1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
DRUG SAFETY AND RISK MANAGEMENT
ADVISORY COMMITTEE
IN JOINT SESSION WITH
THE
DERMATOLOGIC AND OPHTHALMIC
DRUGS
ADVISORY COMMITTEE
Hilton
2
PARTICIPANTS
Peter Gross, M.D., Chair
Kimberly Topper, M.S., Executive
Secretary
CONSULTANTS (VOTING)
Wilma F. Bergfeld, M.D.
Michael E. Bigby, M.D.
Margaret Honein, Ph.D.
Arthur H. Kibbe, Ph.D.
Sarah Sellers, Pharm.D.
Amarilys Vega, M.D., Ph.D.
Jurgen
Venitz, M.D., Ph.D.
DRUG SAFETY AND RISK
MANAGEMENT ADVISORY COMMITTEE
Michael R. Cohen, R.Ph., M.S.,
D.Sc.
Stephanie Y. Crawford, Ph.D.,
MPH
Ruth S. Day, Ph.D.
Jacqueline
S. Gardner, Ph.D., MPH
Arthur
A. Levin, MPH (Consumer
Representative)
Robyn S. Shapiro, J.D.
Brian
L. Strom, M.D., MPH
DERMATOLOGIC AND OPHTHALMIC
DRUGS ADVISORY
COMMITTEE
Roselyn E. Epps, M.D.
Robert Katz, M.D.
Paula Knudson (Consumer
Representative)
Sharon S. Raimer, M.D.
Eileen W. Ringel, M.D.
Kathleen Y. Sawada, M.D.
Jimmy D. Schmidt, M.D.
Elizabeth S. Whitmore, M.D.
Michael G. Wilkerson, M.D.
FDA STAFF
Jonca Bull, M.D.
John Jenkins, M.D.
Sandra Kweder, M.D.
Paul Seligman, M.D., MPH
Anne Trontell, M.D., MPH
Jonathan Wilkin, M.D.
3
C O N T E N T S
PAGE
Call to Order
Peter Gross, M.D. 4
Conflict of Interest Statement:
Kimberly Topper, M.S. 4
Effectiveness of the Isotretinoin
Risk Management
Program for the Prevention of Fetal
Exposure to
Accutane and its Generic Equivalents
and
Consideration of Whether
Changes to this
Isotretinoin Risk Management
Program would be
Appropriate
Open Public Hearing
Representative Bart Stupak 8
Gordon Day 21
LaDonna Williams 25
Boni Elewski, M.D. 29
Paul L. Smith 35
Debbie Banner 40
Carter Crosland 46
Lisa Crosland 51
Jeffrey Federman 57
Responses from Slone Epidemiology Center
Allen A. Mitchell, M.D. 66
Introduction of Questions:
Paul Seligman, M.D., MPH 101
Committee Discussion 106
FDA Presentation:
Kathleen Uhl, M.D. 183
Carl Kraus, M.D. 192
Anne Trontell, M.D., MPH 205
Hoffmann-La Roche Presentation:
Martin H. Huber, M.D. 208
Committee Discussion 243
4
1 P R O C E E D I N G S
2 Call to Order
3
DR. GROSS: We would like to begin
by
4
reading the Conflict of Interest Statement
5 Conflict of Interest
Statement
6
MS. TOPPER: The following
announcement
7
addresses the issue of conflict of interest with
8
respect to this meeting and is made a part of the
9
record to preclude even the appearance of such at
10
this meeting.
11
The topics to be discussed at today's
12
meeting are matters of broad applicability. Unlike
13
issues before a committee in which a particular
14 sponsor's
product is discussed, issues of broad
15
applicability involve many sponsors and their
16
products.
17
All FDA participants have been screened
18 for
their financial interests as they may apply to
19 the
products and companies that could be affected
20 by
the committee's decisions. Based on this
21
review, it has been determined that there is no
22
potential for an actual or apparent conflict of
5
1
interest at this meeting with the following
2
exception:
3
In accordance with 18 U.S.C. 208(b)(3),
4 Dr.
Ruth Day has been granted a waiver that permits
5 her
to participate fully.
6
A copy of the waiver statement may be
7
obtained by submitting a written request to the
8
Food and Drug Administration's Office of Management
9
Programs, Division of Freedom of Information HFI-35
10 at
5600 Fishers Lane in Rockville, Maryland 20857.
11
Because issues of broad applicability
12
involve many sponsors and their products, it is not
13
prudent to recite all potential conflicts of
14
interest as they apply to each member, consultant,
15 and
guest speaker.
16 There will be no industry
representative
17 at
today's meeting. As you are aware, the
Food and
18
Drug Administration has appointed industry
19
representatives who currently serve on each of
20
these committees, but Annette Stemhagen, the
21
industry rep from the Drug Safety and Risk
22
Management Committee, and Peter Kresel, the
6
1
industry rep from Dermatologic and Ophthalmic Drugs
2
Advisory Committee, work with sponsors that are
3
directly impacted by the matter before the
4
committee.
5
FDA has contacted three other industry
6
representatives from other Center for Drug
7
Evaluation and Research Committees that have
8
experience in risk management and with the FDA
9
Advisory Committee process, however, none were
10
available to participate in this meeting.
11
Dr. Stemhagen and Mr. Kresel are present
12 in
the audience and attending as interested
13
observers. Further, we would like
to note that Dr.
14 Lou
Morris, a member of the Drug Safety and Risk
15
Management Advisory Committee, has been recused
16
from participating in today's meeting.
Dr. Morris
17 is
also present in the audience and attending as an
18
interested observer.
19
We would like to remind the FDA
20
participants not to discuss issues at hand outside
21 the
advisory committee meeting.
22
In the event that the discussions involve
7
1 any
other products or firms not currently on the
2
agenda for which FDA participants have a financial
3
interest, the participants involvement and
4
exclusion will be noted for the record.
5
With respect to all other meeting
6
participants, we ask in the interest of fairness
7
that they address any current or previous financial
8
involvement with any firm whose product they may
9
wish to comment upon.
10
Thank you.
11 Open Public Hearing
12
DR. GROSS: We will begin with the
open
13
public hearing.
14
Both the Food and Drug Administration and
15 the
public believe in a transparent process for
16
information gathering and decisionmaking. To
17
ensure such transparency at the open public hearing
18
session of the Advisory Committee meeting, FDA
19
believes that it is important to understand the
20
context of an individual's presentation.
21
For this reason, FDA encourages you, the
22
open public hearing speaker, at the beginning of
8
1
your written or oral statement to advise the
2
committee of any financial relationship that you
3 may
have with the sponsors of any products in the
4
pharmaceutical category under discussion at today's
5
meeting. For example, this
financial information
6 may
include the sponsor's payment of your travel,
7
lodging, or other expenses in connection with your
8
attendance at the meeting.
