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
19
raised yesterday.
20
DR. MITCHELL: Thank you very
much, Dr.
21
Gross, and committee, I really appreciate your
22
offer of a few minutes to respond to some of the
62
1
concerns raised in the FDA review.
2
Yesterday, I mentioned that I
was not here
3 on
behalf or speaking for the FDA, and then this
4
morning's remarks, I just want to point out that
5 not
only is that the case for these remarks, but I
6 am
not speaking on behalf of the generic sponsors
7 or
Hoffmann-La Roche. I guess that leaves
me
8
speaking on behalf of the Slone Epidemiology
9
Center, which I think they will allow me to do.
10
This presentation has not been shared with
11
anyone other than our own group.
12
[Pause.]
13
DR. GROSS: We have a few
questions from
14
yesterday. I would like to start
with Dr. Day.
15
DR. DAY: Thank you. I did have questions
16
yesterday, however, I would like to defer that
17
comment and use it for an additional comment on the
18
questions today.
19
Would that be all right, Dr. Gross?
20
DR. GROSS: That's fine.
21
Dr. Bigby.
22
DR. BIGBY: I have a couple of
questions.
63
1 The
first is to Hoffmann-La Roche.
2
The question was asked I think yesterday
3
about annual sales, and you found the number, but
4 didn't say what it was, the number of 450
million
5
came out today.
6
What are the annual sales of Accutane?
7
MS. REILLY: What year, sir?
8
DR. BIGBY: Last year.
9
MS. REILLY: In 2003, our U.S. net
sales
10
were $144 million.
11
DR. BIGBY: Do you have any idea
sort of
12
what you have spent in terms of legal fees and
13
lawsuits around the issue of teratogenicity?
14
MS. REILLY: No, sir, I do not.
15
DR. BIGBY: Is that an obtainable
figure?
16
MS. REILLY: I would defer to our
counsel.
17
DR. GROSS: Dr. Cohen, Michael,
did you
18
have a question from yesterday?
19
DR. COHEN: No, I will hold it
until a
20
discussion later.
21
DR. GROSS: Dr. Katz.
22
DR. KATZ: I wanted to ask Dr.
Huber, on
64
1 the
people who enroll, what percentage of those,
2 how
soon do they get a notice that they have
3
enrolled do they get a questionnaire, and what
4
percentage of the people that enroll fill out those
5
questionnaires, the two or three questionnaires
6
they get?
7 On the enrollment form, it says you
will
8 get
two or three questionnaires through the
9
treatment. So, what percentage of
the people that
10
enroll get the questionnaires and answer them, and
11 how
quickly do they get them?
12
DR. HUBER: I will refer to Dr.
Blesch who
13
will answer your question.
14
DR. BLESCH: The Accutane survey
is
15
divided into two sections. Eighty
percent of the
16
patients who enroll, 80 percent get questionnaires
17
immediately upon enrollment. The
other 20 percent
18 get
a questionnaire approximately six months after
19
they enroll, and then a final questionnaire six
20
months after they finish treatment.
21
All Accutane-surveyed patients are
22
followed, continue to receive questionnaires until
65
1 six
months after their treatment has stopped.
2
DR. KATZ: What percentage of
patients who
3 you
send that questionnaire to fill out the
4
questionnaire?
5
DR. BLESCH: I don't have that
exact
6
number, but I believe it is about 80 percent.
7
DR. KATZ: Thank you.
8
DR. GROSS: Then, the last
question from
9
yesterday was from Mr. Levin.
10
MR. LEVIN: I will defer questions
until
11
later, but I do have one.
12
I am just curious what the sales for
13
Accutane for Roche were in 2002, prior to generic
14
entry into the market.
15
MS. REILLY: In 2002, that year to
date
16
figure was 380 million.
17
DR. GROSS: Thank you.
18
Before proceeding, I would like to read a
19
comment that Dr. Jackie Gardner suggested I read,
20 and
I concur.
21
We would like to publicly thank the people
22 who
came forward during the open public hearing
66
1
with their personal stories and acknowledge how
2
difficult that was.
3
Thank you.
4
Allen Mitchell.
5
Responses from Slone Epidemiology Center
6
DR. MITCHELL: Thank you. I think we have
7
things working.
8
[Slide.]
9
If I can follow up on Dr. Katz's question
10
from our survey, which is a similar design, the
11
response rate to the during and after treatment
12
questionnaires, the questionnaires that are sent to
13
women at the onset of therapy and the midst of
14
therapy is about 97 percent in our survey. It is
15
extremely high. That is both with
mail and
16
telephone responses included.
17
I wanted to speak about the limitations of
18 the
voluntary isotretinoin survey and perhaps some
19 of
the non-limitations because it seems to us that
20
this is a critical issue in interpreting the data.
21
[Slide.]
22
Quickly, to review some of the questions,
67
1 and
these are questions that we have posed as
2
potential limitations to this or any other survey
3
since 1988 when we first designed it, what is
4
success. The committee is
struggling with this.
5
Of course, there were no pre- and
6
post-comparisons possible, and here we are talking
7
about the data up until the onset of S.M.A.R.T.
8
These are the 14 years of data preceding S.M.A.R.T.
9
What are the critical events that one
10
judges success by, is it pregnancies, live born
11
infants, infants with birth defects?
Is the
12
critical outcome a rate of pregnancy, or is it an
13
absolute number?
14 One could imagine different scenarios
with
15
very different responses to that final question.
16
[Slide.]
17
Two other limitations that we have
18
identified is that survey participation may provide
19 an
unintended intervention and also that recall of
20
risk management may be biased among women who
21
become pregnant.
22
We were well aware of those two concerns
68
1 going into it, and to deal with those
concerns, the
2
design, which is admittedly complicated, includes
3 two
arms, the AT arm, which is the after therapy
4
only interview, if you will, and the DAT arm, which
5 is
the during and after therapy interview with a
6
number of contacts with patients throughout the
7
course of therapy.
8
Those have varying degrees of patient
9
contact, and information in those arms is collected
10
either prospectively or retrospectively with
11
respect to some of these behaviors. So, we think
12
that we have been able to deal with those issues.
13
[Slide.]
14
There is another point about whether the
15
reporting of pregnancies among survey participants
16 is
credible. We are, of course, concerned
about
17
that. If women are avoiding
pregnancy during
18
treatment, one would expect a rebound in pregnancy
19
rates following treatment. That
seemed to us to be
20 an
indirect measure of whether reports may be
21
accurate.
22
[Slide.]
69
1
We have lifted this figure from our 1995
2 New
England Journal paper, which summarized the
3
survey experience to date at that point, to
4
describe the pregnancy rates and outcomes during
5 and
after isotretinoin therapy.
6
I think it becomes fairly clear that
7
during treatment now, which is lumped together, the
8
pregnancy rate is somewhere approximately 9 per
9
1,000 person years. We are using
person years
10
here.
11
And as you can also see, elective
12
termination represents about 70 percent roughly of
13
those pregnancies. In the one
month after
14
treatment, where the risk of malformation is
15
considerably reduced, and in our data doesn't show
16
much increase at all, but in that one month of
17
therapy, you begin to see the pregnancy rates
18
increase, and in the two months, three months, and
19
four months after therapy--and we only go out to
20
four months--what you find is a considerable
21
rebound in the pregnancy rates, which is what one
22
would expect if women are trying to avoid pregnancy
70
1
during the course of therapy.
