the adverse events of drugs. So this is part of

an evolving picture for us and something that we are actively engaged in refining and enhancing our abilities to meet this need.

Mr. WAXMAN. Thank you very much.

Thank you, Mr. Chairman.

Mr. BURTON. We will let you ask more questions if you choose.

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One of the things that bothers me is the question that was just

asked by Mr. Waxman. You kind of just—we are not geared up to

really get that kind of information out to the American people.

That is kind of a copout I think, isn’t it? I mean, the Food and

Drug Administration is supposed to be the person, or the group

that guarantees the safety and the efficacy of pharmaceuticals and

drugs for the people of this country, and if something is going

awry, you are saying oh, it takes so much time to get the information out. I mean 19,000 dermatologists, you can send letters out tomorrow to all of them in big bold print, to all the pharmacists in

the country, you know, put it on e-mail, there is all kinds of ways

to communicate in this age. I think it is a real copout for the FDA

to say oh, we can’t do that.

The other thing I wanted to ask you is this: In 1850-something,

polar bear livers were causing psychiatric problems on people that

were eating them because of large amounts of vitamin A. This

pharmaceutical expert or pharmacologist—— Mr. O’DONNELL. Both.

Mr. BURTON. Both. Indicated that the brain swells up when you

have too much vitamin A in it, which causes severe problems.

When the testing was done back in the 1980’s before you put

Accutane on the market, did anybody check mice brains? Did they

give them large amounts, or any kinds of animals, large amounts

of vitamin A to check to see if it caused any side effects? Did anybody check that out?

Dr. BULL. Mr. Chairman, what I would like to do is for us to look

back at the pharmtox data and get back to you on that.

Mr. BURTON. You came today not prepared, able to answer this

question?

Dr. BULL. In terms of the specificity of your question regarding

mice brains, I am not sure—— Mr. BURTON. Well, any kind of research. Rabbits, I don’t care.

Was large amounts of vitamin A ever injected into any laboratory

animals in a test to see if it caused any kind of mental problems

in the animal, rat or whatever?

Dr. BULL. I would have to check—I think the responsible thing

on my part would be to go back and have our pharmacologic and

toxicological experts look back at the original data base, and we

will get back to you on that.

Mr. BURTON. Dr. Huene, do you know if any tests were done like

that?

Dr. HUENE. Well, I am sure the toxicity of vitamin A has been

well known for a long time. This is a derivative of vitamin A, and

it is not certain that this would produce the same effects on the

brain——

Mr. BURTON. Why don’t you come to the microphone so we can

hear you? We will try not to badger you too much. I won’t cause

you too much of a problem, but I think it is really important.

Dr. HUENE. I am not a toxicologist, but I am sure that there have

been extensive studies done on the effect of hypervitaminosis A on

animal brains.

Mr. BURTON. When you approved this, or you made your recommendation, did any of the studies talk about this at all, about

the possible toxicity or mental side effects or anything else that

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might occur because of this? Because we are talking about vitamin

A or a derivative of vitamin A?

Dr. HUENE. Right. Well, I don’t remember in detail. It was a long

time ago. But I know that extensive animal toxicity studies are

done prior to even initiating clinical studies in any drug that is

planned to be marketed.

Mr. BURTON. Well, can you, Dr. Bull, for our record—and I would

like for you to send it to my right hand here, sitting on my left,

Beth—could you send me any information you have on the studies

that were conducted on the Accutane product before it was approved? And also I would like to have any information you have on

vitamin A, because it just seems like to me, and I don’t know what

my colleague here feels, but it seems like to me, if vitamin A does

have these kinds of side effects when given in large amounts—and

you are talking about giving children who have acne a vitamin A

derivative over a long period of time—that you would think it

might have some kind of side effects which should have been mentioned prior to 1997 in France and 1998 here about possible mental

or worse problems from large amounts of that being ingested.

Dr. BULL. I would add that the label does address a condition

known as pseudotumor cerebri, which is I think the brain swelling

that you referenced that was known to—— Mr. BURTON. That may be. But when we hear people whose children have committed suicide or who have had adverse events occur

because of Accutane, and they didn’t even know anything about

this, were never warned by their dermatologist, were never warned

by their pharmacist, they had no knowledge, they went home,

started giving their child the pills and those side effects occur, my

gosh, what a mistake, what a tragedy.

