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[House Hearing, 106 Congress]
[From the U.S. Government Publishing Office]

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

                    U.S. GOVERNMENT PRINTING OFFICE
73-924 DTP                  WASHINGTON :  2001
_______________________________________________________________________
 For sale by the Superintendent of Documents, U.S. Government Printing 
                                 Office
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               Mail: Stop SSOP, Washington, DC 20402-0001

                     COMMITTEE ON GOVERNMENT REFORM

                     DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York         HENRY A. WAXMAN, California
CONSTANCE A. MORELLA, Maryland       TOM LANTOS, California
CHRISTOPHER SHAYS, Connecticut       ROBERT E. WISE, Jr., West Virginia
ILEANA ROS-LEHTINEN, Florida         MAJOR R. OWENS, New York
JOHN M. McHUGH, New York             EDOLPHUS TOWNS, New York
STEPHEN HORN, California             PAUL E. KANJORSKI, Pennsylvania
JOHN L. MICA, Florida                PATSY T. MINK, Hawaii
THOMAS M. DAVIS, Virginia            CAROLYN B. MALONEY, New York
DAVID M. McINTOSH, Indiana           ELEANOR HOLMES NORTON, Washington, 
MARK E. SOUDER, Indiana                  DC
JOE SCARBOROUGH, Florida             CHAKA FATTAH, Pennsylvania
STEVEN C. LaTOURETTE, Ohio           ELIJAH E. CUMMINGS, Maryland
MARSHALL ``MARK'' SANFORD, South     DENNIS J. KUCINICH, Ohio
    Carolina                         ROD R. BLAGOJEVICH, Illinois
BOB BARR, Georgia                    DANNY K. DAVIS, Illinois
DAN MILLER, Florida                  JOHN F. TIERNEY, Massachusetts
ASA HUTCHINSON, Arkansas             JIM TURNER, Texas
LEE TERRY, Nebraska                  THOMAS H. ALLEN, Maine
JUDY BIGGERT, Illinois               HAROLD E. FORD, Jr., Tennessee
GREG WALDEN, Oregon                  JANICE D. SCHAKOWSKY, Illinois
DOUG OSE, California                             ------
PAUL RYAN, Wisconsin                 BERNARD SANDERS, Vermont 
HELEN CHENOWETH-HAGE, Idaho              (Independent)
DAVID VITTER, Louisiana

                      Kevin Binger, Staff Director
                 Daniel R. Moll, Deputy Staff Director
                     James C. Wilson, Chief Counsel
                        Robert A. Briggs, Clerk
                 Phil Schiliro, Minority Staff Director

                            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

 
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.
    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.
    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.
    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 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 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 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 
of the change until a year later. Claiming ignorance about the 
warning in France is not an excuse or an explanation, it is a 
cover-up, 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:]
    [GRAPHIC] [TIFF OMITTED] T3924.001
    
    [GRAPHIC] [TIFF OMITTED] T3924.002
    
    [GRAPHIC] [TIFF OMITTED] T3924.003
    
    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.
    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 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 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 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 year-old 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 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 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. 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 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 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. 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.
    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.
    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.
    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-the-
counter 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 
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 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.
    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.
    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 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 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 
child-bearing 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 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 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.
    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.
    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 matters, 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.
    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.
    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 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 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 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.
    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, 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.
    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 
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 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 
plain-language 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.
    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 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 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?
    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.
    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 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. 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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