2
But it is also interesting to point out
3
that by the time you get to the fourth month, the
4
proportion of pregnancies that result in elective
5
termination approximates what we see for the U.S.
6
population.
7
So, this provides some indirect assurance
8
that reporting is not terribly inaccurate.
9
[Slide.]
10
But what I want to focus on is the issue
11 of
whether voluntary enrollment may compromise
12
representativeness, and, of course, one always
13
worries about that.
14
The response to that concern is to
15 maximize
enrollment. We all know that, that is
16
basic epidemiology.
17
[Slide.]
18
The second approach is to compare the
19
survey population to the target population, and to
20 do
that, using demographic characteristics, on the
21 one
hand, and ideally, the risk factors in the two
22
groups, on the other hand.
71
1
[Slide.]
2
I think we should make the point and
3
understand clearly that enrolling 60 percent or
4
more of the target population does not, in itself,
5
assure that that population is representative.
6
Conversely, enrolling less than 60 percent
7 of
the target population does not assure that the
8
sample is unrepresentative, and I think that there
9 has
been a fair amount of assumption that because
10 the
enrollment rates are below 60 percent,
11
therefore, the sample population is
12
unrepresentative.
13
[Slide.]
14
It is very difficult to make direct
15
comparisons in trying to respond to the question
16
about is the survey population a biased sample, and
17 we
could spend days, as we have, we have spent
18
months over the past 14 years struggling with how
19 to
evaluate this, the best we can do, and this is
20
based, not only in our own considerations, but
21
suggestions from FDA and from advisory committees
22 and
our own advisory committee that we have, is to
72
1 do
some indirect comparisons.
2
These are necessarily limited and
3
imperfect, and I wish to make that very clear.
4
[Slide.]
5
Two parts of data that I want to present
6
were alluded to in the FDA review document. One
7 was
a comparison we did using United Health Care
8
data, which is a large plan that had I think 14
9
different prescription plans under one umbrella.
10
What we were able to do through a
11
complicated process was to compare women who had
12
received a prescription for Accutane through that
13
plan, and look at those who enrolled in our survey
14 and
those who didn't enroll.
15
[Slide.]
16
There were very few variables that we
17
could identify for comparison, but one of them was
18
age, and what we found was that the age among the
19
Accutane participants was somewhat younger by about
20 two
years than it was in the population that didn't
21
enroll in the survey. This was
actually compatible
22
with some anecdotal reports which we frankly didn't
73
1
believe from one of our colleagues at Roche at the
2
time.
3
This was back in the beginning of the
4
survey, in the '90s, who had said that in his
5
conversations with providers, he was finding a
6
number of them reporting to him that they tried to
7
have women participate in the survey if they felt
8
that woman was at increased risk, that they felt
9
that the survey would provide some additional
10
intervention or a component that would help
11
encourage compliance. It might do
that indirectly,
12 but
it certainly isn't the purpose of the survey.
13
[Slide.]
14
So, this was compatible in that one would
15
expect that women who are older would be at less
16
risk for pregnancy, and, indeed, when you stratify
17
these findings according to age, and now we are
18
looking at this time the participation rate in the
19
survey was estimated to be about 40 percent, what
20 we
found was that that 40 percent rate was fairly
21
consistent across the three youngest age strata.
22
Where the participation rates were lowest were in
74
1 the
oldest group of women, and, in fact, among the
2
women 50 to 59 years old, only 14 percent
3
participated, which would be compatible with the
4
either subselection or doctor's selection of women
5 at
low risk saying don't both participating in the
6 survey, you are not at risk for pregnancy.
7
[Slide.]
8
The other data alluded to in the FDA
9
review, and that we have cited, and these are again
10
previously presented data, is a consumer survey
11
that was conducted by Roche identifying a number of
12
women who had been prescribed Accutane, and asking
13
them whether they enrolled in the survey or not,
14 and
interestingly enough, the age difference was
15
again about two years, that the enrolled women
16
tended to be about two years younger than those who
17
didn't enroll in the survey.
18
Median education wasn't terribly
19
different, the source of their prescription wasn't
20
terribly different, indeed, the women in the
21
survey, 10 percent more than the women who weren't
22 in
the survey reported being sexually active, and
75
1 not
surprisingly, along with that, higher rates of
2
contraception use.
3
Now, one of the things cited in the FDA
4
report was that, well, gee whiz, if you look at
5
this population, use of the birth control pill was
6
reported by 40 percent of the women enrolled in the
7 Slone survey, but only 16 percent among the
women
8 who
did not enroll.
9
On the face of it, there is no question
10
there is a difference there. It
is not accounted
11 for
by condom use or other barrier methods, but it
12 is
striking that the surgical sterilization rates
13
were compensatorily different among the enrolled
14 and
unenrolled women, and if you add up the highly
15
effective contraceptive methods as a percent, what
16 you
find is that they are virtually identical in
17
terms of highly effective contraception use among
18 the
women in the survey and the women who chose not
19 to
participate in the survey.
20
[Slide.]
21
But again, even within this analysis,
22
there is about three times as many women--two and a
76
1
half times as many women on the pill in the survey,
2
suggesting that again, if anything, the survey
3 population
may be at higher risk for pregnancy
4
since surgical sterilization is a highly effective
5 and
more effective method than the pill.
6
[Slide.]
7
Finally, bringing us to the most recent
8
data, we compared the survey data, as did FDA,
9
versus isotretinoin users according to age--and
10
this is in the one year before S.M.A.R.T., and we
11
used the FDA data presented for advanced PCS as
12
representing the base population, the target
13 population, and we have provided the survey
age
14
distributions on the left.
15
I think most observers would say that this
16 is
actually, until you get to the older age groups
17 for
sure, pretty representative, and while there is
18 a
decrease in the proportion of participants who
19 are
15 years of age or under, that decrease is
20
relatively small, where again we see a deficit of
21
participation that is fairly consistent is again in
22 the
older women who are less at risk for pregnancy
77
1 by
and large.
2
[Slide.]
3
And, indeed, when you compare the
4
pregnancies-- this is again in the year
5 pre-S.M.A.R.T.--reported
by our survey, and the
6
total reported by FDA including the spontaneous
7
reports, we see striking similarities in the
8
distributions.
9
[Slide.]
10
So, in answer to the question is the
11
survey population a biased sample, to us, the
12
evidence does not suggest that the survey
13
population is biased towards women at low risk of
14
pregnancy.
15
Indeed, the indirect evidence, and I
16
stress it is indirect, suggests that, if anything,
17 the
survey disproportionately includes women at
18
relatively high risk of pregnancy, and this pattern
19 has
been observed consistently at various points in
20 the
survey's history.
21
[Slide.]
22
That brings us back to this figure that we
78
1
showed in our presentation yesterday, where we
2
observed, again in the pre-S.M.A.R.T. era, 14 years
3 experience,
a decrease in the pregnancy rate from
4
roughly 4-fold to a little bit over 1-fold, a
5
rather striking and consistent decrease over time.
6
[Slide.]
7
Well, if the survey has any value, we need
8 to consider
what this means, and we think this
9
trend is unlikely to be explained by enrollment
10
biases, which would have to have changed over the
11
14-year period.
12
We have done all sorts of models as to how
13 one
might account for this trend through biases,
14 and
it is very difficult to come up with one.
