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
DRUG SAFETY AND RISK MANAGEMENT ADVISORY
COMMITTEE:
Peter A. Gross M.D., Chairman
Michael R. Cohen, R.Ph., M.S., D.Sc.
Stephanie Y. Crawford, Ph.D., M.P.H.
Ruth S. Day, Ph.D.
Jacqueline S. Gardner,
Ph.D., M.P.H.
Arthur A. Levin, M.P.H.
Robyn S. Shapiro, J.D.
Brian L. Strom, M.D.,
M.P.H.
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.
CONSULTANTS (Voting):
Wilma F. Bergfeld, M.D.
Michael E. Bigby, M.D.
Margaret Honein, Ph.D.,
M.P.H.
Arthur H. Kibbe, Ph.D.
Sarah Sellers, Pharm.D.
Amarilys Vega, M.D., Ph.D.
Jurgen Venitz, M.D.,
Ph.D.
GUEST SPEAKER (Non-Voting):
Richard K. Miller, Ph.D.
3
PARTICIPANTS
(Continued)
FDA STAFF:
Jonca Bull, M.D.
Steven Galson, M.D., M.P.H.
John Jenkins, M.D.
Sandra Kweder, M.D.
Paul Seligman, M.D., M.P.H.
Anne Trontell, M.D., M.P.H.
Jonathan Wilkin, M.D.
4
C O N T E N T S
PAGE
Call to Order and Introductions, Peter
Gross, M.D.5
Conflict of Interest Statement,
Shalini Jain, PA-C, M.B.A., Executive
Secretary 7
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:
Charge to the Committees, Steven Galson,
M.D.,
M.P.H., Acting Director, CDER 12
Background and Regulatory History,
Jill Lindstrom, M.D., Division of
Dermatologic
and Dental Drug Products, FDA 15
Questions to the Speaker from
Committee 49
Open Public Hearing:
Robert A. Silverman, M.D. 68
Sidney Wolfe, M.D.,
Public Citizen Research Group 74
Curt D. Furberg, M.D., Ph.D. (Letter
Read by
Dr. Sherri Shubin, M.D., MPH 83
Hoffmann-La Roche, Inc. Presentations:
Introduction, Joanna Waugh, Group
Director,
Regulatory Affairs 90
Benefit/Risk, Martin H. Huber, Vice
President,
Global Head Drug Safety Risk
Management 94
Regulatory Overview, Joanna Waugh 96
5
C O N T E N T S
(continued)
PAGE
Overview of the S.M.A.R.T. Program,
Susan Ackermann Shiff, Ph.D., Global
Head Risk
Management, Drug Safety Risk
Management 101
Evaluation of S.M.A.R.T. Program,
Martin H. Huber, M.D., Vice President,
Global Head Drug Safety Risk
Management 116
Generic Firms' Presentations:
Isotretinoin Risk Management Program,
Background
Information, Frank R. Sisto, Vice
President,
Corporate Regulatory Affairs,
Mylan Laboratory, Inc. 140
Isotretinoin Survey, Allen A.
Mitchell, M.D.
Slone Epidemiology Center, Boston
University 152
Isotretinoin Enhanced Risk Management
Program,
Program Elements for which Advisory
Committee
Input is Requested, Robert W. Pollock,
Vice
President, Lachman Consultant
Services, Inc. 169
Questions to Roche and Generic Firms from
Committee
174
Isotretinoin Pregnancy Exposure:
Spontaneous
Reports 1 Year Pre- and 1 Year Post-Risk
Management Program,
Marilyn Pitts, Pharm.D.,
Office of Drug Safety, FDA 218
Isotretinoin Pregnancy Prevention Program
Evaluation,
Allen Brinker, M.D., M.S.,
Office of Drug Safety, FDA 237
Kaiser Presentation, Richard A. Wagner,
Pharm.D.,
Kaiser Permanente Drug Use
Management 265
Questions to Kaiser from the
Committee 289
6
C O N T E N T S
(Continued)
PAGE
Organization of Teratology Information
Services,
Interim Report, North American
Isotretinoin
Information and Survey Line, Richard Miller,
Ph.D., University of Rochester 296
Questions to OTIS from the Committee 313
Risk Management Options for Pregnancy
Prevention,
Kathleen Uhl, M.D., Pregnancy Labeling
Team, FDA 321
Selecting Risk Management Tools:
Considerations and
Experience, Anne Trontell, M.D.,
M.P.H. Deputy
Director, Office of Drug Safety,
FDA 338
Questions to Speakers from the
Committee 366
7
1 P R O C E E D I N G S
2 Call to Order and
Introductions
3
DR. GROSS: Good morning. I am Dr. Peter
4
Gross. I am Chair of the Drug
Safety and Risk
5
Management Advisory Committee. I
would like to
6
thank you all for coming this morning, and the
7
first order of business is for us to go around the
8
room and introduce everybody at the table. So, I
9 am
Dr. Peter Gross. I am Chair of the
Department
10 of
Internal Medicine at Hackensack University
11
Medical Center and New Jersey Medical School.
12
MS. JAIN: Shalini Jain, Executive
13
Secretary, FDA, Center for Drug Evaluation and
14
Research.
15
DR. WILKERSON: Michael Wilkerson,
MD.,
16
private practice, Tulsa, Oklahoma.
17
DR. RINGEL: Eileen Ringel, I am
in
18
private practice in Waterville, Maine.
19
DR. DAY: Ruth Day, I direct the
Medical
20
Cognition Laboratory at Duke University and I am on
21 the
Drug Safety and Risk Management Committee.
22
DR. KIBBE: Art Kibbe, Chairman of
the
8
1
Pharmaceutical Sciences Department, Wilkes
2
University School of Pharmacy and Chairman of the
3
Pharmaceutical Sciences Advisory Committee to the
4
FDA.
5
DR. GARDNER: Jackie Gardner,
Professor of
6
Pharmacy, University of Washington, and Drug Safety
7 and
Risk Management Advisory Committee.
8
DR. KATZ: Robert Katz, I am in
private
9
practice in Rockville, Maryland, and Clinical
10 Assistant Professor of Dermatology at
Georgetown
11
University.
12
DR. SELLERS: Sarah Sellers,
Pharm.D. I am
13 a
Masters in Public Health Candidate at Bloomberg
14
School of Public Health.
15
DR. TRONTELL: Anne Trontell,
Deputy
16
Director of the Office of Drug Safety in the FDA
17
Center for Drugs.
18
DR. SELIGMAN: Paul Seligman,
Director of
19 the
Office of Pharmacoepidemiology and Statistical
20
Science, also in the Center for Drugs at the FDA.
21
DR. WILKIN: Jonathan Wilkin,
Director of
22 the
Division of Dermatologic and Dental Drug
9
1
Products in CDER, FDA.
2
DR. BULL: Good morning. Jonca Bull,
3
Director, Office of Drug Evaluation V in the Office
4 of
New Drugs, Center for Drug Evaluation and
5
Research.
6
DR. KWEDER: Sandra Kweder, Deputy
7
Director of Office of New Drugs in CDER.
8
DR. GALSON: Steve Galson, I am
the Acting
9
Director of the Center for Drug Evaluation and
10
Research.
11
MR. LEVIN: Art Levin, I am the
consumer
12
representative on the Drug Safety Committee.
13
DR. SAWADA: Kathleen Sawada,
14
dermatologist, private practice in Lakewood,
15
Colorado.
16
DR. VENITZ: Jurgen Venitz,
Associate
17
Professor, Virginia Commonwealth University and
18
Chair of the Clinical Pharmacology Subcommittee.
19
DR. STROM: Brian Strom, I am
Chair of the
20
Department of Biostatistics and Epidemiology at the
21
University of Pennsylvania School of Medicine, and
22 I
am a member of the Drug Safety and Risk
10
1
Management Committee.
2
DR. BERGFELD: I am Wilma
Bergfeld,
3
dermatologist and dermatopathologist, head of
4
Clinical Research Department of Dermatology at the
5
Cleveland Clinic.
6
DR. RAIMER: Sharon Raimer,
Chairman of
7
Dermatology at the University of Texas in
8
Galveston.
9
MS. KNUDSON: Paula Knudson, I am
the IRB
10
administrator for the University of Texas at
11
Houston, and I am with the Dermatology Advisory
12
Committee.
13
DR. BIGBY: I am Michael
Bigby. I am a
14
dermatologist at Beth Israel Deaconess Medical
15
Center and Harvard Medical School.
16
DR. HONEIN: I am Peggy Honein. I am an
17
epidemiologist with the Birth Defects Center at the
18
Centers for Disease Control and Prevention.
19
DR. COHEN: Mike Cohen, I am a
pharmacist
20
with the Institute for Safe Medication Practices,
21 and
I am with the Drug Safety and Risk Management
22
Advisory Committee.
11
1
DR. WHITMORE: Beth Whitmore, I am
in
2
private practice in Wheaton, Illinois.