9
Likewise, FDA encourages you at the
10
beginning of your statement to advise the committee
11 if
you do not have any such financial
12
relationships. If you choose not
to address this
13
issue of financial relationships at the beginning
14 of
your statement, it will not preclude you from
15 speaking.
16
The first speaker in the hearing will be
17
Representative Bart Stupak.
18
MR. STUPAK: Good morning. I do not have
19 any
financial interests with anyone,
20
pharmaceuticals or any of the sponsors here today.
21
Thank you for the opportunity to allow me
22 to
address this Accutane Advisory Committee.
I
9
1
have submitted a written statement, so let me
2
highlight some parts of it.
3
The FDA has documented 366 pregnancy
4
exposures since the inception of the S.M.A.R.T.
5
program. Because the reporting of
the pregnancy
6
exposures to isotretinoin is voluntary, there is no
7 way
of knowing how many pregnancies have actually
8
occurred. In fact, Dr. Graham of
the FDA has
9
actually estimated the yearly exposure rate may be
10 as
high as 2,000, and that has recently been
11
revised, may be as high as 3,500 per year. This,
12 of
course, does not include abortions.
13
It seems clear that the only way to
14
dramatically reduce the rate of pregnancy exposures
15 in
Accutane patients is to regulate like the FDA
16
regulates Thalidomide.
17
A toothless, voluntary registry does not
18
work, and we all know it. The
registry should be
19
mandatory for all female and male patients, for all
20
prescribers and dispensers of Accutane.
There
21
should be real consequences for refusal to
22
participate in a program. I plan
to introduce that
10
1
legislation in the coming weeks.
2
For 22 years, we have seen the harm
3
Accutane can do to pregnant women and to our
4
children. How many more babies
have to be born
5
with serious birth defects, how many more women
6
need to have miscarriages, and how many more
7
children have to die before the FDA implements
8 meaningful protections and restrictions on
the use
9 of
Accutane?
10
The risk of severe birth defects caused by
11
Accutane is undisputed. Let's
take a look at the
12
history of this drug a little bit, because I don't
13 think anyone has ever focused on the full
history
14 of
this drug.
15
Go back to the Advisory Committee hearings
16 of
1988, 1989, and 1990. Roche had assured
17
Advisory Committees that Accutane would be
18
prescribed only to women with severe recalcitrant
19
cystic acne and pregnancy exposure rates would
20
dramatically decrease because the average
21
dermatologist would only see less than one female
22 per
year that would require Accutane therapy.
11
1
Therefore, they concluded it would be
2
limited to 5,000 new patients per year, and Roche's
3
advertising would focus, not on Accutane usage, but
4
future ads would, quote, "dramatically" focus on
5
"contraindication and proper use of pregnancy
6
prevention."
7
With those assurances, even the 1988
8
Advisory Committee, by consensus, considered
9
limiting the use, prescription and distribution in
10
four ways, but this consensus was never acted upon
11 and
the committee concerns were largely forgotten
12 as
Roche went on to make Accutane their second
13
highest selling drug.
14
Ten years later, the FDA and Roche
15
implemented the Pregnancy Prevention Program after
16
continued pregnancy exposures. In
this program,
17
pharmacists, patients, and physicians were to work
18
together to decrease the pregnancy exposures to
19
Accutane.
20
Despite the PPP, the red stickers, the
21
voluntary consent form, and the NO pregnancy symbol
22
with the red line through it, Accutane pregnancy
12
1
exposures continued at unacceptable levels. In
2
fact, many patients, when they saw that pregnancy
3
with the line through it, the women actually
4
thought that Accutane was a form of birth control.
5
Not only did the number of female patients
6
receiving Accutane dramatically increase, so did
7 the
off-label use of Accutane. It is
estimated
8
that 90 percent of Accutane use is for off label,
9 and
the FDA is of the opinion that many of the
10
prescribing physicians do not understand the
11
teratogenic effects of Accutane.
12
At the end of the September 2000 Advisory
13
Committee hearing, the Advisory Committee
14
recommended five conditions, and I am sure you are
15 all
familiar with them.
16
The FDA agreed with the Advisory Committee
17
recommendations. FDA and Roche
then began their
18
discussions on how to implement these
19
recommendations.
20
While the focus of these negotiations
21 centered
on a pregnancy risk management program,
22 the
U.S. House of Representatives became involved
13
1
after the death of my son. In
October of 2000, my
2
family and I went public with our concerns that
3
Accutane was associated with suicides in some
4
patients. Back then, Roche and
the FDA claimed
5
there were 37 suicides. I believe
there were at
6
least 54 associated with Accutane use.
7
Congressional hearings were
held in
8
December of 2000 and again on December 11, 2002.
9 The
December 2002 congressional Oversight and
10
Investigation Subcommittee hearing was attended by
11 12
members of the Energy and Commerce Committee.
12
The answers we sought were to the numerous
13
issues relating to Accutane, but included the
14
continued pregnancy exposure and the psychiatric
15
effects of Accutane. Committee
members were
16
appalled when they learned that the FDA had
17
reversed its position and decided it was not
18
necessary to implement the September 2000 Advisory
19
Committee recommendations.
20
The FDA excuses of privacy and HIPAA
21
concerns for not implementing these recommendations
22
rang hollow with congressional committee members.
14
1
In the meantime, Roche continued to
2
aggressively market Accutane, growing to 1.51
3
million prescriptions in 2001.
4
The FDA negotiations with Roche produced
5 an
agreement called the S.M.A.R.T. program.
6
S.M.A.R.T. did not fulfill the recommendations made
7 by
the Advisory Committee. The S.M.A.R.T. program
8
began five months before the December 11, 2002
9
hearing.
10
Witnesses from the March of Dimes and the
11
Organization of Teratology Information Services,
12
OTIS, as we call them, testified that the
13
S.M.A.R.T. program would not achieve its
14
objectives, and the S.M.A.R.T. program did not go
15 far
enough.
16
The OTIS representative further testified
17
that a partial review of their organization had
18
already revealed 17 cases of pregnancy exposure to
19
Accutane and that there was a lot of slippage in
20 the
system.
21
At the hearing, the Chairman of our
22
committee asked the FDA, "What is your fallback
15
1
position if the S.M.A.R.T. program doesn't improve
2
things with the pregnancy exposures?"
3
Dr. Woodcock answered that for a variety
4 of
reasons, FDA would evoke its authority under the
5
Food, Drug, and Cosmetic Act only as a last resort.
6
Members of the committee also learned
7
firsthand the FDA was dragging its feet.
The FDA
8
failed to provide relevant documentation until the
9 day
of the hearing, when they dropped off a number
10 of
boxes filled with information requested by the
11
committee.
12
The FDA had evidence of the failings of
13 the
S.M.A.R.T. program from its inception.
Doctors
14
were pre-dating yellow stickers that signify the
15
female patient had received a negative pregnancy
16
test. Medical clinics were
pre-dating
17
prescriptions so the patient could fill more than
18 one
prescription within the seven-day limit of the
19
negative pregnancy test.