15
[Slide.]
16
Rather, we think it may reflect continuing
17
improvements in the implementation of the risk
18
management program via its incorporation into
19
routine practice and I might add residency training
20
programs and the dermatology programs, so that our
21
summary view is that without respect to S.M.A.R.T.
22
specifically, we do think that the 14 years
79
1
experience preceding S.M.A.R.T. does reflect
2
incorporation of risk management elements to the
3
point where they have actually appeared to result
4 in
a fairly substantial decrease in the pregnancy
5
rates.
6
I will be happy to take questions, and
7
thank you for your consideration.
8
DR. GROSS: Are there any
questions? Yes.
9
DR. KIBBE: My question deals with
the
10
characteristics of the individuals in the two
11
groups, those that undergo therapy and don't get
12
pregnant, and those that undergo therapy and end up
13
having either been pregnant when they start or end
14 up
getting pregnant during the time frame.
15
I guess we could say that 99 percent of
16 the
women who enroll in therapy are successful in
17 not
having a pregnancy occur during that, and 1 or
18 2
percent do, but what characterizes the
19 differences
between those two groups, because if we
20
want to improve what we do, we don't have to change
21 it
for the 98 percent who go through the process
22
effectively, but if we could find some handle that
80
1
would help our clinicians identify individuals that
2
needed an additional activity or procedure, it
3
would help us a lot.
4
DR. MITCHELL: Actually, it is
obviously a
5
relevant question. First of all,
from these data
6 in
the most recent years preceding S.M.A.R.T., the
7
pregnancy rate would be 99.9 percent, it's roughly
8 1
in 1,000. I don't mean to quibble, but
it is
9
useful to keep that in mind.
10
What we would call the
analysis you are
11
describing is a risk factor analysis.
What one of
12 the
public speakers called it was a failure mode
13 and
effects analysis.
14
We are in the midst at the present time
15 frankly
in doing a detailed analysis of exactly
16
that consideration. We have
certainly identified
17
crudely that there are no gross characteristics
18
that appear to predict an increased risk of
19
pregnancy.
20
As one might expect, we have seen the
21
chosen method of birth control is directly related
22 to
the risk of pregnancy. We have seen that
the
81
1
typically effective methods are effective and the
2
typically ineffective methods are ineffective.
3
We have also seen and published in this
4
paper in 1995, our experience which indicates that
5 for
any given mode of contraception, we provide
6
data to suggest considerably higher efficacy than
7 the
generally published data on efficacy, and that
8 is
because we think the motivation of this
9
population is unusually high.
10
What we are doing now is looking at all
11 the
elements in the Pregnancy Prevention Program,
12 the
pre-S.M.A.R.T. Pregnancy Prevention Program, to
13 see
if we can identify any elements that do exactly
14
what you are describing, that characterize the
15
women who become pregnant and distinguish those
16
women from the women who did not become pregnant,
17 so
that interventions could be targeted to that
18
population, and we are hoping to have that
19
completed--Dr. Trussel, James Trussel is going to
20 be
joining us in that analysis as he has in the
21
past--and we hope to have completed in the next few
22
months.
82
1
DR. KIBBE: A second question has
to do
2
with my interest in the international experiences,
3 if
you will, with this medication. Roche
has said
4
that they have never had a country ask them to take
5 it
off the market, but I can't imagine that there
6
aren't countries that are interested in eliminating
7 the
risks.
8
Do you have any access to any data that
9
would help us understand how their interventions
10
differ from ours and how their risk ratios might
11
differ from ours, and how that might impact our
12 decisionmaking?
13
DR. MITCHELL: The short answer is
no, we
14
don't have any data and we have certainly tried to
15
find such data. One of the concerns that we have is
16
that the way drugs are managed philosophically in
17 some
other countries, and particularly one
18
scandinavian country with which I am aware, is very
19
different culturally from the U.S.
20
In one country, the attitude was that we
21 do
what we do and after that it is not our concern,
22 and
they don't track the outcomes of exposures, not
83
1
pregnancy exposures, but even pregnancy rates.
2
I think the U.S. is frankly, uniquely
3
providing information that has a denominator.
4
Other countries have not, to our knowledge, taken
5
this concern nearly as seriously as it has been
6
taken in the U.S., and the result is that there is
7
very little data.
8
DR. GROSS: Thank you, Dr. Kibbe,
for your
9
questions.
10
The next question comes from Dr. Honein.
11
DR. HONEIN: Yes. Dr. Mitchell, you
12
mentioned 38 to 45 percent survey enrollment based
13 on
the United Health Care survey for 1990 to 1996.
14
Yesterday, the FDA presented data suggesting a 19
15
percent survey enrollment for the year prior to
16
S.M.A.R.T.
17
Was there that much decline in enrollment
18 in
the survey over that time period, or is this a
19
different methodology for calculating the estimated
20
survey participation?
21
DR. MITCHELL: The methodologies
by which
22 you
calculate participation requires that you know
84
1
what the denominator is, and the denominator is the
2
number of unique women taking the drug.
3
The difficulty in establishing that
4
denominator, the difficulties are considerable, and
5 we
have had a lot of debates over the years about
6
what is an appropriate denominator.
7
I mean if you simply divide the total
8
number of female scripts by 3.7, as the FDA used
9 the
figure from one experience in the Seattle area,
10 you
come up with one estimate of a denominator.
If
11 you
divide that by 4 prescriptions or 2
12
prescriptions, you get very different denominators.
13 The
Kaiser data I think were closer to what we use.
14
But the fact is that we do suspect, based
15 on
indirect evidence, that participation rates
16
declined over time, and it was really because of
17 our
concern that we focused a lot of attention on
18
does the decline also reflect some differences in
19 the
way women are enrolling.
20
What we think, although we can't prove, is
21
that the $10 incentive, which we identified at the
22
outset of the survey back in '89 as an incentive to
85
1 get
women to participate in the survey through the
2
medication package which we came up with the idea
3 of
putting the enrollment form in the medication
4
package to bypass the physicians who may not want
5
women to participate or may not encourage them.
6
So, we said, you know, make it like a
7
toaster rebate coupon and encourage women who might
8 be
noncompliant to participate. But that
was a $10
9
incentive back in 1989, and one of the reasons for
10
increasing the incentive in the most recent efforts
11 was
to adjust, if you will, for inflation that $10
12
incentive. So, we do think that
there has been a
13
decline.
14
DR. GROSS: The next question is
from Dr.
15
Wilkerson.
16
DR. WILKERSON: Considering best
practices
17
once again, considering the women that we have, the
18
ages, the methods of birth control that they have
19
employed and reasonable rates of success of those
20
programs, what would be your calculated rate of
21
pregnancies per 1,000 cases if everybody did
22
exactly what they were supposed to do and they used
86
1 the
methods which are they using, what would this
2
rate actually look like? Instead
of being 1 per
3
1,000 courses of therapy, how much would it go down
4 to?
5
DR. MITCHELL: Can I turn your
question a
6 little
bit?
7
DR. WILKERSON: It depends.
8
DR. MITCHELL: I can't give you
the
9
answer. Okay, I can't give you
the answer, but I
10
want to understand the question, so we could give
11 you
the answer.