3
DR. SHAPIRO: Robyn Shapiro, I am
4
Professor and Director of the Center for the Study
5 of
Bioethics at the Medical College of Wisconsin,
6 and
I am on the Drug Safety and Risk Management
7
Advisory Committee.
8
DR. EPPS: Roselyn Epps, Chief of
the
9
Division of Dermatology in Children's National
10
Medical Center, and also a member of the
11
Dermatologic and Ophthalmic Drugs Advisory
12
Committee.
13
DR. SCHMIDT: I am Jimmy Schmidt,
in
14
clinical practice from Houston, Texas and I am on
15 the
clinical faculty of University of Texas and
16
Baylor Medical School.
17
DR. CRAWFORD: Good morning. Stephanie
18
Crawford, Associate Professor, University of
19
Illinois at Chicago College of Pharmacy, and I am a
20
member of the Drug Safety and Risk Management
21
Advisory Committee.
22
DR. GROSS: Thank you all, and now
I would
12
1
like to ask Shalini Jain to read the conflict of
2
interest statement.
3 Conflict of Interest
Statement
4
MS. JAIN: The following statement
5
addresses the issue of conflict of interest with
6
respect to this meeting, and is made a part of the
7
record to preclude even the appearance of such at
8
this meeting.
9
The topics to be discussed at today's
10
meeting are matters of broad applicability. Unlike
11 issues
before a committee in which a particular
12
sponsor's product is discussed, issues of broad
13
applicability involve many sponsors and their
14
products. All FDA participants
have been screened
15 for
their financial interests as they may apply to
16 the
products and companies that could be affected
17 by
the committee's discussions.
18
Based on this review, it has been
19
determined that there is no potential for an actual
20 or
apparent conflict of interest at this meeting,
21
with the following exception: In
accordance with
22 18
U.S.C. 208(b)(3), Dr. Ruth Day has been granted
13
1 a
waiver that permits her to participate fully.
2
A copy of the waiver statement maybe
3
obtained by submitting a request to the Food and
4
Drug Administration's Office of Management
5
Programs, Division of Freedom of Information,
6
HF1-35 5600 Fishers Lane, Rockville, Maryland
7
20857.
8
Because issues of broad applicability
9
involve many sponsors and their products, it is not
10
prudent to recite all potential conflicts of
11
interest as they may apply to each member,
12
consultant and guest speaker. In
addition, there
13
will be no industry representatives at today's
14
meeting. As you may be aware, the
Food and Drug
15
Administration has appointed industry
16
representatives that currently serve on each of
17
these committees but Annette Stemhagen, Dr.PH., the
18
industry representative to the Drug Safety and Risk
19
Management Committee, and Peter Kresel, M.B.A., the
20
industry representative to the Dermatologic and
21
Ophthalmic Drugs Advisory Committee, work with
22
sponsors that are directly impacted by the matters
14
1
before the committee. FDA has
contacted three
2
industry representatives from other Center for Drug
3
Evaluation and Research committees that have
4
experience with risk management issues and with FDA
5
advisory committee processes.
However, none were
6
available to participate in this meeting. Dr.
7
Stemhagen and Mr. Kresel are present in the
8
audience and attending as interested observers.
9
Further, we would like to note that Dr.
10
Louis Morris, a member of the Drug Safety and Risk
11
Management Committee, has been recused from
12
participating in today's meeting.
Dr. Morris is
13
also present in the audience and attending as an
14
interested observer.
15
We would like to remind the FDA
16
participants not to discuss the issues at hand
17
outside the advisory committee meeting.
In the
18
event that the discussions involve any other
19
products or firms not already on the agenda for
20
which FDA participants have a financial interest,
21 the
participant's involvement and exclusion will be
22
noted for the record. With
respect to all other
15
1
meeting participants, we ask in the interest of
2
fairness that they address any current or previous
3
financial involvement with any firm whose product
4
they wish to comment upon. Thank
you.
5
DR. GROSS: Thank you. The topic for
6
discussion for the next two days is the
7
effectiveness of the isotretinoin risk management
8 program for the prevention of fetal exposure
to
9
Accutane and its generic equivalents, and to
10
consider whether changes to this risk management
11
program would be appropriate. Dr.
Steven Galson
12
will give our committees the charge.
He is Acting
13
Director of the Center for Drug Evaluation and
14
Research.
15 Charge to the Committees
16
DR. GALSON: Thank you very much,
Dr.
17
Gross. I want to thank all of the
committee
18
members for being here. Your
commitment to public
19
service, indicated by the time commitment that you
20
have agreed to make to this subject, is extremely
21
important for the Food and Drug Administration and,
22
indeed, very important for all the patients taking
16
1
this drug and our decision-making process.
2
Today and tomorrow you are going to hear
3
details about the regulatory history of
4 isotretinoin. You are going to review data that
5 has
been collected over the last few years about
6 the
Pregnancy Prevention Program, and you are going
7 to
help us by giving us advice about where this
8
program should go in the future.
These
9
perspectives are extremely important to us. We can
10
spend a lot of time talking to each other and
11
tossing ideas around about what is the best course
12 of
action but when we have outside observers who
13
have taken a fresh look at these programs it is
14
enormously helpful to us as we move down the path
15 to
make decisions.
16
Isotretinoin has been on the market for
17
about 22 years and it may take the record for the
18
single drug with the most advisory committee
19
meetings. I don't know if that is
true but it is
20
certainly very close. When Roche
established the
21
current S.M.A.R.T. program in consultation with the
22 FDA
in 2001, the agency established several goals
17
1 for
the program. They were that no person
should
2
begin isotretinoin therapy if pregnant and that no
3
pregnancy should occur while a woman is taking
4
isotretinoin.
5
I want to just note that although those
6
were the goals, the agency is very cognizant of the
7
fact that setting a zero goal as a metric for
8
something that really depends on human behavior for
9
success and is probably not possible to attain. It
10 is
good to set that goal but when these issues are
11
totally out of the control of manufacturers,
12
physicians or the agency it is really impossible to
13
actually meet that, and we have been criticized for
14
saying our goal is zero. I want
to make it clear
15
that we recognize that it is probably not
16
attainable but we still think it is important to
17 set
these important goals because it helps us set
18 the
stage for figuring out what steps we want to
19
take and we think that is very important.
20
Setting these goals and establishing
21
metrics to get there is very consistent with one of
22 the
evolving foundations of CDER's risk management
18
1
program which is that risk management programs must
2 be
periodically evaluated for effectiveness.
3
Efficiency in risk management is very important
4
and, without measuring the effectiveness of the
5
program and knowing whether we are getting adequate
6
preventive power for the resources devoted we
7
really don't know where to go in the future with
8
this program, and it doesn't help us in terms of
9 establishing
and setting up new programs for
10
additional drugs.
11
Manufacturers of isotretinoin have been
12
challenged by the agency to work together to
13
minimize adverse events related to this drug, and
14 we
are really extremely heartened by the degree of
15
collaboration that has taken place to date and by
16 the
way the manufacturers are working together to
17
look towards the future. We
really expect this
18
collaboration to continue and we think that the
19
goal of minimized the teratogenic risk of this drug
20 is
something that we all share with all the
21
manufacturers and we, again, want to congratulate
22 and
are very heartened by the degree to which these
19
1
groups have been working together.
We look forward
2 to
hearing about how the S.M.A.R.T. program has
3
worked and how the companies have been working in
4
detail together.
5
I want to just talk about the
committee
6
now. We ask you to really remain
focused on the
7
purpose of this meeting, the risk management
8
program for the prevention of fetal exposure. We
9 are
aware that there are other important safety
10
issues related to this drug but we really are going
11 to
focus on prevention of fetal exposure in this
12
meeting. We would like you to
consider the data
13
presented. We want you to
consider the past risk
14
management programs and their achievements, and we
15 are
really looking forward to your recommendations
16 as
to whether the program, as it now exists, should
17
continue; whether it is as effective as it could
18 be;
and how we should enhance it or establish new
19 or
different tools. So, with that I will
close and
20
pass it back to the Chair. Thank
you very much.
21 We
are looking forward to a great meeting.
22
DR. GROSS: Thank you, Dr.
Galson. You
20
1 are
keeping us on time, setting a high target.
The
2
next speaker is Jill Lindstrom, a medical officer
3 for
the Division of Dermatologic and Dental Drug
4
Products at the FDA, who will talk about the
5
background and regulatory history of this
6
medication.
7 Background and Regulatory
History
8
DR. LINDSTROM: Good morning.
9
[Slide]
10
My objectives this morning are to set for
11 you
a clinical context for the use of isotretinoin;
12 to
outline the history of risk management efforts
13 for
this drug; to describe the current risk
14
management plan in some detail; and to provide the
15
committee with some rough guidelines for their
16
assessment of the data that will be presented.
17
[Slide]
18
Isotretinoin is an oral retinoid that is
19
indicated for the treatment of severe recalcitrant
20
nodulocystic acne. It is the only
drug moiety
21
approved for this indication, although there are
22
other oral related products in development. The
21
1
innovator was approved in 1982 and three generic
2
products have recently entered the market.