20
At least one patient was purchasing
21
Accutane with no pregnancy test, no prescriptions,
22 no
consent forms. Some health care plans,
who
16
1
electronically dispense their prescriptions, were
2 not
using the yellow negative pregnancy sticker.
3
Pharmacies were not giving out the Med
4
Guides for Accutane, and that compliance with these
5
toothless regulations were not working. In fact,
6
approximately 50 percent of the doctors were not
7
using the informed consent forms because it's
8
voluntary.
9
The FDA withheld this information from our
10
committee at the December 11th hearing.
11
Now, Roche said they will
support a
12
mandatory registry and submit a proposal. Please
13
understand my and a number of committee members
14
skepticism after going through the numerous
15
Advisory Committee hearings. I
still do not
16
believe the FDA and Roche will ever institute a
17
registry and certification program similar to that
18 of
S.T.E.P.S. for Thalidomide.
19
Equivalent effects call for equivalent
20
restrictions. There must be a
mandatory
21
isotretinoin registry for patients, doctors, and
22
pharmacists. Pregnancies will
continue to occur if
17
1 any
element is left out of the registry.
There
2
must be consequences for failure to comply with any
3
part of the program.
4
FDA complains that if we do this, we will
5
send this drug to a black market.
Since 1999,
6
myself and other members of Congress have tried to
7
address this issue on the Internet.
We have asked
8 for
the FDA to comment on our legislation, where
9 can
we improve upon it. To date, FDA has not
10
answered.
11
The manufacturer of Accutane, Hoffmann-La
12
Roche, is just as culpable as the FDA in allowing
13
Internet and mail order of Accutane in the country.
14
Roche hides behind the FDA's inaction to complain
15 of
Internet sales. Yet, their product
coding
16
allows them to determine the exact location of
17
where products are shipped, to whom, and when.
18
We can cut down on these illegal sales, it
19 can
be done. In fact, our committee has
convinced
20
Purdue Pharma to stop shipping oxycotin to Mexico
21 as
it is being brought back across the U.S. border.
22
Yet, when we pointed this out, what we have been
18
1
able to do in Mexico, and that Mexico does not have
2 the
same regulatory scheme for Accutane as we have
3 in
this country, Roche has refused to stop the
4
shipment of Accutane to Mexico.
5
Answers as to why Roche isn't really
6
serious about entering into a mandatory registry
7 for
Accutane for patients is very clear.
Roche did
8 all
it could to defeat the registry for Accutane as
9
recommended by the September 2000 Advisory Panel.
10
In fact, the recommendations or the defeat
11 of
those recommendations was a cause to celebrate
12
because, as Roche says, there is no psychiatric
13
registry.
14
Not only did Roche view the defeat of the
15
registry as a cause to celebrate, and they
16
protected their $450 million sales in Accutane,
17
Roche does not want any form of registry that would
18
provide insight into the psychiatric effects on
19
patients.
20
Roche is so fearful that a registry may
21
provide evidence of Accutane causing psychiatric
22
injury to young, developing brains that it will
19
1
stop at nothing to prevent the registry.
2
If you go back and take a look at the
3
history of this drug, Roche, in its initial
4
application to the FDA, they forgot to submit a
5
study, a study which was uncovered, which shows
6
that Accutane does adversely affect the central
7
nervous system in mice.
8
The committee has uncovered three more
9
studies, subsequent studies, that also suggest
10
Accutane does have some effect on the central
11
nervous system. Even the FDA,
which has been
12
working with the National Institute of Mental
13
Health and the National Institute of Health has
14
kept from the Advisory Committee and the American
15
people their preliminary studies which do suggest a
16
causation between Accutane and psychiatric
17
injuries. Both the FDA and Roche
have misled and
18
failed to protect the American people, unborn
19
children, and young adults from the devastating
20
effect of this drug.
21
I hope this time the FDA does not allow
22 the
manufacturers of Accutane and its generics to
20
1
come in and water down the recommendations that may
2 be
made by this Advisory Committee.
3
I am not sure Congress is willing to let
4
them do that anymore. As I said
earlier, I will be
5 introducing
legislation to establish a mandatory
6
registry of patients, doctors, and pharmacists,
7
similar to that of the Thalidomide registry.
8
Within the documents provided by the FDA,
9
there is a statement provided by an exasperated FDA
10
investigator who cries out, how could the FDA grant
11 a
patent extension on Accutane for use in young
12
patients with the devastation this drug has caused?
13 One
begins to ask, what special powers or charm
14
does Roche have over the FDA?
15
It is time to put restrictions on the
16
users, prescribers, dispensers and marketers of
17
Accutane and its generics.
18
Thank you and if there is any questions, I
19
will be pleased to answer them.
20
DR. GROSS: Thank you very much,
21
Representative Stupak.
22
The second speaker is Gordon Day, who is
21
1
President-Elect of the Society of Dermatology
2
Physician Assistants.
3
MR. DAY: Good morning, Advisory
Members.
4
My name is Gordon Day, and I am a
5
certified physician assistant, and I practice
6
dermatology in Sandy, Utah, a suburb of Salt Lake
7
City.
8
I am the President-Elect of the Society of
9
Dermatology Physician Assistants.
The SDPA is a
10
national medical association of 900 members whose
11
mission is to improve patient care by providing
12 additional education and training for our
members.
13
Physician assistants are but one group of
14
physician providers that prescribe isotretinoin.
15 We
are an integral component of the medical team.
16 The
collegial and dependent relationship we have
17
with dermatologists contributes
directly to the
18
quality of diagnostic and
therapeutic care
19
furnished to our patients.
20
The uniqueness of our position allows us
21 to
spend more time with patients, providing
22
education on the therapeutic options for acne
22
1
treatment including the risks and benefits of
2
isotretinoin therapy. This also
includes
3
contraceptive counseling.
4
Our Society firmly believes it is
5
necessary to assure the public that our members who
6
prescribe medications such as isotretinoin are
7
qualified to do so. Continuing
medical education
8 and
other life-long learning opportunities offered
9 by
our Society include compliance with the
10
manufacturer-developed and FDA-approved risk
11
management program for fetal exposure.
12
It is also essential that medical
13
providers using isotretinoin be proactive in ways
14
that guarantee the continued availability of this
15
drug for qualified patients, and that is why I am
16
here today.
17
There are few other therapeutic options
18
available to us to effectively treat nodulocystic
19
acne. Additionally, it is
important to the
20
dermatology health care team that patients be
21
compliant in all aspects of isotretinoin therapy,
22
including adherence to contraceptive practices
23
1
which are in place to minimize the likelihood of
2
adverse outcomes.
3
The importance of isotretinoin cannot be
4
emphasized strongly enough for our patients with
5
severe acne, who can avoid scarring and
6
disfigurement by use of this medication.
7
As a physician assistant in dermatology, I
8 see
older patients on a daily basis who would have
9
benefited from isotretinoin, but whose bouts of
10
this severe acne occurred before this wonder drug
11 was
approved for sale in the United States.