12 DR. WILKERSON: In other words, if you
13
take the current women and their methods of birth
14
control that they are currently using, use
15
optimally as real, everyday life people use them,
16
what would be the predicted rate of pregnancy per
17
1,000 courses or however you want to express this.
18 We
know that methods fail, we know that.
19
That zero is not obtainable in this
20
process short of females not taking this drug right
21
now, but I mean best practices in normal settings,
22
what would be the predicted rate of pregnancy in
87
1
this setting.
2
DR. MITCHELL: I think I can parse
that
3
question, to use an old term. One
question is in
4
efficacy in the normal use of the method, and, in
5
fact, what our data suggests is that efficacy is
6
better than normal data would suggest.
We can
7
spend a lot of time on defining on how best
8 efficacy was defined some years ago.
9
In the population we have observed, what
10 we
see is roughly 1, 1.2 per 1,000. If all
women
11
were on the pill, I could actually get you some of
12
those estimates, it's in the paper, but I think the
13
real question is what is the efficacy if women are
14 on
two methods of contraception, which is what is
15
specified in the risk management program.
16
The difficulty in assessing that is trying
17 to
find out whether women who report two methods
18
were reporting two simultaneous methods.
Those
19
kinds of questions become extremely, not only
20
invasive, but they become extremely difficult to
21
ask, because you essentially have to understand if
22 a
woman is on the pill, did she take a pill every
88
1
day, if she was using the pill and the condom, did
2 she
use the condom with every act of sexual
3
intercourse with the male partner.
4
One of the concerns is that women may be
5
interpreting the two methods, may be using two
6
methods, but forgetting the simultaneous. It is
7
conceivable, this is sort of the law of unintended
8
consequences that Dr. Trontell mentioned yesterday.
9 A
concern we have, although we don't have data to
10
support it, is there going to be a fraction of
11
women who say, okay, I have got to use two methods,
12 I
will use the pill a couple days a month and I
13
will use the condom when I think of it.
14
I don't mean to dodge your question.
We
15 can
give you contraceptive efficacy rates for any
16
single method that was reported, and it's in the
17 paper,
in the New England Journal paper from '95,
18 but
we can't answer the question any more directly
19
than that.
20
DR. GROSS: Dr. Kweder, do you
want to
21
comment on that?
22
DR. KWEDER: Yes, basically, it is
similar
89
1 to
what Allen had to say. We have some
slides that
2
display contraceptive method effectiveness rates as
3
generally understood, but there really are not data
4 that help us with the two methods
simultaneously
5
used, and Allen's point is exactly what we have
6
struggled with, as well, does it mean, you know,
7 how
many women actually interpret use of two
8
methods as simultaneous all the time.
That, we
9
don't know.
10
DR. GROSS: The next question is
from
11
Sarah Sellers.
12
DR. SELLERS: I am wondering if
you have a
13
regional distribution of the study participants.
14
DR. MITCHELL: We do, and it is
compatible
15
with the sales. I could get the
slide out, I would
16 be
happy to provide you. It will take me a
couple
17
minutes to find it, but it is similar.
18
DR. SELLERS: Just one more
follow-up, and
19 we
may have addressed this yesterday, but has the
20
survey been validated at all with any medical
21
records or exam data?
22
DR. MITCHELL: Specifically, how
would
90
1
you--
2
DR. SELLERS: To confirm in
particular any
3 way
to validate voluntary reporting on pregnancies.
4
Primarily, that would be the only thing that we
5
could look at.
6
DR. MITCHELL: I think the concern
is
7
false negatives, in other words, women who fail to
8
report pregnancies, and we have not done that.
9
That raises some privacy issues that are a little
10
tricky to get around.
11
Pregnancies that are reported are followed
12 up,
and any pregnancy that is identified with any
13
suggestions of malformations, the records are
14
obtained if the woman will allow us to.
15
DR. TRONTELL: I would like to try
and
16
address Dr. Sellers' question. I
just wanted to
17
point one challenge in assessing pregnancy. Many
18
health plans do not cover termination of pregnancy,
19 so
individuals who self-diagnose pregnancy and
20
elect to terminate outside their usual medical care
21
system will never be captured or ascertained.
22
DR. MITCHELL: Which is one of the
reasons
91
1
that we rely on voluntary reporting from
2
participants.
3
DR. GROSS: Thank you, Dr.
Trontell.
4
Dr. Strom.
5
DR. STROM: I wanted to follow up
on Dr.
6
Kibbe's question with a comment and then a question
7 to
the company in follow-up. You were
asking about
8 the
international experience in particular.
9
Anecdotally, my colleagues in other
10
countries tell me that Accutane is seen as a
11
uniquely American problem, but that is not because
12 we
are the only ones looking, but because we are
13 the
only ones using it so widely, that other
14
countries don't use it anywhere nearly as widely as
15 we
use it, so use is much less.
16
What I wonder about from the company is
17
whether you could give us sales data by population
18 for
some selected countries, so, for example, to
19 try
to nail down whether that anecdotal experience
20 is
correct, in other words, what is the rate of use
21 in
the U.S. population, how does that compare to
22
perhaps the English population or the Swedish
92
1
population or otherwise.
2
DR. HUBER: We do not have the
data on
3
sales broken down by country here.
That would take
4 us
a little time to compile and we don't keep those
5
here in the U.S., so it would take us some time.
6
DR. STROM: But I think that is
why you
7 are
not seeing the sensitivity from other
8
countries.
9 DR. KIBBE: I think there is an underlying
10
social issue, too, and that general acceptability
11 of
birth control methods in Sweden and some other
12
countries in Europe are going to be quite a bit
13
different than the United States.
I am trying to
14
figure out what factors are out of the direct
15
control of the system that we have are impacting
16 it,
that's all.
17
DR. GROSS: Thank you, Dr. Kibbe.
18
Dr. Whitmore has the last question.
19
DR. WHITMORE: Can you clarify,
you had a
20
graph up there talking about the number of
21
pregnancies during Accutane and then for the
22
subsequent months after therapy, and I thought it
93
1 was
10 per 1,000 person years, is that correct?
2
DR. MITCHELL: It was about 9
during
3
therapy, 9 per 1,000 during the course of therapy
4 at
that time.
5
DR. WHITMORE: So, just to
clarify, that
6
would be 1 in 100 essentially as opposed to 1 in
7
1,000.
8
DR. MITCHELL: Well, yes, but I am
sorry,
9 I
accept your correction. I am confusing
10
different--our usual rate estimators per course,
11 per
1,000 courses, correct.
12
DR. WHITMORE: And that was person
years,
13 and
therapy can range anywhere from 24 to 48 weeks
14
depending how dosing is done essentially. I think
15
that is a point that need to be re-emphasized as
16
opposed to if birth control pills and a second form
17 of
contraception were used effectively, maybe more
18
like 1 in 1,000 rate of pregnancy.
I mean those
19
numbers are not correct, but I think just to give
20 us
a ballpark idea.
21
One more question about your survey.
22
There is incentive to fill out the survey. For
94
1
teenagers, their parents probably make them fill it
2
out. For adults, there is a
monetary reward for
3
doing it, and also there are probably some adults
4 who
think oh, if I don't fill this out, something
5 bad
is going to happen, or think that it is part of
6 all
the program or something they need to do
7
particularly with all the PR about Accutane and
8
everything else.