3
[Slide]
4
This patient has nodular acne, a
5
devastating disease that can result in significant
6
scarring and permanent disfigurement.
You can see
7 that he has many lesions, to include large
8
fluctuant nodules on his forehead, his cheeks, his
9
chin and his nose.
10
[Slide]
11
This patient also has nodular acne and,
12
again, you can see the many lesions on his face,
13 the
large fluctuant nodules extending down onto his
14
trunk.
15
[Slide]
16
This is the same patient, a view of his
17
back.
18
[Slide]
19
Again, a view of that patient's face prior
20 to
isotretinoin therapy--
21
[Slide]
22
--and following conclusion of a course of
22
1
isotretinoin therapy--he is dramatically improved.
2
[Slide]
3
And a third clinical example of a patient
4
with severe nodular acne. Again,
you can see the
5
nodules, sinus track formation and scarring. This
6 is
the patient prior to a course of isotretinoin
7 therapy--
8
[Slide]
9
--and at completion of his course of
10
therapy.
11
[Slide]
12
Because of its unique effectiveness,
13
current practice standards have expanded the use of
14
isotretinoin to the setting of non-nodular but
15
still scarring acne.
16
[Slide]
17
This patient does not have nodules, does
18 not
have classic nodular acne. She has
severe
19
papulopustular acne and her disease is scarring.
20 You
can also imagine that, in addition to the
21
cutaneous morbidity, she has significant
22
psychosocial morbidity from her disease.
This is
23
1 her
presentation prior to treatment with
2
isotretinoin--
3
[Slide]
4
--and her result at conclusion of therapy.
5
[Slide]
6
And a second patient, again without
7
nodular acne but with severe scarring papular acne.
8
This is a front view--
9
[Slide]
10
--and a side view prior to treatment with
11
isotretinoin--
12
[Slide]
13
--and the patient's result at conclusion
14 of
therapy, again dramatically improved.
15
[Slide]
16
Now, isotretinoin is unique among the
17
therapies in the acne armamentarium in that it
18
addresses all four of the known pathogenetic
19
mechanisms of acne. It decreases
sebum production
20 and
shrinks the size of the sebaceous glands.
It
21
normalizes follicular hyperkeratinization and
22
reduces follicular plugging. It
decreases P. acnes
24
1 colonization, although not through a direct
2
antibacterial mechanism but probably through making
3 the
micro climate of the follicle inhospitable to
4 the
organism. Finally, it is mildly
5
anti-inflammatory.
6
[Slide]
7
These events can be seen in this
8
histological specimen, this biopsy of a comedo
9
prior to isotretinoin therapy.
You can see the
10
dilated follicle filled with keratinous debris, the
11
large sebaceous glands. Not well
appreciated in
12 the
black and white photograph is the
13
perifollicular inflammation and the numerous
14
bacteria in the follicle.
15
[Slide]
16
In a biopsy of a follicle following
17
isotretinoin therapy the sebaceous glands--again, I
18
regret that I don't have a pointer but the
19
sebaceous glands are much smaller in size; the
20
follicular lumen is narrow. There
is no follicular
21
plugging and there is an absence of perifollicular
22
inflammation.
25
1
[Slide]
2
Isotretinoin is also unique in that a
3
course of therapy is temporally circumscribed.
4
Other anti-acne agents have no long-term impact and
5 are
effective only while they are being used.
A
6
course of isotretinoin, however, can result in
7
complete and prolonged disease remission. Thus,
8
patients with severe scarring acne like the
9
clinical examples that I just showed you prior to
10 the
approval of isotretinoin would have faced
11
years, perhaps even decades, of therapy with oral
12
antibiotics in combination with topical agents.
13 Now
such patients, after a course of isotretinoin
14
therapy, will see their disease become quiescent
15 and
the progression of their disfigurement halted,
16 and
they are spared the risk, the expense and the
17
inconvenience of years of oral and topical
18
therapies.
19 [Slide]
20
However, isotretinoin does present its own
21
risks. It is a known human
teratogen. In utero
22
exposure to isotretinoin can result in an increased
26
1
risk of spontaneous abortion and premature births,
2 as
well as structural abnormalities.
Approximately
3 28
percent of exposed fetuses will have sufficient
4
stigmata at the time of birth to be diagnosed with
5
retinoid embryopathy.
Additionally, many babies
6 who
are exposed to isotretinoin in utero will
7
appear normal at birth and will go on later in life
8 to
manifest neurodevelopmental deficits.
9
[Slide]
10
What has been done to manage this risk?
11 At
the time of approval in 1982 it was understood
12
from animal data that isotretinoin was likely a
13
teratogen, and in labeling the drug was classified
14
pregnancy category X. Prescribers
and patients
15 were advised in the contraindications,
warnings and
16
precautions sections of labeling not to become
17
pregnant while using the drug.
18
[Slide]
19
The first report of a human malformation
20
following in utero exposure to isotretinoin was
21
published in 1983. In response,
red warning
22
stickers were distributed to pharmacies to be
27
1
affixed to each isotretinoin prescription that was
2
dispensed. Additional reports of
exposed
3
pregnancies were received raising the concern both
4 in
the agency and the manufacturer.
Multiple "dear
5
doctor" letters were issued to inform the medical
6
community of this risk and the label was revised as
7
information became available.
8
[Slide]
9
In 1988 the sponsor proposed a
10
multi-tiered program to augment the risk management
11
plan which they entitled the Pregnancy Prevention
12
Program. An advisory committee
was convened to
13
review this proposal. There were,
as I said,
14
multiple components. First, the
label was altered
15 to
include warnings printed directly on the
16
package, and the "avoid pregnancy" icon was
17
introduced, the familiar red circle with the slash
18 and
the pregnant figure. And, the packaging
was
19
changed to blister packaging.
20
[Slide]
21
The package insert was updated to include
22 a
boxed warning informing physicians and patients
28
1 of
a need for a negative pregnancy test seven days
2
before treatment initiation; the importance of
3
using two reliable forms of contraception; waiting
4 to
begin therapy until the second or third day of
5 the
next menses; and limiting the supply dispensed
6 to
30 days; and the importance of repeating
7
pregnancy testing and contraceptive counseling on a
8
monthly basis.
9
[Slide]
10
An informed consent form for females was
11
introduced in that program. A kit
for prescribers
12 was
provided to explain the details of the program,
13 and
the first iteration of the voluntary patient
14
survey was introduced at that time.
Additionally,
15
there was a tracking survey to assess prescriber
16 use
of the program. That advisory committee
17
recommended approval of the Pregnancy Prevention
18 Program
and the program was implemented in 1989.
19
[Slide]
20
What was the impact of the program?
It is
21
somewhat difficult to say. From
the time of
22
approval of isotretinoin in 1982 pregnancies have
29
1
been reported to the agency. At
the time of the
2
introduction of the Pregnancy Prevention Program we
3
gained a new tool to gather information about
4
pregnancy reports, the patient survey.
Those
5
pregnancy reports are represented by the light blue
6
bars from 1989 on.
7
Both of these reporting mechanisms,
8
spontaneous reports as well as reports through the
9
survey, are voluntary reporting mechanisms and so
10 it
is difficult to ascertain an accurate pregnancy
11
rate. I want to remind you that
this is a
12
historical view prior to the implementation of the
13
current risk management program, but what we can
14 say
is that the public health burden from exposed
15
pregnancies continued to be large.
16
[Slide]
17
Additionally, during this time or during
18 the
'90s Accutane use was increasing significantly.
19
Because of these reasons, the large public health
20
burden from exposed pregnancies as well as the
21
increasing use, an advisory committee was convened
22
again to consider augmentation of the risk
30
1
management plan.
2
[Slide]
3
This advisory committee was convened in
4
September of 2000 and they determined that there
5
was, indeed, a compelling need for augmentation of
6 the
risk management plan. The agency agreed
and
7
this was communicated to the sponsor in a letter
8
dated October 6, 2000. This
letter has been
9
included in the briefing package for the committee.
10
[Slide]
11
In this letter risk management is
12
addressed from two perspectives, both pregnancy
13
prevention and potential neuropsychiatric adverse
14
events. Pregnancy prevention is
the focus of this
15
advisory committee. However,
since the letter was
16
included in your packet and does address
17
neuropsychiatric risk management I want to briefly
18
update the committee on the status of risk
19
management efforts with regards to potential
20
neuropsychiatric risk.
21
[Slide]
22
Three points of action were
recommended by
31
1 the
committee and communicated in that letter.
2
First, that the informed consent be amended to
3
inform patients of the potential for
4
neuropsychiatric adverse events, and this has been
5
done. Second, it was advised that
an educational
6
program for prescribers be implemented, and this
7 has
also been done. Third, it was
recommended that
8 a
comprehensive research program be undertaken to
9
include clinical trials.
10
The sponsor submitted clinical protocols
11 to
investigate neuropsychiatric risk to the agency.