They
12
will be scarred forever.
13
I have observed firsthand how patients
14
with severe cystic acne may be so concerned with
15
their appearance that it affects their daily
16
living, self-concept and quality of life. There
17 are
patients I care for who will not go swimming
18
because of the severe cystic acne lesions and
19
scarring on their backs and shoulders.
20
I have female patients that have limited
21
outings socially because of their severe cystic
22
acne, and I have those patients who suffer from low
24
1
self-esteem and required psychiatric treatment
2
because of their severe acne.
Isotretinoin is an
3
important tool for helping these patients when all
4
other options fail to improve their condition.
5
In the dermatology practice where I
6
provide care, in an attempt to avoid adverse
7
outcomes, I not only employ the S.M.A.R.T. program,
8 but
also have developed a protocol that I and my
9
supervising physician, and other members of our
10
health care team use to make sure that all the
11
necessary risk management program components are
12
documented when using isotretinoin.
13
This enhanced protocol encompasses review
14 of
side effect profiles, pregnancy testing,
15
contraceptive counseling, the completion of
16
time-specific laboratory testing, a thorough review
17 of
the patient's own responsibilities,
18
participation in the survey, and completion of the
19
informed consent process.
20 It is an unfortunate fact that a
small
21
number of fetal exposures still occur in female
22
isotretinoin patients, relative to the overall
25
1
number of female patients taking this drug.
2
Therefore, the Society of Dermatology
3
Physician Assistants would like to collaborate with
4 the
American Academy of Dermatology Association and
5 the
FDA on improving the effectiveness of the
6 current risk management program in ways that
lead
7 to
fewer adverse outcomes and safeguard patient
8
confidentiality and rights in the health care
9
system.
10
This process, once completed, should serve
11 as
an educational tool for the patients, the
12
prescribers, and the pharmacists.
13
Thank you.
14
DR. GROSS: Thank you, Mr. Day.
15
The third speaker is LaDonna Williams,
16
Executive Director, Inflammatory Skin Disease
17
Institute.
18
MS. WILLIAMS: Good morning. I am LaDonna
19
Williams, and I am the Executive Director of the
20
Inflammatory Skin Disease Institute, a patient
21
advocacy group that provides education, public
22
awareness, and support to those patients with
26
1
inflammatory skin disease and their families.
2
Inflammatory skin disease is a broad
3
category of conditions ranging in severity. As you
4 can
imagine, these diseases are very distressing to
5
those who have them, causing great discomfort and
6
real emotional distress.
7
You can learn more about inflammatory skin
8
disease by visiting our web site
9
www.isdi.online.org.
10
I feel it is important to be here today on
11
behalf of the patients who suffer from the
12
inflammatory skin disease acne.
Severe acne is
13
characterized by papules, pustules and inflamed
14
nodules. Acne is a common skin
disease and can be
15 a
very serious medical condition.
16
For many Americans it is more than a
17
temporary cosmetic problem that can be treated by
18
over-the-counter lotions and creams.
19
For many Americans it is more than a
20
condition that can be treated by antibiotics, oral
21
contraceptives, or steroids.
Indeed, for thousands
22 of
unfortunate Americans, acne can be a
27
1
life-altering and a socially terminal medical
2
condition for which isotretinoin is the only
3
effective method of treatment.
4
I am representing hundreds of acne
5
patients who cannot be here today.
These patients
6 are
both male and female, teenagers and adults who
7
have contacted me to express their strong support
8 for
continued access to isotretinoin. This
drug
9
literally worked wonders for them and they want to
10
make certain that it remains available for other
11
severe acne sufferers.
12
You have already reviewed reams of
13
briefing material and listened to hours of
14
testimony about the current risk management effort
15 to
reduce fetal exposure to isotretinoin.
16
The Inflammatory Skin Disease Institute
17
agrees it is necessary to provide and improve a
18
program and reduce the number of pregnancies
19
associated with this drug keeping in mind I have
20
received numerous letters from teenagers and adults
21
stating how isotretinoin saved their skin and their
22
self-esteem.
28
1
Many parents have written to me on behalf
2 of
their children. One grateful mother told
me how
3
isotretinoin improved her daughter's skin, and not
4
only made positive changes in her teenager's life,
5 but
made positive changes in the whole family
6 because
they could go out in public and do social
7
things together again.
8
I have received calls in my office from
9
patients and their parents explaining how academics
10 in
high school has improved dramatically because
11 attendance became 100 percent after
isotretinoin
12
cleared up their student's acne.
13
One patient had to consider to leave her
14 job
that she loved very much because her acne was
15 so
severe that her face was in a constant state of
16
being red, swollen, and painful, with disfiguring
17
pustules. Children were afraid of
her, which in
18
turn made her withdrawn and depressed.
She took
19
isotretinoin and she feels it saved her job, her
20
relationships, and her life.
21
I could go on and on with personal
22
accounts from patients for whom isotretinoin made a
29
1
positive difference in their lives.
It is on their
2
behalf that I speak with you today.
3
I thank you for your time and your
4
attention in listening to these stories, and I hope
5 you
will keep these testimonies in mind as you
6
debate the future direction of the isotretinoin
7
risk management program.
8
If I may close with somewhat of a cliche -
9 the
effectiveness of isotretinoin goes beyond skin
10
deep. I hope that I have
impressed upon this
11
committee how absolutely essential it is for this
12
drug treatment for acne to remain on the market,
13 and
I hope I have impressed upon you how essential
14 it
is for the qualified patients
15
Thank you.
16
DR. GROSS: Thank you.
17
The next speaker is Dr. Boni Elewski,
18
President of the American Academy of Dermatology,
19 the
fourth speaker.
20
DR. ELEWSKI: Good morning,
everyone.
21
My name is Dr. Boni Elewski. I am
a
22
practicing dermatologist and Professor of
30
1
Dermatology in the Department of Dermatology at the
2
University of Alabama in Birmingham.
3
In addition to my medical duties, I am
4
also President of the American Academy of
5
Dermatology Association. On
behalf of the 14,000
6
members of the Association, and our hundreds of
7
thousands of acne patients, I thank you for the
8
chance to speak with you about the current
9
pregnancy risk management program for isotretinoin.
10
The health, safety, and welfare of our
11
patients is of paramount importance to
12
dermatologists, as is the integrity of the
13
doctor-patient relationship.
Indeed, because of
14
these concerns, our organization is committed to
15
optimizing the safety of our patients taking this
16
drug, as well as ensuring continued access to
17
isotretinoin for all qualified prescribers.
18
Education and communication with our
19
members and their patients about isotretinoin
20
compliance is essential to the safe use of this
21
drug.
22
The current risk management program has
31
1
been promoted in numerous education and
2
communication efforts, such as CME activities,
3
Member Alerts, articles on our web site, in our
4
official publication Dermatology World, and will be
5
augmented by new initiatives.