9
So, I would say that a lot of people would
10
probably fill out the survey, fill it out because
11 of
incentive reasons of some sort, and then I would
12 ask
you, these women are signing a form that says I
13
will be abstinent or I will use two forms of
14
contraception throughout therapy.
15
What makes you think that a non-anonymous
16
survey is going to capture any information about
17
people actually not doing these things, they have
18
signed on a document saying they are going to do?
19
Also, reports about abortions, what makes
20 you
think that these women who have signed this
21
document, if they do get an abortion, if they are
22 not
going to tell their doctor, what makes you
95
1
think they are going to report it to you?
2
DR. MITCHELL: Probably the fact
that we
3 are
dealing with human beings would be a large part
4 of
that answer. We were similarly skeptical
going
5 in,
and remain somewhat skeptical, but less so.
6
What is very interesting is how often we
7
find women telling us things they have not told
8
their doctor. In fact, we
did--and, Dr. Katz, you
9 had
asked the question yesterday and I couldn't
10
remember what it was when we bumped into each
11
other, but it comes to mind now--and that question
12 is
really how accurately do the data reflect what
13 the
physician is doing.
14
We identified back in I think it was the
15
early '90s, a group of women who reported to us
16
that they had not had pregnancy testing prior to
17 the
prescription of Accutane. From their enrollment
18
forms, we were able to identify the physicians who
19
were in that loop.
20
We called those physicians' offices to ask
21
sort of an anonymous survey question about we are
22
just calling from Boston University, we are
96
1
querying physicians about their practices with
2
respect to Accutane, and typically, very often the
3
person responding would be an office manager or the
4
office nurse rather than the physician.
5
We asked whether they routinely did, in
6
fact, do pregnancy testing as one of a number of
7
questions, and a surprising number--not a
8
surprising number--a large number of physicians
9
indicated that they routinely do pregnancy--I mean
10 the
office nurse said oh, we always do pregnancy
11
testing, but a number of offices said to us we
12 don't.
13
Now, would you expect a physician's office
14 to
tell a survey that they don't do pregnancy
15
testing? The converse is also the
case, that when
16 we
identify a woman who reports that she is
17
sexually active and does not use contraception, we
18
consider that woman at such great risk for
19
pregnancy that the design of the survey calls for
20 us
to call that woman.
21
We call it reading the riot act.
We call
22
that woman and say to her that the behaviors you
97
1
reported to us put you at high risk for pregnancy,
2 and
we urge you to immediately call your physician,
3
stop taking the drug. Incidentally, would you also
4 be
willing to allow us to talk to your doctor.
5
When the woman gives us permission to call
6 her
doctor, you would assume that the doctor would
7
give you some response that would be compatible
8
with what the woman is reporting, and, in fact, I
9
can't give you the quantitative response, but there
10
were a disturbing number of times where the
11
physician would get on the phone with us, once the
12
woman gave us permission, and would go to the
13
medical record and read us from the medical record
14
that the woman said she was actively--so here was a
15
woman inviting us to find out, and what she was
16
doing was telling the survey--this is a long answer
17 to
your question, but I think it deserves that--she
18 was
telling us something that she wouldn't tell the
19
doctor.
20
So, the survey is actually in a position
21 to
find out things that a woman wouldn't tell the
22
doctor.
98
1
DR. WHITMORE: I had no idea that
you
2
called patients. I think that is
absolutely
3
fantastic.
4
DR. GROSS: Dr. Mitchell, thank
you very
5
much for your presentation.
6
DR. MITCHELL: Thank you.
7
DR. GROSS: Dr. Katz.
8
DR. KATZ: I want to clarify. You call
9 the
doctor's office, and you said some said they
10
didn't do any pregnancy testing, but you talked to
11 the
office manager and most doctors' offices--I
12
happen to draw blood in the office, but most don't
13
draw blood in the office--so, the office manager
14
says no, we don't do pregnancy testing.
They send
15 them
to the laboratory, but they don't do it.
16
DR. MITCHELL: First of all, let
me
17
explain this was a very biased sample.
This was a
18
sample of women, a small sample of women who had
19
told us they had not gone through a compliant
20
process, so we are already dealing with a subset
21
that is hopefully small.
22
When we called--Dr. Katz, I can't remember
99
1 the
specific questions, but we can get them for
2
you--we asked a series of questions of someone who
3
would be familiar with the offices practices, it
4
often was the nurse, but it represents only a very
5
small fraction, and we did incidentally try to
6
reach those doctors subsequently and get them
7
informed of what the appropriate practices were. I
8
don't mean to suggest that was a widespread
9
phenomena.
10
DR. GROSS: Thank you again, Dr.
Mitchell.
11
We will now move on to Dr. Trontell, who
12 had
some information to present to us that will be
13
helpful in our consideration of the questions.
14
DR. TRONTELL: There were some
questions
15
yesterday about the specifics of the clozapine
16
program and also of the S.T.E.P.S. program. I am
17
thankful to the representative from Celgene who
18
came and provided information, which I will repeat,
19 and
I will also invite that individual to come to
20 the
microphone to supplement it.
21
But relative to the registration of
22
patients in the S.T.E.P.S. program, patients are
100
1
registered by their Social Security number. In the
2
event that that number is not unique, a second
3
unique number is assigned to those individuals.
4 So,
the provision of patient anonymity in
5
S.T.E.P.S. it isn't truthfully there.
If you have
6
their Social Security number, that can be readily
7
linked to an individual's name.
8
The other question that was asked was
9
about clozapine and the mechanism that led to its
10
institution. In fact, information
provided to me
11 by
one of the members of the Division of
12
Neuropharmacologic Drug Products told me, in fact,
13
that some of the experience that I cited with
14
agranulocytosis related to post-marketing
15
experience abroad where the product was marketed
16
with recommended monitoring for white counts and
17
prevention for agranulocytosis.
18
That rate was on the order of 1 to 2
19
percent, and that had been described in the era of
20 the
clozapine national registry in practice with
21
mandatory monitoring of white count to be less than
22 1
percent, specifically 0.38 percent.
101
1
If there are additional questions, I would
2
invite the individuals who know each of those
3
registries to come to the microphone to address
4
them.
5
DR. GROSS: Hearing none, we will
move on
6 now
to Dr. Paul Seligman, Director of the Office of
7
Pharmacoepidemiology and Statistical Science at the
8
FDA, who will introduce the questions to us.
9 Introduction of Questions
10
DR. SELIGMAN: Good morning. I have been
11
asked to present the issues and questions for
12
consideration by the committee this morning and
13
this afternoon.
14
Please note that these questions are part
15 of
the agenda that was distributed for the meeting
16 and
can be found after the agenda.
17
Before I begin, I just want to take a
18
brief moment on behalf of myself and my colleagues
19 at
the FDA to also thank the members of the public
20
this morning who were here to share their testimony
21 and
their personal experiences.
22
The issues and questions fall into the
102
1
following sort of broad categories.
We are asking
2 the
committee today to evaluate the performance of
3 the
current program and the data that have been
4 presented both yesterday and today, to
consider
5
options for improvement of this current risk
6
management program, to consider how best to monitor
7 any
recommended changes, and to consider benchmarks
8 for
success as noted yesterday morning.
9
I think it was the first question out of
10 the
gate by Dr. Bigby, as well as others this
11
morning, who have focused on how best to determine
12
whether subsequent changes or any program that
13
comes out of these deliberations should be
14
determined to be successful.