12
When the agency reviewed them and gave the area
13 some
additional considered thought it was
14
recognized that more basic science groundwork
15
needed to be done before moving on to clinical
16
trials, and this basic science groundwork is now
17
being undertaken in collaboration with the National
18
Institute for Mental Health. As
that data is
19
accrued we will move on at the appropriate time to
20
clinical trials.
21
That is all I am going to say today about
22
risk management of neuropsychiatric risk. I want
32
1 to
remind both the committee and the public that it
2 is
not the subject of this advisory committee.
3
[Slide]
4
Moving on to pregnancy prevention, also
5
addressed in that letter, two goals, as Dr. Galson
6
already mentioned, were articulated.
The first,
7
that no one should begin isotretinoin therapy if
8
they are pregnant and the second, that effective
9
pregnancy prevention would occur throughout the
10
course of isotretinoin therapy.
Implied in these
11 two
goals is that we would have the ability to
12
assess whether or not they have been achieved.
13
[Slide]
14
To achieve these two goals, five points of
15
action were advised: augmentation of patient
16
education; registration of all patients;
17
registration of prescribers; implementation of a
18
pregnancy registry; and linkage of prescription
19
dispensing to adequate pregnancy testing.
20
[Slide]
21
The agency and the sponsor, having heard
22 the
committee's recommendations, entered into
33
1
extensive discussions and negotiations in an
2
attempt to design a plan that would incorporate the
3
five points of action to achieve the two goals that
4 had
been articulated.
5
However, obstacles were encountered,
6
particularly regarding patient privacy issues and
7
compliance with the newly passed Health Insurance
8
Portability and Accountability Act.
Eventually,
9
however, a plan was crafted and was approved in
10
October, 2001. The innovator was
the only product
11 on
the market at that time and they named their
12
risk management plan S.M.A.R.T., a System to Manage
13
Accutane-Related Teratogenicity.
I will refer to
14
their plan and the subsequent generic risk
15
management plans as the current risk management
16
plan so when I use the term the current risk
17
management plan, you can think of that as
18
interchangeable with S.M.A.R.T., S.P.I.R.I.T,
19
I.M.P.A.R.T., etc.
20
I want to now move and describe how the
21
plan that was crafted sought to incorporate those
22
five points of action and then I will describe for
34
1 you
the mechanics of the plan in some detail.
2 [Slide]
3
The first point of action articulated by
4 the
committee was a heightened educational program
5 for
each patient that included verifiable
6
documented written informed consent.
This is
7
fairly straightforward and is a component of the
8
current risk management plan.
9
[Slide]
10
The second point was complete registration
11 of
all patients, both male and female. This
was
12
intended to provide the denominator for
13
ascertainment of the pregnancy rate.
However,
14
registries raise issues regarding patient privacy.
15 The
sponsor proposed an alternative proposal to
16
estimate the denominator using pharmacy databases
17 and
survey data. This, of course, would
avoid
18
those patient privacy issues but the accuracy of
19 the
alternative proposal was dependent on
20
increasing the survey response rate.
The sponsor
21
felt that this would be achievable.
22
[Slide]
35
1
The third point of action was complete
2
registration and certification of all prescribers.
3 The
sponsor objected that they did not have the
4
authority to certify prescribers and so a plan of
5
voluntary registration was devised in which
6
prescribers self-attest that they possess the
7
relevant competencies needed to safely prescribe
8
isotretinoin. Additionally,
prescribers singed a
9
commitment to use the current risk management plan.
10 The
sponsor does provide prescribers with
11
information about the plan, but the responsibility
12 for
obtaining the necessary education to achieve
13 the
relevant competencies rests with the
14
prescriber. I will detail these
competencies in a
15 few
moments.
16
[Slide]
17
The fourth point of action was a
18
comprehensive plan to track fetal exposures to
19
isotretinoin to include a formal pregnancy
20
registry. This was intended to
provide the
21
numerator for ascertainment of the pregnancy rate.
22
Again, because it involved a registry, it raised
36
1 concerns
regarding patient privacy and issues
2
regarding compliance with the newly passed HIPPA.
3
Again, to avoid these obstacles and to
4
speed the implementation of augmented risk
5
management measures, the sponsor proposed
6
extrapolation of the numerator from survey response
7
data. Accurate extrapolation from
survey response
8
data would require an increased survey response,
9
which the sponsor identified as an increased
10
response rate of greater than 60 percent. Now,
11
they did feel that this would be achievable and, in
12
order to achieve the increased rate, they planned
13
targeted education of prescribers to increase
14
awareness of the survey and they increased
15
reimbursement for patient participation by 300
16
percent.
17
[Slide]
18
The final point of action advised by the
19
committee was the linking of dispensing of
20
isotretinoin to verification of adequate pregnancy
21 testing.
This is accomplished in the current risk
22
management plan through the use of yellow
37
1
qualification stickers. The
physician verifies the
2
negative pregnancy test and fills out the
3
qualification sticker. The
patient takes the
4
prescription with the qualification sticker to the
5
pharmacist who then verifies that the patient has,
6
indeed, been qualified. However,
in the current
7 plan
the pharmacist does not independently review
8 the
negative pregnancy test lab report.
Pharmacist
9
participation in the current plan is voluntary but
10
encouraged through the way that the plan is
11
designed.
12
[Slide]
13
I want to take a moment now and describe
14 in
some detail the mechanics of how the current
15
risk management plan works. It
can be a bit
16
complex if you haven't used it yourself in a
17
clinical setting. The program
begins with a
18
physician who decides that they would like to
19
prescribe isotretinoin and that they possess the
20
relevant competencies necessary to do so.
21
The physician will sign a one-time letter
22 of
understanding with the manufacturer, attesting
38
1
that they do possess the necessary knowledge and
2
experience in order to safely prescribe the drug,
3
specifically that they are knowledgeable about the
4
different forms of acne and its treatment; that
5
they are knowledgeable about isotretinoin and its
6
risks for teratogenicity; that they are
7
knowledgeable about the risks for and the
8
prevention of unplanned pregnancy; and finally,
9
that they are knowledgeable about the current risk
10
management plan and that they agree to use its
11
mechanisms.
12
When the manufacturer receives this signed
13
letter of understanding, they then forward to the
14
prescriber the qualification stickers and separate
15
educational materials for both the prescriber as
16
well as for patients. Prescriber
educational
17
materials consist of things like best practices
18
guides that inform the prescriber how to use the
19
components of the current risk management plan.
20
Educational materials for patients include things
21
like brochures and videos.
22
The physician then encounters a patient
39
1 for
whom they believe treatment with isotretinoin
2 is
indicated. From this point forward, as I
am
3
describing the mechanics when I refer to a patient
4 I
am speaking specifically of a female patient.
5 So,
when the prescriber encounters a patient for
6
whom isotretinoin is indicated the first thing that
7
they will do, having made the preliminary decision
8 to
prescribe the drug, is obtain a screening
9 pregnancy test. They would also provide
10
educational materials to the patient and the
11
informed consent forms, which I will talk about in
12 a
minute.
13
Also at this time, contraception
14
counseling and contraception would be provided.
15
This can be accomplished in one of two ways, the
16
prescriber him or herself, if they possess the
17
necessary expertise, can provide the counseling
18
themselves or they can refer to a reproductive
19
health specialist such as a gynecologist for
20
provision of the contraception counseling and the
21
contraception. The female
patient, unless they
22
select complete abstinence, must be on two forms of
40
1
contraception, at least one of which must be a
2
primary form, for 30 days prior to the initiation
3 of
isotretinoin therapy.
4
The patient reads the educational
5
material, obtains the contraception counseling and
6 the
contraception and reads through the informed
7
consent documents, signs those and returns them to
8 the
physician. There are actually two
informed
9
consent documents. The first is
an informed
10
consent/patient agreement which is given to both
11
male and female patients. This
outlines the risks
12 for
teratogenicity, as well as the potential risk
13 for
psychiatric adverse events, and also elicits
14
agreement from the patient that they will abide by
15 the
risk management principles of the current risk
16
management program, such as that they will not
17
share their isotretinoin with other people; they
18
will not give blood until at least 30 days after
19 the
conclusion of their therapy; that they will
20
return to their physician on at least a monthly
21
basis. The second informed
consent document is
22
specific for female patients and goes into much
41
1
greater detail about the risks of unplanned
2
pregnancy and the risk of teratogenicity with
3
isotretinoin therapy.
4
Both of those informed consent forms and
5 the
informed consent/patient agreement need to be
6
signed and returned to the physician.
7
Additionally, before prescribing isotretinoin the
8
physician must obtain a second pregnancy test, this
9
time timed to the woman's cycle within the first
10
five days of the menses or, if the patient is
11
amenorrheic, at least 11 days after the last
12
episode of unprotected intercourse.
After these
13
steps have been accomplished the physician then
14
fills out the prescription form, affixes the
15
qualification sticker and fills that out with the
16
date of qualification signifying that two negative
17
pregnancy tests have been obtained; that the
18
patient understands the risk management program;
19
that adequate contraception, either two forms or
20
absolute abstinence, have been initiated.