6
In addition, the Association hosted a
7
scientific consensus conference on the safe and
8
optimal use of isotretinoin to which key
9
decisionmakers in the FDA and the scientific
10
community were invited. The
proceedings will be
11
published next month.
12
Recently, the Association sent a letter to
13 the
FDA Commissioner with a list of web sites that
14
sell isotretinoin on line. We
hope this
15
information will assist the agency with addressing
16 the
problem of illicit sales of this powerful drug.
17
You have just heard a number of compelling
18
stories about the benefits of isotretinoin therapy.
19 I
myself have treated hundreds of patients whose
20
quality of life has improved tremendously because
21 of
this drug.
22
This is because acne is not simply a
32
1
cosmetic problem. In 1948,
renowned dermatologist
2 Dr.
Marion Sulzberger said, and I quote, "There is
3 no
single disease which causes more psychic trauma,
4
more maladjustment between parents and children,
5 and
general insecurity and feelings of inferiority
6 and
greater sums of psychic suffering than does
7
acne." More than a half
century later, his
8
observation still rings true.
9
When all other treatment options fail,
10
isotretinoin is the miracle drug that clears away
11 the
redness, painful swelling, and lesions of
12
severe, nodulocystic acne, which may lead to
13
painful and disfiguring scars.
14
Unfortunately, a small number of women are
15
pregnant or become pregnant while taking this drug.
16 As
always, our goal is to ensure both patient
17
safety and continued access to isotretinoin for all
18
qualified patients. For this reason, we would like
19 to
offer the following recommendations for
20
improving the current risk management program.
21
First, the survey of female patients
22
should be mandatory, not voluntary.
We propose
33
1
that isotretinoin therapy be prescribed for
2
qualified female patients only if they participate
3 in
the survey. Data generated by this
mandatory
4
survey would be more complete. Of
course, it is
5 the
ultimate responsibility of the female patient
6 to
comply with the birth control requirements of
7 the
program and to avoid pregnancy.
8
Second, a single questionnaire and vendor
9 for
the female patient survey should be designated.
10 The
present situation with the generic
11
manufacturers using one questionnaire and vendor,
12 and
Hoffmann-La Roche using another questionnaire
13 and
vendor, is confusing to prescribers and
14
patients alike.
15
Furthermore, differences in the surveys
16
make it difficult to compare data.
A single
17 questionnaire
and vendor would minimize this
18
confusion, improve data gathering, and promote
19
patient safety and education, and ultimately
20
improve the health, safety, and welfare of our
21
patients taking this drug.
22
Third, the survey questionnaire should be
34
1
re-evaluated and simplified to obtain the pertinent
2
information to assess the risk management program.
3
Ultimately, this will improve the health, safety,
4 and
welfare of our patients taking isotretinoin.
5
Fourth, the current risk management
6
program must be clarified and simplified to address
7
ongoing issues of concern for doctors and patients
8
alike.
9
And finally, it is crucial that program
10
materials warn patients to avoid Internet sales,
11
avoid re-use, or sharing of isotretinoin.
12
Let me close by saying, the preservation
13 of
the doctor-patient relationship is crucial, and
14 may
I add, an integral component to the risk
15
management system. As we strive
to improve the
16
current risk management program for isotretinoin,
17 the
American Academy of Dermatology Association's
18
guiding principle has always been, and will
19
continue to be, the health, safety and welfare of
20 our
patients.
21
Thank you.
22
DR. GROSS: Thank you, Dr.
Elewski.
35
1
The next speaker, the fifth speaker, is
2
attorney Paul Smith.
3
MR. SMITH: Good morning. My name is Paul
4
Smith and I am an attorney practicing law in
5
Austin, Texas.
6
My practice relates
exclusively to
7
pharmaceutical litigation and for the past two
8
years I have worked nearly full time on behalf of
9
families and individuals who have experienced
10
devastating and catastrophic side effects from
11
Accutane.
12
In connection with this privilege, I have
13
personally seen and known dozens of individuals and
14
families whose lives have been horribly altered as
15 a
result of this powerful and dangerous drug.
16 The tragedy of a parent who has lost
their
17
child to suicide and the tragedy of these parents
18 and
babies who have to live with serious and
19
permanent birth defects is beyond description.
20
I understand that as my role, I am charged
21
with the responsibility to seek redress for these
22
people in the court system.
However, today, I am
36
1
stepping out of my role as a legal advocate, today,
2 I
come before you as a member of the public who has
3
talked to and seen many who have been harmed by
4
Accutane.
5
Today, I am asking you to take a serious
6 and
deliberate look at risk presented by this drug,
7
which has not, in my opinion, been fairly and
8
accurately examined.
9
You are fortunate to have the ability to
10
suggest and ensure that the tragedies that I have
11
seen in connection with this drug are substantially
12
reduced.
13
For over 20 years now, the FDA has made an
14
effort to regulate this product by adding warnings
15 and
warnings in connection with this drug.
This is
16 a
laudable goal to try to ensure some safe use of
17 this
product, however, as has been well established
18 and
is beyond dispute today, the various programs
19
that have been instituted have failed miserably.
20
The admission and concession by Roche that
21 a
registry is needed is too late for many.
If
22
there is a registry, however, there are two
37
1
components which must be incorporated.
2
The first involves paternal exposure, that
3 is,
where the father takes Accutane when the mother
4
conceives the fetus. This is
limited to treatment
5 of
the father with Accutane.
6
The second is the incredible failure of
7
Roche to consider the known psychiatric component
8 of
the drug to impair complete compliance with any
9
rational program aimed at preventing fetal
10
exposures.
11
The dangers and risk of paternal exposure
12 is
something that must be better studied and
13
understood. I point you to the
Thalidomide
14
warnings which strongly advised male patients
15
taking Thalidomide to use contraceptive measures.
16
This is in dramatic contrast to the Accutane,
17
which suggests that there is no risk to the fetus
18 as
the result of paternal exposure.
19
I have with me recently released documents
20
that indicates that Roche's own internal experts
21
has, in reviewing 13 potential paternal exposures,
22
found that in 5 of those cases, a possible
38
1
relationship could not be excluded.
2
This is a document that Roche fought hard
3 to
keep from the public. I have it here
with me.
4 It
is sitting here for your review. I would
5
welcome and request that you get a copy of this and
6
review it thoroughly.
7
Carter Crosland, who is here with his
8
mother and father, is, in fact, one of the five
9
whose medical records were examined by the Roche's
10
internal geneticist. The Roche
consultant
11
concluded that Carter's difficulties could very
12
well be related to Accutane embryopathy.
13
Roche's response to this phenomena and the
14 risk
associated with paternal exposure is
15
inadequate. The public should be
aware the
16
potential exposure does exist, and there should be
17
warnings specifically advising that there is
18
problem with paternal exposure.
19
We would strongly urge a registry
that
20
includes males using Accutane that specifically
21
tracks their sexual activities.