In any event, we would like to have that information submitted

for the record, and I would like to have a list, if we don’t have it,

of all of the dermatologists in the country. And if your Association

won’t contact them, then I will figure out a way to do it myself, and

the committee will. I think that we ought to put on our e-mail to

all pharmacists in the country the warning that Roche is now putting on their labels so that they will all be aware of it as well.

Mr. Waxman.

Mr. WAXMAN. I would like to review some chronology about this

Accutane product.

In June 1985, Roche amended the Accutane package insert under

adverse reactions to state, ‘‘The following CNS reactions have been

reported and may bear no relationship to therapy: Seizures, emotional instability, including depression, dizziness, nervousness,

drowsiness, malaise, weakness, insomnia, lethargy and paresthesia.’’

That was in 1985 they first mentioned that there may be an adverse reaction, including depression. Now, this was after the drug

had already been approved, but it had been approved in 1982. But

in May 1988, FDA required stronger warnings and physician mailings on Accutane’s risk of birth defects, and FDA also required additional studies, including followup patient surveys. An advisory

committee to the FDA said that they recommended FDA restrict

prescribing Accutane to board certified dermatologists, but FDA

wouldn’t go along with that recommendation; predictably, the

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American Medical Association and the industry didn’t want the

prescriptions limited to this board certified specialty, they wanted

any doctor to be able to prescribe the drug.

Then, it is interesting that in 1997, FDA issued a warning letter

to Roche for failing to submit serious adverse event reports in a

timely manner, and then Roche said well, their computer systems

were responsible for delays of up to 8 years in complying with the

law. So you shouldn’t be criticized if you are trying to get the information and Roche is not giving it to you.

Then, finally, February 25, 1998, FDA required these warning labels, in new boldface, warnings about Accutane’s association with

suicide and all of that. And that was at a time when FDA was still

not informed that the same warning labels had already been put

on the year before in France, and Roche never informed the FDA.

So it seems like—and then I gather, Dr. Jacobs, you testified at the

hearing when they finally—which resulted in these warning labels—but you testified giving some suggestion that maybe it was

more complicated than the causation or the clear relationship; is

that a fair statement?

Dr. JACOBS. Yes. And I think, because I think it is important to

emphasize, because I think even, Mr. Chairman, if I may just state

something——

Mr. WAXMAN. Well, let me just, because I have some things I

want to pursue in the few minutes I have. But your position was

that it was a lot more complicated at that time. FDA heard your

testimony. Roche, I presume, did not willingly agree—do you know

whether they did, Dr. Bull, to these warning labels in 1998?

Dr. BULL. When you say ‘‘willing,’’ to make the labeling change?

Mr. WAXMAN. At the time the FDA was telling Roche you ought

to put a warning label, you have to put a warning label about the

association of Accutane and psychiatric problems, Roche issued a

press release saying, there is no proof of causation, and that ‘‘Teenagers are at risk for depression,’’ which would suggest that they

were saying to the public, teenagers are often depressed, teenagers

because of that depression may commit suicide, in effect suggesting

it is not related to Accutane.

Now, FDA did its job and said well, the warning labels have to

be on this product. When that warning label was put on the product, what was it put on, the patient package insert or on the box?

Where would it go?

Dr. BULL. The warning label in 1998 went into the professional

labeling. The existing patient label at that point already included

in capital letters changes in mood.

Mr. WAXMAN. So that the clearer warning label identifying the

possible association of Accutane with suicide and depression went

to professionals.

Dr. BULL. Yes, sir.

Mr. WAXMAN. Isn’t it fair to say, Dr. Pariser, that most of the

Accutane prescribed in this country is prescribed by board certified

dermatologists?

Dr. PARISER. It is my understanding it is about 85 percent.

Mr. WAXMAN. Now, don’t dermatologists as professionals get the

information from the FDA about warnings?

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Dr. PARISER. Sure. They all would have received that letter in

1998.

Mr. WAXMAN. So they received a letter in 1998. They didn’t have

to wait for an ad in a dermatological publication. They got a warning right from FDA to the professionals?