21
The patient then takes the prescription
22
with the qualifying sticker affixed and filled out
42
1 to
the pharmacist. The pharmacist verifies
that
2 the
sticker has been affixed, has been properly
3
completed, and also that the receipt of this
4
sticker and the dispensing of the isotretinoin
5
occur within seven days of the date of the
6
physician's qualification of the patient. If all
7 of
those criteria are met the pharmacist dispenses
8 the
isotretinoin along with a medication guide
9
which is an information brochure for patients
10
which, by law, must be dispensed each time
11
isotretinoin is dispensed that describes in
12
layman's language the risks of the drug and the
13
steps that need to be taken to minimize those
14
risks.
15
The patient then initiates their course of
16
isotretinoin therapy and on a monthly basis will
17
return to the prescriber to be requalified.
18
Requalification consists of repeating the pregnancy
19
test and verifying that the test is negative;
20
re-counseling the patient regarding contraception;
21 and
ensuring that the risk management program is
22
being abided by.
43
1
We receive data about the program from
2
several sources, first, spontaneous adverse events
3
reports come to the agency from physicians, the
4
manufacturer, from patients as well as from
5
pharmacists. Additionally, the
patient is
6
encouraged to participate in the voluntary patient
7
survey and data is gathered through that mechanism.
8
Finally, pharmacies are surveyed and the
9
prescriptions are audited to check for compliance
10
with the sticker program.
11
[Slide]
12
The risk management plan, as I have
13
described, was approved for the innovator in
14
October of 2001. Since that time
three generic
15
products have been approved and have entered the
16
market. Their risk management
plans are identical
17 in
the essential elements that I have just
18
described to the innovator plan.
So, again, when I
19
speak of the current risk management plan, that
20
would be interchangeable for either the innovator
21
plan or the plan of the three generic products.
22
[Slide]
44
1
However, while the four risk management
2
plans are identical in their essential elements and
3 can
be considered interchangeable, there are some
4
differences that have caused marketplace confusion.
5
Besides having different trade names for the four
6
drugs, each manufacturer has elected to name their
7
risk management program by a different name so for
8
Accutane with have S.M.A.R.T., the System to Manage
9
Accutane-Related Teratogenicity.
For Amnesteem we
10
have S.P.I.R.I.T, the System to Prevent
11
Isotretinoin-Related Issues of Teratogenicity. For
12
Sotret it is I.M.P.A.R.T., Isotretinoin Medication
13
Program Alerting you to the Risks of
14
Teratogenicity. For Claravis it
is A.L.E.R.T, the
15
Adverse Event Learning and Education Program
16
Regarding Teratogenicity.
Additionally, different
17
survey contractors have been employed by the
18 innovator
who uses Degge/SI and the generic firms
19 who
all use the Slone Epidemiology Unit.
Finally,
20
mid-course changes by the patient's pharmacy
21
provider in brand of isotretinoin dispensed can
22
result in patient confusion and perhaps multiple
45
1
enrollment in the voluntary survey.
2
[Slide]
3
When this current risk management plan was
4
approved the sponsor was instructed to submit a
5
comprehensive report on the metrics of the program
6
after one year of implementation.
This advisory
7
committee has been convened to comment on those
8
data. The advisory committee in
2000 did not
9
address benchmarks nor define success.
Indeed, to
10 do
so is challenging. But at this time I
want to
11
provide you with some rough guidelines that you can
12 use
as you are thinking about three parameters in
13
particular, the survey response rate, the sticker
14 use
and the number of fetal exposures.
15
[Slide]
16
The survey response rate, by the sponsor's
17 own
assertion, would need to be greater than 60
18
percent. The success of the
current risk
19
management program in terms of accurate estimation
20 of
that numerator for the pregnancy rate is
21
dependent on this higher survey response rate. The
22
agency's approval of the current risk management
46
1
plan was based on the sponsor's assertion that they
2
would be able to achieve this threshold.
3
[Slide]
4
The qualification stickers serve as a
5
surrogate endpoint for the use of the current risk
6
management plan. When the agency
approved the plan
7 it
was understood that the stickers were an
8
imperfect surrogate and, in fact, as the data has
9
come in they may be more imperfect than we had
10
realized, and other speakers will describe to you
11 the
linkage between the stickers and various
12
components of the program such as pregnancy
13
testing. However, at the time of
approval the
14
sponsor was informed that because the sticker
15 served
as a surrogate, and an imperfect surrogate
16 at
that, the threshold for success would be very,
17
very high and, in fact, would approach 100 percent
18 in
terms of sticker use.
19
[Slide]
20
Finally, and perhaps most importantly,
21
fetal exposures--it would be difficult to identify
22 an
acceptable number for fetal exposures.
In
47
1
considering what success would look like in terms
2 of
fetal exposures the committee may want to think
3 of
this in parallel with the two goals that were
4
articulated by the 2000 advisory committee, the
5
first goal being that no one initiate isotretinoin
6
therapy if pregnant. This goal,
the responsibility
7 for
which rests largely on the shoulders of
8
prescribers, may best be achievable.
9
The second goal, that no one become
10
pregnant while on isotretinoin therapy, is more
11
complex because it depends on patient behavior.
12
Again, in considering the threshold of success in
13
terms of fetal exposure you may want to think of
14
these two populations independently, and also in
15
considering what risk management tools would impact
16
these populations you may want to consider them
17
separately as different tools may be appropriate.
18
[Slide]
19
In summary, isotretinoin is a uniquely
20
effective drug for the treatment of severe,
21 scarring acne, a truly devastating
disease. There
22 has
been a long history of risk management efforts
48
1 to
prevent fetal exposures to this drug which were
2
built sequentially. The current
risk management
3
program has introduced some new tools and the
4
advisory committee is being asked to comment on the
5
effectiveness of these new tools and the current
6
program.
7
I and my colleagues look forward to
8
hearing your considered input on the data and how
9 we
can optimize the public health by ensuring that
10
isotretinoin is available to the patients who
11
needed it in a context that minimizes and best
12
manages the risks. So, I thank
you for your
13
attention this morning and I would be happy to take
14
your questions.
15
DR. GROSS: Thank you very much,
Dr.
16
Lindstrom. Before the questions,
I would like to
17
introduce an additional consultant who will be
18
participating in our joint advisory committee
19
session, Dr. Vega. Dr. Vega,
would you please
20
introduce yourself?
21
DR. VEGA: Yes, good morning. I am a
22
Board-certified pediatrician with a Masters in
49
1
Public Health and a Fellowship in
2
Pharmacoepidemiology from the Food and Drug
3
Administration. I am also a
former medical
4
epidemiologist from the Office of Drug Safety, with
5
extensive experience with the isotretinoin
6
pregnancy prevention issue. I
presented at the
7
last advisory committee the data on the different
8
options to modify the Pregnancy Prevention Program.
9 I
currently work for PSI International in their
10
adverse event reporting project.
11 Questions from the Committee
12
DR. GROSS: Thank you. Now Dr. Lindstrom
13
will entertain questions from the committees. Yes?
14
DR. CRAWFORD: Dr. Lindstrom,
thank you
15 for
the overview. In terms of considering
possible
16
risk management tools to enhance pregnancy
17
prevention, one thing I am not sure of after
18
reading all the materials we were provided is
19
whether the reasons for failure have been
20
identified. So, has there ever
been any thought
21
given to some type of failure mode analysis
22
determining for those patients who do become
50
1
pregnant, exactly what went wrong so efforts could
2 be
targeted on preventing those failures in the
3
future?
4
DR. LINDSTROM: That is an
excellent
5
question. The speakers that
follow will be
6
addressing the data and I believe also, as much as
7 we
know, the reasons for failures. So, if
you
8
don't mind, I think I will defer the answer to that
9
question to the presentations that will follow
10
mine.
11
DR. GROSS: Dr. Gardner?
12
DR. GARDNER: Dr. Lindstrom, could
you
13
give us some idea of the epidemiology of the severe
14
acne for which these drugs are both specifically
15
indicated and also for which they are being used?
16 For
example, can you tell us the incidence or even
17 the
prevalence of the condition in the population
18 and
the distribution by gender and by age, if you
19
know?
20
DR. LINDSTROM: I will do my best
to
21
answer that question. Acne is
extremely common,
22
particularly in the adolescent age range. The
51
1
incidence has been reported to be 80 percent in the
2
12-20 year-old group and falling to about 3 percent
3 in
the over 45 year-old age group. You can
sort of
4
extrapolate the decrease during that time.
5
DR. GARDNER: Is that severe acne?
6
DR. LINDSTROM: No, that is all
acne.
7
There is not an ICD-9 code for severe acne so it is
8
difficult--I don't actually know and I couldn't
9
find, in preparing for this committee meeting, an
10
incidence or a prevalence for severe acne. I can
11
tell you that recalcitrant nodular acne is not the
12
majority of acne. Severe scarring
acne is a larger
13
proportion of acne patients. As a
practicing
14
dermatologist, it was not uncommon.
I saw scarring
15
acne on essentially a daily basis but I don't have
16
incidence or prevalence figures for you, other than
17 the
prevalence of acne in the population at large.