15
[Slide.]
16
The first issue that we ask the committee
17 to
consider this morning is that based on the
18
reports and patient surveys, there does not appear
19 to
be a meaningful decrease in the number of
20
pregnancies reported in women taking a course of
21
isotretinoin since implementation of the current
22
risk management program.
103
1
We would ask you then to discuss the
2
measurement and implementation factors that may
3
have contributed to these findings.
4
[Slide.]
5
The second issue is based on prescription
6 audits and patient surveys, use of the
7
qualification sticker is high.
Patient surveys
8
suggest an inconsistent link between monthly
9
pregnancy testing and use of the stickers.
10
Reported pregnancies and patient surveys indicate
11
incomplete or inadequate birth control measures
12
among females.
13
Again, we ask you to please comment on
14
measurement and implementation aspects of the
15
current program that may have contributed to these
16 findings.
17
[Slide.]
18
Question 3. FDA's goals for the
19
Isotretinoin Pregnancy Prevention Risk Management
20
Program are that: no woman who is
already pregnant
21 be
prescribed and dispensed isotretinoin, and that
22 no
pregnancies should occur while on this therapy,
104
1 and
that effective pregnancy prevention occur
2
throughout the course of treatment.
3
[Slide.]
4 In recommending any changes to the
risk
5
management program, we ask the committee to
6
consider the potential tools and strategies in
7
light of the likelihood of effectiveness in further
8
reducing fetal exposure, the practical impact on
9
health care providers who prescribe and dispense
10 the
product, and the impact on patients who must
11
navigate any such program.
12
[Slide.]
13
Given these factors, we are asking the
14
committee to consider the following options:
15
(a) Continue the current risk management
16
program without additional tools, and if this is
17 the
recommendation, if so, what approaches do you
18
recommend to improve adherence with the program by
19
patients, physicians, pharmacists and others, such
20 as
health educators?
21
[Slide.]
22
(b) Or to consider modification of the
105
1 current program with additional risk
management
2
tools to reduce fetal exposure.
3
We list a number of them here, such as
4
programs to enhance education and interaction with
5
patients to identify and minimize high risk
6 behaviors; to tighten the linkage of
prescriptions
7
dispensed by pharmacists with required check of
8
pregnancy test results; the registration of
9
patients, pharmacists, physicians and/or others
10
such as health educators; limiting the access or
11
distribution of the drug, or other tools. In
12
recommending the other tools, we would ask you to
13
describe them.
14
I should note that in the course of our
15
discussions and deliberations, other tools have
16
also been mentioned, but not listed here.
17
[Slide.]
18
Question 4. In order to
adequately
19
monitor the risk management program, we ask the
20
following:
21
(a) Would it improve monitoring of risk
22
management program performance to register
106
1
patients, pharmacists, physicians, and other
2
relevant participants?
3
(b) If participants in such a risk
4
management program are registered, how can this be
5
more effectively done in a multi-source
6
environment, so that individuals are not registered
7
multiple times or double-counted?
8
[Slide.]
9
Finally, we are asking the committee to
10
identify critical benchmarks for determining the
11
success or failure of the
pregnancy risk
12
management program, and suggest, for example, such
13 as
reducing to zero the number of women who are
14
pregnant at the initiation of isotretinoin
15
treatment, and others.
16
I am happy to answer any questions about
17
these issues and provide any clarification as need
18 be.
19
DR. GROSS: Thank you, Dr. Seligman.
20 Committee Discussion
21
As Chair, I am going to make a suggestion
22
that we consider Question 3 last because that is
107
1 the
recommendation of the committees on what the
2
program should be in the future.
3
Question 4, I suggest be considered before
4 3
because it talks about whether or not registers
5
would be helpful, and that may be part of the
6 ultimate
plan that we come up with in Question 3,
7 and
assessing success and failure is something that
8 we
can also consider beforehand.
9
Is that okay with the committee if we do
10 it
in that order, Question 1, 2, 4, 5, then 3?
11
Does anybody have any objections to that? Okay.
12
Why don't we begin with Question No. 1.
13
Based on the reports and patient surveys, there
14
does not appear to be a meaningful decrease in the
15
number of pregnancies reported in women taking a
16
course of isotretinoin since implementation of the
17
current risk management program.
18
Data has been presented on that.
Please
19
discuss measurement and implementation factors that
20 may
have contributed to these findings. If I
may
21 be
so bold as to say that insufficient data has
22
been presented to answer that part of the question,
108
1 but
let's hear what committee members think on
2
those issues.
3
Dr. Gardner.
4
DR. GARDNER: As a non-clinician,
it would
5
help me greatly to understand what happens in the
6
clinician's office in terms of the implementation
7 of
these processes both from the standpoint of
8
physician and patient burden, and also the
9
logistics we heard yesterday, a scenario of trying
10 to
get a pregnancy test, is it the result or a new
11
request, and so on.
12
Could the clinicians comment
on how these
13
processes are implemented in practice for example?
14
DR. GROSS: Any dermatologist want
to--Dr.
15
Katz.
16
DR. KATZ: We will walk you
through it
17
from the beginning. First of all,
the patient has
18
been seen multiple times previously, on every other
19
treatment we know, different antibiotics starting
20
with the least risk of inducing and most used for
21
decades, and then antibiotics with a high risk
22
profile.
109
1
Then, the patient is evaluated, and if it
2 is
a minor, the parent is in the office initially,
3 a
complete discussion of all side effects are done,
4 and
then the female patient, one can't portray in
5
this meeting the doctor-patient contact and the
6
validity of patient response, reliability of
7
patient, we can't project that here, but the
8
physician assesses that, as well.
9
Then, you give the patient a choice of
10
having a parent leave the room, so you can discuss
11 the
contraception end. We ask them if they
are
12
using contraceptives, and it is burdensome going
13
through this entire thing, then, of all the side
14
effects involved.
15
All risks are mentioned and if it is
16
decided to go ahead with the Accutane, in female
17
patients, baseline bloodwork is done, CBC, hepatic
18
profile, lipids, and HCG pregnancy test, and they
19 are
told to come back at the time of the next
20
period for another pregnancy test, or they can get
21
that done, since they are not coming, that might be
22 in
10 days, they wouldn't have to come back to the
110
1
office, they can go to the lab and get the
2
laboratory test. They will often fax it, and then
3
they can come by and get a prescription with the
4
yellow stickers.
5
They are told to come back in two weeks
6 and
then every four weeks through the course of
7
treatment. Bloodwork is obtained
each time, and
8
then they are given a prescription again. They are
9
reminded each time about the necessity of two means
10 of
pregnancy.
11
They are asked about the side effects, how
12
they are feeling as far as generally, and once
13
again you can't project everything.
You are
14
looking at their face to see how they are doing.
15
With all this said and done, you remind the patient
16
each time about the necessity of two means of
17
contraception.
18
A lot of times people say yes, it happened
19 to
me, to bear on this question further, how can
20
these adverse effects be reduced, it can't be to
21
zero because a patient says that she is not
22
sexually active, and each time she remarks a little
111
1
bit, she said I told you that last time, and each
2
time I remind her, she reminds me that, doctor, I
3
told you I am not sexually active, and then two
4
weeks later she calls me and says she missed her
5
period. This happens. So, how do
you eliminate
6
that?
