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