22
The second issue for your consideration is
39
1 the
inability of certain patients to comply with
2
warning and instructions as a direct result of
3
known psychiatric side effects presented by this
4
drug.
5
Only Roche disputes that Accutane may
6
cause depression and behavioral changes.
It seems
7 to
be well accepted within the rest of the
8
scientific community that there is a strong
9
relationship between Accutane and psychiatric
10
adverse events and depression.
11
I have seen nothing publicly which
12
suggests that Roche has even considered this
13
foreseeable and predictable phenomenon of pregnancy
14
secondary to impaired capacity as a result of
15
depression.
16
Debbie Banner is here to explain to you
17 how
she got depressed and was unable to comply with
18 the
program in effect at the time to prevent her
19
pregnancy.
20
I thank you for your attention and your
21
kind consideration and again the paternal exposure
22
study itself that was submitted to the FDA is here
40
1 for
your review.
2
Thank you very much.
3
DR. GROSS: Thank you, Mr. Smith.
4 The sixth speaker is Debbie Banner.
5
MS. BANNER: Good morning. My name is
6
Debbie Banner. I am here with my
husband Kevin. I
7
have known my husband since I was 17, and we have
8
been married for seven years. I
appreciate this
9
opportunity to share with the members of this
10
honorable committee my horrifying experience with
11 the
drug Accutane.
12
Starting today, we will offer one of the
13
answers to this question, why are girls continuing
14 to
become pregnant while on Accutane despite the
15
warnings that Accutane causes birth defects?
16
I am afraid that one of the answers I will
17
propose today is one that neither the FDA, this
18
committee, or Hoffmann-La Roche has adequately
19
studied or considered.
20
I am also here to describe the nightmare
21 of
having a child who has been born with Accutane
22
birth defects.
41
1
I became pregnant while on Accutane.
I
2
survived this nightmare by the grace of God, strong
3
faith, a loving husband, and an overwhelming
4
commitment to my son.
5
I was devastated that I played a role in
6
causing my own child to be deformed.
So, I vowed
7 to
sacrifice everything to give him the best life I
8
could possibly give. Because I
accepted my fate
9
humbly, I believe that is why God finally revealed
10 the
other side of the story to me, the missing
11
piece of the puzzle.
12
On October 4th, 1996, my son Deven was
13
born. There is no medical doubt
that his birth
14
defects are due to the effect of Accutane on him as
15 a
developing fetus. He has been seen by
the best
16
physicians and was diagnosed with Accutane
17
embryopathy.
18
Deven was diagnosed with an underdeveloped
19
cerebellum resulting in cerebral palsy and
20
hypotonia. At the age of 7, he is
fed through a
21
feeding tube that is surgically inserted into his
22
stomach, he suffers from seizures.
42
1
After four eye surgeries, he has visual
2 perceptual
problems. He has sensory integration
3
problems which manifest as autistic-like behaviors.
4 He
has verbal expressive disorder, speech problems,
5 and
requires physical therapy, occupational
6
therapy, and speech therapy.
7 He has a chronic history of
pneumonia. He
8
requires special education services in school and
9
special accommodations. Along
with these and other
10
medical problems, as well as fine motor and gross
11
motor impairments, it is likely that he will be
12
unable to take care of himself as an adult.
13
I was on Accutane in 1995 when I was 24
14
years old. I was an aerobics instructor and
15
attending school. I was working
two jobs. I was
16 of healthy
mind, body, and spirit, so when I first
17
visited the dermatologist, I was a happy person
18
although I had an acne problem.
19
Days after ingesting Accutane, I began to
20
react as if I were poisoned. I
developed severe
21
headaches and sharp, piercing head pains. I was
22
nauseous day and night. I was
weak, dizzy,
43
1
confused, forgetful, suffering from hypersomnia and
2
severe crying spells.
3
Eventually, I developed suicidal thoughts.
4 I
just wanted to sleep and never wake up again.
I
5 was
too sick when I was awake.
6
At the initiation of treatment, I had
7
chosen abstinence as my method of birth control. I
8
chose this for religious reasons and did not plan
9 to
be sexually active again until I was married.
10
However, once in a state of severe
11
depression, I became mentally incapable of making
12 appropriate
decisions. My thoughts were filled with
13
thoughts of suicide and death, which eventually
14
required psychiatric intervention.
15
At the time of conception, I was no longer
16 a
patient that was reliable and capable of
17
complying with mandatory pregnancy prevention
18
procedures and reliable in carrying out
19
instructions.
20
The missing piece of the puzzle was given
21 to
me when I learned that the psychiatric problems
22
that led to my pregnancy were a side effect of
44
1
Accutane.
2
Through my research, I have now met other
3
mothers who became pregnant on Accutane.
I have
4
learned that depression was a factor in their
5
inability to comply with the warnings that, like
6 me,
led to a nightmare of birth defects.
7
I have spoken to one mother who actually
8
attempted suicide while on Accutane and became
9 pregnant weeks later. To this day, there is
no
10
instruction, education, or warning on how
11
psychiatric side effects of this drug may prevent
12
you, despite the best intentions, from complying
13
with the pregnancy prevention program.
14
It seems fundamental to me now, but how
15 can
you educate someone that may not be able to
16
protect themselves. How can anyone including the
17
doctors who prescribe it believe that the drug
18
could do this when Roche refuses to admit that
19
there is a psychiatric component to the drug?
20
I am here to tell you from my own
21
experience, and experience told to me by other
22
mothers admitted in a cloud of shame and stigma
45
1
that depression can and does interfere with
2
pregnancy prevention even when patients have chosen
3
other forms of birth control.
4
Because women and girls are continuing to
5 become pregnant, I plead with this committee
to
6
require that females of childbearing potential
7
receive an initial psychiatric evaluation and are
8
then monitored by a psychiatrist throughout
9
treatment.
10
To leave this decision to patients who may
11 be
in denial and cannot protect themselves is to
12
guarantee more birth defects and abortions.
13
Because Accutane is such a powerful drug, it is
14
worth the extra effort and expense to save children
15
from a lifetime of deformity and pain and to
16
finally bring an end to the outrageous number of
17
Accutane abortions.
18
Warning is simply not enough when
19
psychiatric side effects are involved.
20
In conclusion, I want to express my
21
sympathy for people suffering from acne, but even
22 in
the very worst cases of acne, their suffering
46
1
cannot compare to the suffering endured daily by
2
children born with Accutane birth defects.
3
Thank you.
4
DR. GROSS: Thank you, Debbie, and
Kevin
5
Banner.
6
The seventh speaker is Carter Crosland.
7
MR. CROSLAND: Good morning. My name is
8
Carter Crosland.
9
Today, you will hear my story.
Not only
10 do
I speak for myself, but also for the hundreds,
11
perhaps thousands of children whose voices will
12
never be heard. Those dreams and hopes will never
13 be
realized. Today, I am their voice.