18
DR. GROSS: Sarah Sellers?
19
DR. SELLERS: A quick question on
the
20
qualification in the current program, the
21
qualification sticker that goes to the pharmacy has
22 a
qualification date on it?
52
1
DR. LINDSTROM: Yes.
2
DR. SELLERS: And, is that date
the date
3 of
the confirmed negative test?
4
DR. LINDSTROM: Yes, it is. For
5
initiation of therapy it would be the date of the
6
second confirmed negative pregnancy test and for
7
ongoing therapy it would be the date of the
8
repeated negative pregnancy test.
9
DR. SELLERS: It is not the date
that a
10
sample was taken for a pregnancy test?
11
DR. LINDSTROM: No, I believe it
is the
12
date--I am sorry, I didn't follow actually your
13
question.
14
DR. SELLERS: The qualification
date is
15
actually when the negative result is received--
16
DR. LINDSTROM: That is my
understanding.
17
DR. SELLERS: --not the date a
sample is
18
drawn for analysis to go to the lab?
19
DR. LINDSTROM: Correct.
20
DR. SELLERS: Thank you.
21
DR. GROSS: Yes, Robyn??
22
DR. SHAPIRO: I guess I am curious
about
53
1 the
HIPPA problem that you have found with some of
2 the
registry ideas. Why couldn't the
patients
3
simply authorize release of particular information
4 in
order for them to get the drug and, therefore,
5
make that information available?
6
DR. LINDSTROM: At the time of the
prior
7
advisory committee and at the time that the agency
8 and
the sponsor were working to craft the plan,
9
HIPPA had just been approved and towards the end of
10
that time period was being implemented.
In working
11
with consul from the company as well as consul
12
within the agency, working out the details of HIPPA
13
compliance proved difficult and while it probably
14
would have been achievable, it was taking a lot of
15
time. So, the sponsor proposed
and the agency
16
approved these alternative methods in order to have
17 a
plan in a more timely fashion that could be
18
implemented that could augment the risk management
19
program. As understanding of
compliance of HIPPA
20 has
matured, I think it would be much easier to
21
navigate those waters at this time but at that time
22 the
Act had just been passed and was in the process
54
1 of
being implemented and understanding was not yet
2
mature.
3
DR. GROSS: Dr. Bigby?
4
DR. BIGBY: I have two
questions. The
5
first one is that you stated that some patients who
6
take Accutane never have acne again.
Are you or
7
someone else going to actually tell the committee
8
what the actual numbers are in terms of the
9
long-term efficacy of Accutane?
10 DR. LINDSTROM: What I had hoped to state
11 was
that patients may achieve complete and
12
long-term remission. I have read different figures.
13
Approximately 10-20 percent of patients who are
14
treated with Accutane never require treatment with
15
Accutane again. Another way to
state that would be
16
that 10-20 percent of patients who undergo a course
17 of
isotretinoin therapy do require a second course
18 of
isotretinoin therapy. Of the 80-90
percent that
19
only require one course of isotretinoin therapy, a
20
portion of those are then able to be maintained
21
with no treatment at all. A
portion would require
22
only topical therapy and some may require oral
55
1
antibiotic therapy.
2
DR. BIGBY: I just think that it
is
3
important for the committee to know actually what
4
those proportions are and I just hope somebody
5
brings that data to the table.
6
DR. LINDSTROM: I don't have those
7
numbers. All I can tell you is
that between 10-20
8
percent of isotretinoin patients do undergo a
9
second course of therapy.
10
DR. BIGBY: Well, those numbers do
exist
11 and
I just hope it is sort of made known to the
12
committee what those numbers are.
13
The other question I had was of the
14
pregnancies that occurred prior to S.M.A.R.T. and
15
during S.M.A.R.T., is there any data about who the
16
prescribers were?
17
DR. LINDSTROM: I am sorry, can
you repeat
18
your question?
19
DR. BIGBY: You presented
information
20
about pregnancies that occurred for the year prior
21 to
S.M.A.R.T. and during a year of S.M.A.R.T.
What
22 I
would like to know is who the prescribers of
56
1
Accutane were for those women who got pregnant.
2
DR. LINDSTROM: Yes, actually I
did not
3
present any data about pregnancies during
4
S.M.A.R.T. My objectives at this
point of the day
5
were to set the historical context so the slide
6
that I showed was that reported pregnancies to the
7
agency were from 1982 through 1999.
Speakers later
8
today will update you with the current pregnancy
9
data, the more recent data during the
10
implementation of the current risk management
11
program.
12
Now, there were two parts to your question
13 and
I only answered half. Can you tell me
again
14 the
second part of that question?
15
DR. BIGBY: No, you answered it.
16
DR. LINDSTROM: Okay.
17
DR. GROSS: Dr. Michael Cohen?
18 DR. COHEN: Earlier you mentioned that
19
there may occasionally be some confusion between
20 the
various risk management programs for
21
isotretinoin that exist and perhaps also the brand
22
names. Are you saying that that
occasionally
57
1
contributes to some of the problem that we are
2
seeing with isotretinoin and the way that it is
3
handled? Also, who actually does
the selection?
4 Is
it the prescriber or the pharmacist? Is
it a
5
substitution that is made? I
didn't understand
6
that.
7
DR. LINDSTROM: In stating the
various
8
names and alluding to confusion, my point is just
9 to
give the perspective of patients and
10
prescribers. It is a somewhat
complex plan and
11
there are various names out there, and to just make
12 the
committee aware that that is a potential source
13 of
confusion, the multiple names for the risk
14
management plans. I did not mean
to imply that
15
there should not be different trade names for the
16
products of the various manufacturers but, rather,
17
that the risk management plan having multiple names
18
does present some confusion for patients. The
19
second part of your question?
20
DR. COHEN: Well, I guess I am a
little
21 bit
confused about who actually selects the brand
22
that will be used. You mentioned
that occasionally
58
1 a
patient can go from one brand to another--
2
DR. LINDSTROM: Right.
3
DR. COHEN: --does that contribute
to any
4
confusion that we should be concerned about? I
5
understand the plans are pretty much the same.
6
DR. LINDSTROM: Right.
7
DR. COHEN: They have the same
baseline
8
requirements but are there any errors that this
9
contributes to that, you know, might have an
10
adverse outcome that we should know about?
11
DR. LINDSTROM: Sure.
12
DR. COHEN: In other words, should
there
13 be
one plan?
14
DR. LINDSTROM: I think that is an
15
excellent question and one that the committee will
16
need to be considering as the day goes forward.
17
Other speakers will present to you the details of
18 the
data that has been obtained from the current
19
risk management plan and will be in a better
20
position to address confusion from the agency's
21
perspective in terms of data collection from
22
multiple plans.
59
1
As far as whether a patient receives one
2
particular manufacturer's isotretinoin or another,
3 a
physician can specify that as they write the
4
prescription but I think in many instances it is
5 the
pharmacy provider that makes that determination
6 of
which patient receives which brand. So,
it is a
7
little bit outside of the prescriber-patient
8
relationship.
9
DR. GROSS: Dr. Kweder?
10
DR. KWEDER: Yes, I think I can
clarify a
11
little bit. We do not have
specific data on the
12
frequency of switching between brands.
We have
13
heard for patients and providers that this is a
14
potential source of difficulty but we do not have
15
data saying how common it is for patients to be
16
required to switch mid-course.
Just like any
17
medication, the source of imposing a change could
18 be
anything from the patient wanting a cheaper
19
brand to the pharmacist pressing for that, or the
20
physician or even the health insurance plan that
21
will only pay a certain amount.
22
DR. GROSS: Dr. Trontell?
60
1
DR. TRONTELL: I was going to just
2
elaborate on Dr. Kweder's remarks.
We don't yet
3
have any data to document that confusion has
4
occurred between these programs.
5
DR. GROSS: Thank you. Dr. Whitmore, did
6 you
have a question?
7
DR. WHITMORE: The answer came up
already,
8
thank you.
9
DR. GROSS: Dr. Day?
10
DR. DAY: Was any provision made
for
11
providing the risk management plan for mail order
12
prescriptions? I assume that
originally Accutane
13 was
available through mail order.
14
DR. LINDSTROM: The prior risk
management
15
plan did allow for mail order prescriptions. For
16 the
current risk management plan, as I understand
17 it,
a mail order prescription might be challenging
18 in
that the drug needs to be dispensed within a
19 seven-day
window of qualification. Not only that,
20 but
there are other features of the plan that might
21 not
happen. So, it is not allowed.
22
DR. GROSS: Dr. Honein?
61
1
DR. HONEIN: I just want to
follow-up with
2
some questions on the multiple risk management
3
programs. I wondered if there was
any data on how
4
often women get one set of information from a
5
prescriber and a different set of information from
6 the
pharmacist at the time it is dispensed, and if
7
there are any reports of that contributing to
8
confusion.
9
DR. LINDSTROM: The information
that the
10
patient receives from the pharmacist would be the
11
medication guide which would be the same for all of
12 the
manufacturers' products, the innovator as well
13 as
the generic. The pharmacy has the option
of
14
providing additional patient education information
15 that is not part of the current risk
management
16
plan that would be in addition to that.