Dr. PARISER. Yes, sir.

Mr. WAXMAN. Now, then the issue that has been raised by my

colleagues is does the Association of Dermatologists try to continue

to impress upon dermatologists that this is a real concern. I assume that dermatologists are informed in a number of ways. They

get their warnings from the FDA when they prescribe this drug

and when they are contemplating using the drug for their patients.

They get publication information from the Association of—whatever

your Association is called.

Dr. PARISER. American Academy of Dermatology.

Mr. WAXMAN. I assume they would put in its publications information about this problem?

Dr. PARISER. Yes, sir.

Mr. WAXMAN. And then there are ads, but they are the weakest

link because the ads are put in by the manufacturer, but even an

ad put in by the manufacturer, they have to put in all of the warnings that go into the—as required by FDA in the fine print of the

ad. So the issue is, are there better ways for your Association to

inform dermatologists? They get the information, they are professionals, they get it from FDA, they get it from you.

At your annual meetings do you think there ought to be a greater emphasis on trying to educate dermatologists about this problem, and aside from the annual meetings, are there other ways you

might try to drive this issue home to dermatologists, at least for

the simple reason that, one, they ought to be careful not to prescribe the drug, unless it is a severe case, and second, if they have

a patient, they ought to be asking the patient, are you suffering

from—do you see any change in your mood? Do you feel weird? Do

you feel sad? Sort of to followup, to see whether that patient might

be experiencing some reaction to the drug?

Dr. PARISER. Well, I agree with what you are saying. Obviously

the message has to get sought. In the cases we heard testimony

from today, in some cases it hasn’t. I don’t know what the numerator and the denominator is in this equation of how many dermatologists really do get the message and really do it correctly. All

the venues that you described are ways that professionals such as

dermatologists educate themselves. Pharmaceutical venue, which is

perhaps not the greatest, but it happens, is education through the

pharmaceutical representatives that call on physicians’ offices.

That is a sales situation, it is not an educational situation, but

there is an opportunity there to provide some education as well.

Mr. WAXMAN. Well, it could be, or it would be Roche handing out

the press release saying that there is no proof of causation that—

there is no root of causation that teenagers are generally at risk

of depression.

Dr. PARISER. That is true, but anything that is handed out in the

physician’s office has to be approved by the FDA, so if they were

going to hand that out, the FDA would have had to approve it.

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Mr. WAXMAN. Then the chairman raised, it seems to me, the

most important point: Let the patients and their families know. We

generally assume doctors know, because they are the professionals,

they have gone to medical school; if they are dermatologists, they

have gone through specialty training, they have had to get board

certification, which means they had to show some skill and proficiency in their specialization, and we assume they keep up with

the information from FDA and from the pharmaceutical companies

and from your Association. But just in case, shouldn’t—does anybody disagree that the patient should get this information as well?

Dr. PARISER. No, they should; and it should be the patient’s

choice as to whether they are going to take Accutane or not and

it should be an informed choice. I personally never tell a patient

you have to take Accutane. Never.

Mr. WAXMAN. Do you ever tell a patient—— Dr. PARISER. Not to take Accutane?

Mr. WAXMAN. No. Do you ever tell a patient that if you take

Accutane, there is an associated risk with depression and suicide;

and do you want to recognize that and balance it out with the fact

that a patient may be very down on himself or herself because of

the acne, but things could be worse?

Dr. PARISER. Well, in my own personal practice I always do that,

and I discuss the issue of mood changes, potential suicide, as objectively as I do of getting chapped lips or elevation of triglycerides

and the chance of pregnancy. Obviously there are some who do not

do that, but I think it is important that it be done.

Mr. WAXMAN. I have to tell you, as a father of no longer a teenage boy, but if the doctor said to me, by the way, you have an elevated risk of chapped lips, I might not pay so much attention; but

if he said elevated risk of suicide, I certainly would want to pay

more attention to it. So there is a question of do the dermatologists

know about it or are they telling the patients. And whether they

are telling the patients or not, shouldn’t the patients know directly

from the company or the FDA? And I guess the FDA is working

on this med alert in order to inform the patients.