14
I was born January 22, 1985, in a small
15
rural town in central Utah, the first child of my
16
parents. As a young boy, I was
told that I was a
17
miracle and that I had something important to share
18
with the world. I have been
blessed with the
19
health, strength, and mental faculties to speak
20
before you today. Perhaps that is
my purpose.
21
As a young boy, I dreamed of being a
22
wrestler. I loved sports and had
an unusual talent
47
1 for
learning statistics. I played T ball
with my
2
friends and they ran the bases for me while I
3
stopped the ball with my wheelchair tires.
4
And then the boys moved on to minors and
5
majors and I stayed behind. I
became the batboy
6 and
then the base ump. Then the coach,
manager, or
7
anything else just to stay involved.
The same was
8
true with football and wrestling.
As I matured, I
9
realized I would be left behind again.
Not only in
10
sports, but in every single aspect of my life.
11
My parents sacrificed to get me where I
12 am,
and because they worked hard, we didn't qualify
13 for
disability funding from the government.
I was
14 too
smart. I passed all the cognitive tests,
15
despite missing a third of my brain to a cyst.
16
I passed all the skills and vocabulary
17
tests. I could even pick up the
blocks with my
18
mouth and put them in the holes quickly.
19
Therefore, by their standards, I wasn't disabled,
20 and
I was at the end of the waiting list without
21
assistance.
22
I had generous people who helped me get
48
1
arms as a young boy, but we couldn't keep up with
2 the
constant re-fitting and trips to the city.
My
3 mom
worked full time to keep insurance for me, but
4 she
couldn't keep leaving work for sick kids and
5
trips to the prosthetic specialist, so I gave up on
6 the
arms. They were too costly.
7
When I entered first grade, my mom quit
8
work, so that I could go on field trips, birthday
9
parties, and to the library with my friends. Where
10 I
went, my chair went, and also my parents and my
11 van
went. That made our financial situation
even
12
worse, but I appreciated having my mom around.
13
I took drivers ed at 15 and passed with
14
flying colors, well, all except for the driving
15
test. You see, I can't afford the
car for me to
16
drive and the school district can't provide it. I
17
completed high school and graduated with my class.
18 I
was voted most preferred senior probably because
19 I
had the gift of gab and I like to visit with
20
everyone.
21
My school built a ramp so that I could
22
participate in pomp and circumstance with my peers.
49
1 I
now attend college and I am studying
2
communications. I hope to be a
sports broadcaster
3 or
work for some firm as a public relations guy.
4
My voice is the only asset I have that
5
puts me on the same playing field as those around
6
me. It is literally the only
thing I can do on my
7
own. This is what I have
accomplished so far in my
8
life against all odds. Now I
would like to tell
9 you
what I cannot do.
10
I room with a friend at college.
I pay
11 him
to help me bathe, get dressed, cook my meals,
12
charge my wheelchair, get my books, help me on
13
dates, drive my car, and anything else I want to
14
do. My friends lift me up the
stairs to their
15
place or to any other place that is not accessible.
16
I have to plan for bathroom breaks because
17 I
need help. My friend will get married
soon, and
18 I
will find another person and then another, and
19
another. My parents travel to
bring me home and
20
back on weekends because I cannot afford a car that
21 I
can drive on my own. My buddies take me
shopping
22 and
help prepare and eat my meals. They
clean up
50
1 for
me and do my wash.
2
Because I have all my mental faculties, my
3
dreams are the same as every other young man my age
4 - a
car, a job, a girlfriend, and someday a wife
5 and
family. I hope for these things, but I
take it
6 one
day at a time, and I don't know what the future
7
holds for me.
8
I keep being determined to make the best
9 of
it and to find happiness in every small thing
10
around me. Some of these dreams I
can realize now
11 if
I could afford it. Money is a tremendous
12
limitation, nearly as limiting as my disability.
13
Please do not make money a factor in your decision
14 to
research and regulate this drug.
15
They say that I don't fit into any
16
category or syndrome because of my intelligence. I
17
feel that my mental abilities are a gift from God
18 and
are for a purpose. Today, I hope that
purpose
19 is
to bring this matter before you to your
20
attention.
21
I hope that you will look deep into your
22
heart and do everything you can to study, research,
51
1 and
take every step possible to prevent this from
2
happening to one more child. Most
are not as
3
fortunate as I am. Their voices
will never be
4
heard. Please hear mine.
5
I thank you for your time.
6
DR. GROSS: Thank you, Mr.
Crosland.
7
The eighth speaker will be Lisa Crosland.
8
MRS. CROSLAND: Ladies and
gentlemen, good
9
morning. I am Lisa Crosland, and
I am here with my
10 husband
Russell and my son.
11
A first pregnancy is supposed to be a
12
happy time filled with anticipation and excitement,
13 but
mine was neither. For me, I was a
19-year-old
14 in
college, in love. We had big plans, big plans
15 and
dreams that included marriage and children, but
16
things changed when Russell began using Accutane.
17
Our relationship became a disaster filled
18
with unkept promises and unpredictable behavior.
19 An
engagement was broken and so was my heart, and
20
then I found out I was pregnant and alone.
21
Things went from bad to worse. I
had
22
recurring nightmares that the baby inside me was
52
1 not
right. I didn't grow enough, the baby
banged
2
back and forth. An ultrasound at
almost six months
3
confirmed my worst nightmare.
4
We were told that our baby had no arms and
5
legs, no sex organs. The child had
a third of its
6
brain covered with fluid that was increasing. They
7
felt his eyes were too big and his head too large.
8 A
large growing hernia and funny-shaped mouth was
9
also evident.
10
Most doctors felt the child would abort
11
itself. Others said that if it lived, it would be
12 on
life support, unable to suck, and
13
institutionalized. I was
devastated and so was
14
Russell. We prayed for a miracle
that our child
15
would not suffer.
16
Our miracle was not what we expected, our
17
child lived, and today we are telling his story.
18 As
parents, our first concern was why did this
19
happen, what did I do. Parents
need to know why
20
this has happened to them.
21
I had lived what I thought was a clean and
22
healthy life. I did not smoke, I
did not drink or
53
1 use
drugs. Every effort was made to
determine what
2 I could
have done to prevent this as a mother.
3
Yet, we turned up empty-handed.
4
The first time I heard the word Accutane
5
embryopathy was from a genetics counselor at the
6
University Hospital in Salt Lake City.
Carter was
7
almost three months old and had just had his second
8
surgery. The doctor felt Carter's
symptoms were
9 too
similar to maternal Accutane exposure to
10
ignore.
11
I told her that I had never used the drug,
12 but
his father had before, during, and after I
13
became pregnant. Carter has been
worked up by the
14
best doctors and the best facilities.
Everyone
15
wanted to know whether Russell or I carried some
16 odd
genetic code that would cause this in the
17
future.
