[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
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73-924 DTP WASHINGTON : 2001
_______________________________________________________________________
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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
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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?
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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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