7
Now, it so happens, then, we got a
8
pregnancy test, she wasn't pregnant, she had just
9
missed a period. But she was
concerned because
10
obviously, she wasn't sexually inactive.
So, these
11 are
the problems that face us, and that is why this
12 is
going to happen anyway.
13
Does that answer your question?
14
DR. GARDNER: Thank you.
15
DR. GROSS: Dr. Crawford has a
question.
16
DR. CRAWFORD: A follow-up either to Dr.
17
Katz or any other member of the committee. Other
18
than actual pregnancy testing, what would be
19
different with the male patient prescribed
20
isotretinoin?
21
DR. KATZ: No, except that
contraception
22
isn't discussed, which might bring up some points
112
1
that came up with the male patients, but, no, that
2 is
not discussed.
3
DR. GROSS: That is an issue we
will need
4 to
consider later on, whether male contraception
5
should be recommended.
6
At this point, I would like to encourage
7 the
committees to specifically stick to the
8
question.
9 The first part of the Question 1,
does
10
anybody disagree with the statement, the statement
11
being there does not appear to be a meaningful
12
decrease in the number of pregnancies?
Does
13
anybody disagree with that? Yes.
14
DR. BERGFELD: I would like to
speak to
15
that. This was a new program, the
S.M.A.R.T.
16
program for the dermatologists, and when they were
17
asked to participate, the American Academy of
18
Dermatology put in place very intensive teaching
19
courses at all of their meetings to inform the
20
dermatologists of their behaviors.
21
We were also visited by the company in our
22
offices in which the S.M.A.R.T. programs were
113
1
introduced to us. We then had
didactic sessions to
2 go
through what our responsibilities were to be in
3
this program, and we were requested, and it was
4
inferred, that unless we signed up, we would not be
5
prescribing this drug and that we would be out of
6
order to prescribe this drug.
7
So, in my practice at the Cleveland
8
Clinic, we did abide by what we felt was the best
9
thing for our patients, we became informed, we
10
abided by the sticker qualifications, and we did
11
somewhat what you did, Dr. Katz.
We used the forms
12
that are given to us to go over with the patients.
13
But what I would like to say about this is
14
that what happened was that the compliance of the
15
dermatologists went up with informed consent and
16
education of the patient.
17
I think that is reflected by the fact that
18 you
have decreased numbers of prescriptions being
19
written overall, but a constant number of
20
pregnancies, and I think there has just been an
21
increased reporting that has gone on because of the
22
educational program.
114
1
I think when you open or begin a new
2
program, this is what you would expect, and I would
3
think that what we here do today would be to
4
enhance this program to make it more efficient and
5
improve it, so the reporting continues and the
6
education continues, with the ultimate objective to
7
reduce the pregnancies to zero if possible.
8
DR. GROSS: Okay. I am still trying to
9
answer Question No. 1. Let me
take the prerogative
10 of
the Chair and say there does not appear to be a
11
meaningful decrease in the number of pregnancies.
12
Would anybody disagree with that?
Dr.
13
Whitmore.
14
DR. WHITMORE: The one thing that
you
15
asked was are there contributing factors.
16
DR. GROSS: That is the second
part of the
17
question. Let's do the first part
first.
18
Otherwise, we are never going to get through the
19
day.
20
Does anybody disagree? Dr.
Ringel.
21
DR. RINGEL: I think the real
honest
22
answer is that we really don't know.
We don't know
115
1 if
Dr. Bergfeld's comment about the number being
2 artificially high because of increased
reporting is
3
true.
4
On the other hand, if that number really
5
reflects the actual rate, that is problematic
6
because the rate should have decreased, in fact,
7
because there were decreased numbers of
8
prescriptions written.
9
I think the only thing that this shows is
10 we
don't have the answer to that, and we really
11
need a registry.
12
DR. GROSS: So, we have one
dissenter.
13 Does
anybody else dissent on the statement there
14
does not appear to be a meaningful decrease in the
15
number of pregnancies? Dr. Bigby.
16
DR. BIGBY: The suggestion has
been raised
17
should we consider as an objective, the rate or the
18
absolute number, so if, in fact, you could show,
19 and
you could probably do this, that the rate had
20
actually decreased and the absolute numbers in the
21
hundreds, is that a success. That is the point I
22
think we should think about, so maybe rate isn't
116
1
what we should be looking at.
2
DR. GROSS: Could I see a show of
hands on
3 the
question there does not appear to be a
4
meaningful decrease in the number of pregnancies?
5 We
are never going to get through the program.
We
6 are
going to be stuck on Question 1 until 5:00 p.m.
7 To
me, the answer seems obvious. Yes.
8
DR. SCHMIDT: Yesterday, on page
70 in
9
this Pregnancy Rate and Accutane Survey, this, I
10
thought was meaningful that it decreased, that
11
there was almost like a 2- to 4-fold decrease in
12
some of the slides that were shown in the decrease
13 in
pregnancy rate.
14
I want to add one other thing to back up
15
Wilma. You know, people are very,
very anal about
16
doing these different things in the offices.
17
At least in Houston, I mean we really bend
18
over backwards to do everything and cross out t's
19 and
dot our i's on these, and from a clinical
20
experience, I took a straw vote at one of our major
21
meetings, our Thursday morning conference, and
22
since this S.M.A.R.T. program started, I could only
117
1
identify in this group one pregnancy that had
2
occurred at least in our group, which probably
3
includes a lot of people doing a lot of Accutane.
4
DR. STROM: To bring it to resolution, I
5
think the problem is an issue of terminology and
6
people are confusing numbers and rates.
The
7
question is there does not appear to be a
8
meaningful decrease in the number of pregnancies
9
reported. I think it is very
clear that is the
10
case. That is based on
spontaneous reports, the
11
numbers are roughly even.
12
All of the issues everybody is raising are
13
correct in terms of issues of reporting that maybe
14
that the rates have gone down despite the fact that
15 the
numbers haven't, and I think those are the two
16
things that people have confused.
17
But the question says not a meaningful
18
decrease in the numbers, and those numbers are
19
based on spontaneous reports, that is clearly the
20
case. The numbers are roughly the
same.
21
MR. LEVIN: I just want to add to
Brian's
22
comment that I think what people are responding to
118
1 is
the second part. I mean the issue of
whether we
2 are
seeing better reporting, more accurate
3
reporting or actually that things are remaining the
4
same is a question of measurement, and that is in
5 the
second part of the question.
6
DR. GROSS: So, a show of hands on
the
7
first part of the question.
8
DR. DAY: Excuse me. Could I ask a
9
clarification? I know these questions have been set
10 for
some time, but is there a way for us to ever
11
modify it, so that we could have a second part that
12 we
could vote that the number has not decreased,
13 but
that we do not have sufficient evidence about
14 the
rate or the rate has or has not? Can we
15
address number and rate in this question?
16
Otherwise, some of us will be uncomfortable in
17
voting quickly one way or another to get it off our
18
agenda.
19
DR. GROSS: Sure, there is no
reason. I
20
think we should answer the question, then, if you
21
want to put another statement, there is no reason
22 we
can't do that.
119
1
DR. TRONTELL: May I offer some
2
clarification from the Agency? We
do our best to
3
express the questions clearly, but our intent in
4
this question was, in fact, to engage the committee
5 is
some discussion on the issue of ascertainment of
6 pregnancy, some of which have already been
raised
7 in
some of the remarks around the table.