18
We looked everywhere, but there was
19
nothing else but Accutane. We
reported an adverse
20
reaction to Hoffmann-La Roche, who responded that
21
this could not be the cause of our child's
22
deformities. A few years later I
spoke directly to
54
1 a
doctor at Hoffmann-La Roche who told me that
2
there were a few other reports of paternal
3
exposure, but all could be attributed to another
4
cause.
5
I even asked for and received films and
6
study materials from Roche. You
see, as we have
7 now
learned from Roche's internal documents made
8
public only after Roche fought and lost the battle
9 to
keep it private. Carter has all the
clinical
10
signs of Accutane embryopathy.
11
Roche initially agreed that paternal
12
exposure to Accutane could not be ruled out. Why
13
then hasn't this been researched?
Are kids like
14
Carter not worth it?
15
Since this time, I have seen warning
16
labels and adverse reports increase, more children
17
aborted and affected. I have
studied and found
18
more and more similarities to things Carter was
19
experiencing in his life that other children whose
20
mothers were exposed were experiencing.
21
His mouth, his dental problems, his
22
problems with temperature regulation are just a few
55
1 of
the less visible problems. Some children
whose
2
only link is a mental I.Q. of under 85 have been
3
attributed to Accutane. I find it
impossible not
4 to
include Carter in this category simply because
5 his
father was the user and he is normal in
6
intelligence.
7
Of course, it may very well be that women
8 who
become pregnant from a father who has taken
9
Accutane may never put the issue together. The
10
possibilities of hundreds and thousands of
11
abortions simply attributed to poor development or
12
unwanted pregnancy may have occurred, with the
13
public being kept in the dark of these risks.
14
The fact that there has not been more
15
reporting of this issue does not mean that there is
16 not
a serious risk and danger. It only means
that
17
Roche has been successful in keeping this from the
18
public.
19
This drug Accutane has devastated my
20
family emotionally, physically, and financially.
21 It
has been carelessly over-prescribed and
22
under-regulated. It has destroyed
our dreams and
56
1
shattered our lives, yet we stand before you today
2
united in our efforts to demand a change.
3
We want adequate research and funding into
4 the
possibility of paternal exposure of retinoids.
5 We
want the prescription of this drug for
6
dermatological reasons restricted to dermatologists
7 who
are forced to prescribe it only as a last
8
resort for both men and women.
9
We want those greedy individuals who
10
facilitate unprescribed Internet sales of this drug
11 stopped
and prosecuted.
12
Most of all, we want answers, not only for
13
ourselves, but for the hundreds of babies aborted
14 who
may very well be exactly like Carter, but
15
discarded.
16
I cannot stand before you today and tell
17 you
exactly how Accutane is responsible for my
18
son's disabilities, only that we know that it is.
19 Our
family and many others have suffered long
20
enough at the hands of Hoffmann-La Roche. We urge
21 you
to take a stand and ensure the safety of this
22
drug.
57
1
Thank you for your time.
2
DR. GROSS: Thank you, Mrs.
Crosland.
3
Is there anyone from the public who wants
4 to
speak at this point?
5
[No response.]
6
DR. GROSS: Hearing none, we will
declare
7 a
recess at this point, and we will reconvene at
8
9:15.
9
[Break.]
10
DR. GROSS: While we had closed
our public
11
hearing, we are going to reopen it briefly. The
12
tenth speaker from earlier today, Jeffrey Federman
13
will speak.
14
MR. FEDERMAN: Good morning. My name is
15
Jeff Federman, and I am President of Paragon Rex, a
16
company that provides services to the
17
pharmaceutical industry.
18
For purposes of disclosure, we are not
19
engaged with the manufacturers involved in today's
20
meeting. In addition, my
colleagues and I authored
21 a
book about pharmaceutical risk management.
22
Let me begin my proposing that today's
58
1
proceedings provide two insights about what can
2
reasonably be expected about the design and
3
improvement of risk management programs.
4
The first focus is on the expectations of
5
rigor and precision. We are all
associated with a
6
pharmaceutical industry that is famous for the
7
rigor and precision of its well-controlled clinical
8
trials. We expect to be able to
determine drug
9
efficacy using scientific and statistical methods,
10 and
would hope to bring a similar level of rigor to
11 pharmaceutical
risk management.
12
Our colleagues in other risk-intensive
13
industries, such as nuclear energy and aerospace,
14
have much to teach us about applying a similar
15
degree of rigor to risk assessment and program
16
design. Validated
well-established methodologies
17
exist to guide the design of risk management
18
programs in these industries.
19
Research of these practices, as well as
20 the
disease management and adult learning
21 disciplines,
suggest that effective drug risk
22
management may have several key elements.
59
1
1. Evidence-based assessment and
design
2
process, perhaps such as failure mode and effects
3
analysis, or FMEA, that targets interventions to
4
address specific process-related causes of failure.
5
2. Redundancies that back up the
6
inevitable human failures.
7
3. Collaborative design with
practicing
8
physicians to help program elements fit seamlessly
9
into their day-to-day practice of medicine.
10
4. Predictive modeling or
pre-testing to
11
determine the likely effectiveness of any proposed
12
program and anticipate where program weaknesses may
13
exist.
14
5. Innovative implementation
approaches,
15
perhaps such as scenario-based learning, that build
16 on
the way clinicians and patients learn.
17
Finally, ongoing monitoring and
18
measurement with the anticipation that initial
19
programs change over time.
20
Certainly, rigorous design is achievable,
21
yet, in the world of every-day clinical practice,
22
where care is delivered based on the judgments and
60
1
knowledge and motivations of well-meaning men and
2
women, high precision in terms of predicting
3
program compliance and use may be an unrealistic
4
expectation at the time of program introduction.
5
This key difference between the controlled
6
clinical trial environment to which we are
7
accustomed and the realities of clinical practice
8
lead to a second expectation.
9
I suggest that expecting a definitive
10
precise or final design at the time of risk
11
management program introduction may not be
12
reasonable. Quality improvement
standards in other
13
industries are built on the foundation of
14
continuous quality improvement, or CQI.
15
The concept of intervening with an initial
16
program, then, monitoring and measuring for early
17
opportunities to improve the program may be a more
18 achievable
expectation.
19
The approach of showing continuous
20
movement towards a goal may require a frequency of
21
analysis and potential redesign occurring in
22
intervals of months, not years.
61
1
Today's discussions are another step in
2 the
ongoing improvement of Roche's pioneering PPP
3 and
enhanced S.M.A.R.T. programs. We support
these
4 FDA
initiatives and believe these hearings today
5
will help lead to the next generation of effective
6
pharmaceutical risk management programs that
7
incorporate both rigorous evidence-based program
8
design, as well as continuous quality improvement
9 to
provide the degree of product we are all seeking
10 to
achieve.
11
Thank you.
12
DR. GROSS: Thank you, Mr.
Federman.
13
At this point, we will close the open
14
public hearing again, and we will move on to some
15 other orders of business.
16
Allen Mitchell, Director, Slone
17
Epidemiology Center, Boston University, will have a
18 few
minutes to comment on some questions that were