17
DR. HONEIN: Don't they get
enrollment
18
forms both from the prescriber and the pharmacy,
19 and
wouldn't those be different if they got
20
different sets of material?
21
DR. LINDSTROM: Thank you. That is a good
22
point. The enrollment forms are
included with each
62
1
prescription that is dispensed and the enrollment
2
form for the innovator uses one contractor and the
3
enrollment forms for the generics utilize a
4
different contractor so you are correct that that
5
would be another potential source of confusion for
6 a
patient.
7
DR. GROSS: Dr. Knudson?
8
MS. KNUDSON: I am curious about
the age
9
distribution of the women taking the drug. I would
10
like to know does the enrollment form or the survey
11
form or the qualifying sticker carry the age?
12
DR. LINDSTROM: The qualifying
sticker
13
does not. Age may be obtained by
the pharmacy as
14
part of an independent pharmacy data collection
15
with age, date of birth and so forth to ensure that
16 the
correct prescription is dispensed to the
17
correct patient. Age is a
component of the
18
voluntary patient survey.
19
DR. GROSS: Dr. Ringel?
20
DR. RINGEL: This is a quibbling
point
21
from the "nothing in life is perfect" department.
22 You
mentioned that it should be possible to prevent
63
1
initiation of isotretinoin therapy before a
2
pregnancy, and there are ways you can actually
3
manage it if you consider that there is a certain
4
number of false-negative pregnancy tests,
5
particularly early in pregnancy, and also there can
6 be
confusion with bleeding at implantation and
7
bleeding for other reasons with menses.
If you put
8
those together, in fact, it would be possible to be
9
pregnant, despite all of our efforts, before
10
initiating Accutane.
11
DR. GROSS: Dr. Strom?
12
DR. STROM: In the era of
increasing
13
computerized data entry, how would this risk
14
management plan work?
15
DR. LINDSTROM: I am sorry, can
you
16
elaborate on your question?
17
DR. STROM: Sure. The current risk
18
management plan, as I understand it, relies on a
19
sticker program.
20
DR. LINDSTROM: Yes.
21
DR. STROM: There is increasing
use of
22
computerized prescribing and a big push nationwide
64
1 to
increase that.
2
DR. LINDSTROM: Yes.
3
DR. STROM: How could this be
4
operationalized? How could this
plan possibly work
5 in
that context?
6
DR. LINDSTROM: The current risk
7
management plan does not allow for computerized
8
prescriptions.
9
DR. STROM: Just to clarify, given
the
10
current environment in pharmacy, neither mail order
11 nor
computerized prescriptions are compatible with
12 the
current plan.
13
DR. LINDSTROM: Computerized
prescriptions
14 are
not compatible with the current plan and I
15
think mail order would be difficult with the
16
current plan. Again, I have set
the historical
17 context and described the current plan.
18
DR. GROSS: Dr. Kibbe?
19
DR. KIBBE: I have just a question
about
20 the
two figures that you gave us and the data that
21 is
contained therein. Have you taken the
number of
22
reports of pregnancies for the years from '91 to
65
1 '99
and divided them by the number that you show
2 for
the number of female patients during those same
3
years and gotten, even though it is an inaccurate
4
number, at least an estimate of number of
5
pregnancies per 1,000 patients over that time
6
frame?
7
DR. LINDSTROM: I believe that you
are
8
bringing up the issue of pregnancy rate.
While the
9
absolute number of pregnancies reported to the
10
agency was relatively constant, the number of women
11
receiving isotretinoin prescriptions was rising. I
12
don't want to belabor this point but there are two
13 issues
related to deriving a rate from the data
14
that I showed. First, pregnancy
reporting is
15
voluntary, both the spontaneous reports and those
16
received through the survey. They
are voluntary.
17
Both are voluntary mechanisms. We
know that
18
adverse event reporting declines over time and we
19
know that it does not capture all events so it is
20 an
imprecise number.
21
Second, even if that numerator in terms of
22 the
number of pregnancies reported was reflective
66
1 of
the total number of exposed pregnancies that had
2
occurred, even if that number, indeed, did stay
3
flat the public health burden of those exposed
4 pregnancies, of those affected babies, was
not
5
declining. Those two slides were
actually
6
presented to the advisory committee in 2000, and
7 for
those reasons it was determined to be important
8 to
increase the risk management for this drug
9
because the public health impact has remained
10
significant.
11
DR. KIBBE: So, your answer is no?
12
DR. LINDSTROM: Yes.
13
DR. GROSS: Dr. Bull?
14
DR. BULL: I just wanted to remind
you,
15
going back to the issue of computerized
16
prescriptions, that this whole risk management plan
17 is
predicated on a high level of interaction
18
between the patient and the healthcare provider.
19
These are non-refillable prescriptions.
The
20
patient has to return to the healthcare provider
21 for
an interaction, hopefully a face-to-face
22
evaluation of how the acne treatment is
67
1 progressing,
such that because of the fact that
2
these are not prescriptions that are automatically
3
refilled it is not a course of therapy where you
4 are
given a prescription that you renew for five
5
months. It is one where every month
during that
6
course of time there is a need to return to the
7
healthcare provider of record.
8
DR. GROSS: I am going to take the
9
prerogative of the chair and declare a break at
10
this particular time. We have no
breaks scheduled
11 for
the morning and I think we will hold questions
12
until a little bit later. Thank
you. We will
13
reconvene at 9:30.
14
[Brief recess]
15 Open Public Hearing
16
DR. GROSS: Both the Food and Drug
17
Administration and the public believe in a
18
transparent process for information gathering and
19
decision-making. To ensure such
transparency at
20 the
open public hearing session of the advisory
21 committee meeting, which we are about to
start, the
22 FDA
believes that it is important to understand the
68
1
context of an individual's presentation.
For this
2
reason, the FDA encourages you, the open public
3
hearing speaker, at the beginning of your written
4 or
oral statement to advise the committee of any
5
financial relationship that you may have with the
6
sponsors of any products in the pharmaceutical
7
category under discussion at today's meeting. For
8
example, the financial information may include the
9
sponsor's payment of your travel, lodging or other
10
expenses in connection with your attendance at the
11
meeting. Likewise, FDA encourages
you at the
12
beginning of your statement to advise the committee
13 if
you do not have any such financial
14
relationships. If you choose not
to address this
15
issue of financial relationships at the beginning
16 of
your statement it will not preclude you from
17
speaking.
18
We have two registered speakers for the
19
morning, Dr. Robert A. Silverman is first. Dr.
20
Silverman?
21
DR. SILVERMAN: Dr. Gross, members
of the
22
advisory committee, thank you for giving me the
69
1
opportunity to speak about the continued
2
availability of isotretinoin. My
statement will
3
focus on the benefits of this drug and the impact
4 of
pregnancy prevention risk management efforts on
5 its
availability to patients.
6
I have been practicing pediatric
7
dermatology for nearly two decades.
At first I was
8 in
Cleveland at Rainbow Babies and Children's
9
Hospital. Since 1989 I have
maintained a private
10
practice in Northern Virginia and a dermatology
11
clinic in the Department of Pediatrics at
12
Georgetown University. For the
record, I have not
13
participated in any pharmaceutical company
14
sponsored acne drug studies, nor am I taking any
15
reimbursement from the AADA, and the only thing I
16
have taken today is one bottle of water.
17
[Laughter]
18
I am a physician who treats patients, not
19 a
healthcare provider who sees clients. I
make the
20
distinction to emphasize the trust and close
21
relationship between a physician and patient that
22 is
necessary for obtaining the best results when
70
1
treating acne while minimizing side effects of any
2 of
the medications that we use. As a
pediatrician,
3 I
recognize the social and psychological impact
4 that an acne-scarred body image has on
teenagers.
5 I
know of no drug that has changed the lives of my
6
patients with acne more than isotretinoin. It has
7
been a Godsend to adolescents and to young adults
8
with recalcitrant, nodular, nodulocystic and
9
scarring disease.
10
Unlike dermatologists entering the medical
11
work force today, I remember how we used to treat
12
severe nodulocystic acne. One of
the most painful,
13
gruesome procedures that I learned in my training
14 at
the Children's Hospital in Boston was the
15
incision and drainage of multiple purulent
16
abscesses, like you saw earlier, on the faces of
17
young men and women afflicted with recalcitrant
18
nodulocystic acne. The procedure
is nearly a
19
historical footnote since we have the availability
20 of
isotretinoin.
21
There is not a week that goes by in my
22
practice that a concerned parent, with facial scars
71
1
themselves, brings in a preadolescent with minimal
2 or
no acne for anticipatory guidance in hopes of
3
their child avoiding the same fate that they had
4
when they were growing up. Of
course, the vast
5
majority of these children never-ever reach the
6
point of needing isotretinoin.
But for the few who
7
progress and require it, I am thankful that I have
8 the
option to use this medication. The
reason I am
9
here today is to keep this drug available to all
10
people who need it.