8
We would appreciate some discussion or
9
closure around it, not so much an issue of debating
10
whether or not the numbers have changed.
We can
11
make our assessment of that, but the issue of
12
ascertainment, as well as implementation are what
13 we
would like the committee to address.
14
DR. GROSS: So, ascertainment
really
15
relates to the second part of the question.
16
A show of hands on the number of
17
pregnancies. Do all people think
the number of
18
pregnancies appear not to have decreased
19
meaningfully? A show of hands
that they agree that
20 is
the case.
21
[Show of hands.]
22
DR. GROSS: Those who disagree?
120
1
DR. KIBBE: Abstentions? I think the data
2 is
inconclusive and I will not vote one way or the
3
other when the date is unreliable.
4
DR. GROSS: Fine. So, the majority agree
5 and
there is one abstention.
6
DR. KWEDER: Dr. Gross, if there
is a
7
vote, we would appreciate it if you could record it
8 for
the record in the instances when you do vote.
9
Thank you.
10
DR. GROSS: For the record, the
group
11
agrees there does not appear to be a meaningful
12
decrease.
13
Do you want to go around the room, is that
14
what you mean by record?
15
MS. TOPPER: For the record, we
are
16
required to go around the room individually and
17
have each person record their vote.
If you will
18 say
your name and you agree or disagree, we will
19
need to have that. Thank you.
20
DR. GROSS: Art, do you want to
start?
21
MR. LEVIN: Arthur Levin. I agree.
22
DR. SAWADA: Kathy Sawada. I agree.
121
1
DR. VENITZ: Jurgen Venitz. I agree.
2
DR. STROM: Brian Strom. I agree.
3
DR. BERGFELD: Wilma
Bergfeld. I agree
4
with the number, but I do not agree with the rate.
5 I believe
the rate has gone down.
6
DR. GROSS: You believe the rate
has gone
7 up?
8
DR. BERGFELD: Down.
9
DR. RAIMER: Sharon Raimer. I am going to
10
abstain. I don't think we have
good enough data.
11
DR. GROSS: So, that is an
abstention?
12
DR. RAIMER: Abstention.
13
MS. KNUDSON: Paula Knudson. I agree.
14
DR. BIGBY: Michael Bigby. I agree with
15 the
statement that there hasn't been a meaningful
16
decrease in the number of pregnancies reported. I
17 do
think that there is information that the actual
18
rate has decreased.
19
DR. HONEIN: Peggy Honein. I agree.
20
DR. COHEN: Michael Cohen. I agree.
21
DR. WHITMORE: Beth Whitmore. I agree
22
there has not been a meaningful decrease.
122
1
MS. SHAPIRO: Robyn Shapiro. I agree and
2
also observe that by asking for numbers as opposed
3 to
rates, there seems to be an implied goal about
4
what we should be looking for, whether intended or
5
not.
6
DR. EPPS: Roselyn Epps. I agree.
7
DR. SCHMIDT: Jimmy Schmidt. I agree.
8
DR. CRAWFORD: Stephanie
Crawford. I
9
agree there has not been a meaningful decrease in
10 the
absolute number.
11
DR. GROSS: Peter Gross. I agree.
12
DR. WILKERSON: Michael Wilkerson. I
13
agree with the question.
14
DR. RINGEL: Eileen Ringel. I agree also.
15
DR. VEGA: Amarilys Vega. I think that we
16
don't have sufficient data.
17
DR. GROSS: So, that is an
abstention?
18
DR. VEGA: Yes, sir.
19
DR. DAY: Ruth Day. I agree with the
20
decrease in number reported and make no claims
21
about anything else, numbers that may have
22
occurred, as well as changes in rate.
123
1
DR. KIBBE: Arthur Kibbe. I abstain on
2 the
basis that the data is not conclusive, nor is
3
this an appropriate question.
4
DR. GARDNER: Jackie Gardner. I agree.
5
DR. KATZ: Robert Katz. I agree.
6
DR. SELLERS: Sarah Sellers. I agree.
7
DR. GROSS: Thank you all.
8
Now, for the more difficult part--that was
9
easy, believe it or not--please discuss measurement
10 and
implementation factors. This is really
where
11 the
expertise of the committee could be enormously
12
helpful.
13
Any suggestions, comments?
14
Robyn Shapiro.
15
MS. SHAPIRO: I agree with your
earlier
16
comment that there is insufficient data to weigh in
17 on
that.
18
DR. GROSS: Anyone else? Art.
19
MR. LEVIN: I guess I am just
confused by
20
what the rate, when talking about rates, where we
21
are. If I look at P70 of the
Roche presentation,
22
which is sourced at Slone and tracks the number of
124
1
pregnancies per 1,000 Accutane treatment courses
2 and
the number of pregnancies per 1,000 patients
3 per
year, there does seem to be a decrease, but
4
where we get down to is around the number 3, and we
5
have just heard from 4 to 3. Over
the period of
6
1989 to the year 2002, and if we sort of track
7
into, you know, sort of approximate on this graph
8
where the first prevention program came into effect
9 and
then where S.M.A.R.T. came into effect, which
10 is
probably not on this graph actually. You
know,
11 we
see recent history.
12
But we just heard of a rate of 1, I think,
13 in
the presentation from Slone. So, I am
just
14
personally somewhat confused as to the different
15
presentations of what the rate issue is, whether it
16 is
in the course of treatment or per patient year
17
what we are discussing here.
18
DR. GROSS: Sarah.
19
DR. SELLERS: I would just like to
remind
20
everyone that we are talking about a reporting
21
rate, we are not talking about an incidence rate,
22 and
the primary objective of the risk management
125
1
program is to decrease the number of pregnancies,
2 not
to decrease the reporting rate.
3
These are reported pregnancies and the
4
number of reported cases are small in comparison to
5
what we believe are the overall number of
6
pregnancies that may be occurring and exposures
7
during pregnancy.
8
So, a meaningful decrease in a reporting
9
rate, in my opinion, has very little validity in
10 the
discussion of decreasing pregnancy exposures.
11
DR. GROSS: Thank you.
12
So far we have been talking about
13
measurement on this question. How
about
14
implementation factors, implementation factors that
15 may
have contributed to a lack of a decrease in the
16
number of pregnancies? Dr. Katz.
17
DR. KATZ: Just to take one second
to
18
reiterate an anecdote--I won't reiterate it--but to
19
remind you we don't have part of not being able to
20
improve on it although we have to keep trying and
21 use
every effort is the human fallibility and that
22 was
my only point in mentioning that little
126
1
anecdote. You can't completely
control human
2
behavior, nor can we unfortunately 100 percent
3
control physician behavior and how much time
4
somebody is spending with a patient, and so forth.
5
So, some of it, we are not going to be
6
able to reduce it to zero.
7
DR. GROSS: A point well taken.
8
DR. KATZ: It was also pointed out
9
yesterday, with all the stringent requirements that
10 one
might consider adding, that still doesn't
11
eliminate pregnancies. It will
capture the numbers
12
better and it may be a reminder, an education
13
reminder, but if somebody is going to tell the
14
doctor that they are sexually inactive, you can't
15
force them to take birth control pills.
There is a
16
certain limit to what we can do.
17
DR. GROSS: Exactly. There is going to be