Thank you, Mr. Chairman, for allowing me to proceed beyond my

time.

Mr. BURTON. Let me just say, I don’t want to prolong the hearing, but I would like to have as much information on the research

of the vitamin A as possible, and also, I just cannot fathom how,

with all of the methods of communications that are available from

the FDA to the doctors and everything else, how dermatologists

would not be aware of the side effects of Accutane and how that

would not be conveyed to the patient and the parents of the patient, and how all of those tragedies could be avoided just through

simple communication.

Let me just say, while we are talking about Accutane’s connection to depression and suicide, I was disturbed to learn that both

the FDA and the manufacturer feel that the pregnancy prevention

program is not working at optimum. Is it true that over 1,900

women have become pregnant while on the drug and that over

1,400 have been terminated through abortion? I don’t understand

how that is, after 18 years, that this program hasn’t been fixed so

that you don’t have that kind of a problem. Is that the case? There

133

is still a large number of women getting pregnant while on

Accutane, even though—— Dr. BULL. That data was reviewed at the recent advisory committee, and the data that you reference is generally accurate, which

has led to the agency’s actions to institute the registry that would

ensure that women have a negative pregnancy test, two, before

starting the drug, and that they only get a month’s supply of the

drug; that to get another month’s supply would have to be confirmed by a negative pregnancy test. That is going to be part of

what the registry will entail, because what we have learned is that

the system that was put in place in the 1980’s simply is not working.

Mr. BURTON. The Surgeon General initiated a suicide prevention

program last year. His call to action makes no reference under risk

factors to drugs that can lead to depression and possibly suicide.

What role has the FDA played in development of this program,

and have you examined having the Surgeon General do public service announcements about this as well?

Dr. BULL. I am sorry. In terms of the program, Surgeon General’s program on depression?

Mr. BURTON. Yes. Have you considered talking to the Surgeon

General about doing public service announcements about possible

depression and possible suicide because of things like this?

Dr. BULL. I think that is a very intriguing idea. We could certainly get in touch with this office. We haven’t considered it, but

it certainly is a very intriguing idea.

Mr. BURTON. Well, we would like to have the information that

we talked about regarding the studies and what kind of research

was done.

Do any of you have any final comments you would like to make

to the committee before we adjourn?

Dr. JACOBS. I guess I have one, Mr. Chairman, and that is it is

a very delicate comment, and it has to do with the issue the suicides that we have heard about today, that they have been caused

by Accutane. These suicides are tragic, they occurred in relationship to Accutane, and I think there are steps that are being taken

to address this issue. I think suicide is, after studying it for nearly

30 years, is one of the more complicated behaviors. We only understand that it occurs; we don’t have any study that shows that our

treatments prevent it; that with all of the outbursts of

psychopharmacology, the suicide rate has not dropped. We do not

stop our efforts.

Can one thing prevent suicide? Would informing a family about

the risks of Accutane? I cannot say it. However, is it useful? Obviously, the answer is yes, but I think it is important to keep in perspective that not one thing, from my professional opinion, causes

suicide.

Mr. BURTON. Well, I understand your position, Doctor. You have

made it very clear. But with all due respect, we have had parents

here today who saw dramatic changes in their children when they

started using it.

They had no reason to believe it had anything to do with

Accutane, and yet that was when it started. Two of the three that

testified today, two of the three families, the suicide was successful.

134

One, fortunately, was not. All I can say is that those parents, had

they known about the possible side effects, which has not been

given to the public until recently, for that information to have been

given them in a timely fashion, their children would probably be

alive today. At least I believe they think that.

Anything else, Henry?

Mr. WAXMAN. The only other request, Mr. Chairman, if these

witnesses would be willing, some of us may want to ask them additional questions in writing and ask them to submit responses for

the record in writing.

Mr. BURTON. Sure. Yes, we would request that as a committee.

Thank you, Henry, for mentioning that.

We will look forward to your response from the FDA regarding

those studies.

Thank you very, very much. We may have additional hearings on

this. We really appreciate your cooperation today. We stand adjourned.

[Whereupon, at 4:15 p.m., the committee was adjourned.]

[Additional information submitted for the hearing record follows:]

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Æ