11
Let me share a story that perfectly
12
illustrates the wonders that can be worked by this
13
drug. In 1982, when I was in
Boston, the year that
14
isotretinoin first became available in the United
15
States, I met a beautiful young lady who had a
16
beautiful complexion. During that
year she
17
developed inflammatory acne that then rapidly
18
progressed to severe painful, nodulocystic disease.
19 She
was being cared for by an excellent
20
dermatologist at one of the nation's first and
21
premier HMOs. Minocycline,
benzoyl peroxides,
22
Retin-A and oral contraceptives made no difference
72
1 in
her appearance.
2
Isotretinoin was not widely prescribed and
3 it
was not until 1986 when she saw her fourth
4
dermatologist, after moving to Washington, D.C.,
5
that Accutane was offered to her.
The years
6
between 1982 and 1986 were for her filled with
7
anxiety and self-consciousness. I
know this
8
because this woman is now my wife.
She took
9
isotretinoin safely. She was
aware of the
10
teratogenic risks and used two forms of birth
11
control. We now have two healthy
boys who were
12
conceived well after my wife-to-be's finishing the
13
drug. This story is obviously
close to my heart
14 but
it also illustrates the fact that female
15 patients
of childbearing potential can and do use
16
isotretinoin safely.
17
I have treated many teenaged girls and
18
young women with isotretinoin. I
have personally
19
prescribed isotretinoin since 1986 and have used it
20 according
to the risk management guidelines with
21
utmost caution, and since the S.M.A.R.T. program
22 has
been in effect I have complied with it to the
73
1
best of my ability.
2
As a clinician in the trenches, I am
3
familiar with the difficulties and weaknesses that
4
were outlined that may impede optimal participation
5 in
the S.M.A.R.T. program. Complicating and
6
restricting access will only drive needy patients
7 to
obtain isotretinoin through illicit channels or
8
those that circumvent well-established
9
doctor-patient relationships.
This would be a
10
travesty of monumental proportions.
In grade
11
school I learned the acronym KIS--keep it simple.
12 The
more complicated you make the process of
13
obtaining this medication the more mistakes are
14
going to be made.
15
I would be happy to help in any way that I
16 can
to keep this medication available to all who
17
need it and to address the small, but unfortunate,
18
number of pregnancies that have occurred while on
19
this drug. Thank you for your
time and
20
consideration and I would be happy to entertain any
21 questions if we have a few seconds. Thank you.
22
DR. GROSS: Thank you very much,
Dr.
74
1
Silverman. The next speaker is
Dr. Sidney Wolfe of
2 the
Public Citizen's Health Research Group.
3
DR. WOLFE: Helping out in this
4
presentation is Dr. Sherri Shubin who is a
5
pediatrician and currently doing a preventive
6
medicine residency at Johns Hopkins.
She is
7
spending part of her residency with us.
8
[Slide]
9
I will take a minute or so to go over the
10
first couple of slides. Our
involvement really
11
started shortly after the drug came on the market
12 in
September of '83. We submitted a
petition
13
urging patient package inserts and black box
14
warnings about birth defects and life-threatening
15
adverse events. Prior to
approval, as many of you
16
know, there was a pretty comprehensive program to
17
make sure that no one who got the drug got
18
pregnant, and a number of those strictures were
19
dropped at the time of initial marketing and slowly
20
some of them were reintroduced.
21
On April 26, ADA testified before this
22
committee describing Accutane as an imminent public
75
1
health hazard and saying that unless certain
2
restrictions were imposed it should really come off
3 the
market. The restrictions are listed
there, one
4 of
the most important of which is, of course,
5
limiting prescribing to dermatologists who file
6
sworn affidavits stating they will adhere to the
7
stated indications for the drug.
That is supposed
8 to
be happening, not the sworn affidavit part but,
9
obviously the amount of prescriptions belies the
10
fact that that is what it is limited to.
We then
11
filed a petition to the FDA in May of 1988 with
12
recommendations, saying it should come off the
13
market and only be allowed back on with these
14
restrictions.
15
[Slide]
16
Just finishing up a little bit on that, we
17
continued urging removal from the market unless
18
restrictions were put in and, thus far, these
19
restrictions just have not been put in.
Most
20
recently, in September, 2000, we testified that at
21
that time the issue of depression and suicide had
22
arisen and again we proposed restrictions.
76
1
[Slide]
2
This is testimony before this committee by
3 Dr.
David Erickson, who was then Chief at the
4
Centers for Disease Control and Prevention of the
5
Genetics and Birth Control Branch.
His statements
6 are
very poignant because 15 years later the same
7
issue is there: "The birth of babies with defects
8
caused by fetal exposure to Accutane is
9
unnecessary. FDA decision to
allow the marketing
10 of
Accutane is a failed regulatory experiment. A
11
decision to depend on better contraception alone,
12
without active intervention to reduce the number of
13
users, is a decision to leave the number of
14
affected babies at an unacceptably high level."
15
Finally, one of his suggestions was, "perhaps a
16
formal IND," investigational new drug, "would be a
17
suitable mechanism to reduce the frequency of
18
Accutane embryopathy."
19
[Slide]
20
Now, these are data from the package that
21 was
provided to you a couple of weeks ago--it
22
should have been included. This
is an FDA
77
1
presentation before this committee back in
2
September of 2000. What they said
was that as of
3
that time these are just the reported cases and, as
4
several people said this morning and it understates
5 the
actual magnitude of the problem with 1,995
6
exposed pregnancies; 1,214 elective abortions; 383
7
live births; and 162 infants with birth defects.
8
[Slide]
9
These now are the more recent data from
10 the
first year of the S.M.A.R.T. program.
Again,
11 the
first two points are taken directly from the
12
package that was handed out and 156,800
13
"unique"--the phrase used in there--women were
14
given the drug. Secondly, the
estimated pregnancy
15
rate, and I am sure this is on the low side but
16
that is what was in this information set is 0.35
17
percent. If you take that rate
and apply it to the
18
number of "unique" women given the drug in that
19
first year it means that there have been 548
20
pregnancies and this is 4.6 times higher than the
21
voluntarily spontaneously reported pregnancies that
22 are
also listed in the package, which is a measure
78
1 of
the under-reporting.
2
[Slide]
3
Of the 61 pregnancies with known
4
outcomes--remember, about half of them had outcomes
5
unknown--48 of 61 or 78.7 percent resulted in
6
elective abortions. Again, if you
apply this to
7 the
more likely estimate of the actual number of
8
pregnancies, 548, this means that there would have
9
been 431 elective abortions in that one year ending
10 in
March of 2003.
11
[Slide]
12
Again estimating the number of deliveries,
13 of
61 pregnancies with known outcomes, 7 of 61 or
14
11.5 percent resulted in deliveries.
There were
15
some spontaneous abortions, and so forth that make
16 up
some of the other ones aside from the elective
17
abortions. Again, applying this
to the 548
18
estimated pregnancies, there would have been 63
19
deliveries. Using FDA's and the
CDC's figure,
20
which is probably on the low side, 25 percent birth
21
defects and the 50 percent mental retardation is as
22
close--there hasn't been any really careful study
79
1 on
it but applying those figures to this estimate,
2 we
are talking about 16 infants with birth defects
3 and 31 with mental retardation just in that
one
4
year.
5
[Slide]
6
The reason the S.M.A.R.T. program and even
7 the
new Roche proposal do not seriously address the
8 two
major issues here are as follows: In
1989 CDC
9
estimated that there were no more than 4,000 women
10 of
childbearing age with severe cystic acne.
They
11 did
not even get into the recalcitrant or other
12
therapy. Adjusted for population
growth because
13
these were 1987 data, the number may now be 6,000.
14
Given that there were 156,800 "unique" women of
15
childbearing age who got the drug in that first
16
year of S.M.A.R.T., this represents a 26-fold
17
excess in prescribing over the number of on-label
18
prescriptions.
19
The second point is that unless there is
20
something more than a sticker and an assurance but
21
there is actually the provision of a lab test
22
showing that the woman, in fact, was not pregnant
80
1 and
at least a description of the contraceptive
2
methods--unless that happens, then people are going
3 to
have stickers that are misrepresenting what has
4
actually happened.
5
[Slide]
6
The reason why we are about to file a
7
petition in the next week or two asking for this
8
drug to be taken off the market and made available
9
through an IND is that there have been 20 years of
10
failed voluntary and even more recently some
11
mandatory restrictions, and they have led to
12
actually a total of more pregnancy exposures
13
because the actual amount of prescriptions has gone
14
up. I think it was estimated in
'88 or '89 that
15
there may be 70,000 "unique" women of childbearing
16 age
getting the drug and it is now some 150,000.
17
As we recommended in '88 and the CDC
18
itself suggested as an option the next year, as I
19
showed you in Dr. Erickson's presentation, we now
20
propose a ban on marketing with subsequent
21
availability only under a tightly controlled IND as
22 the
only feasible way to significantly reduce
81
1
prescriptions and pregnancy exposures.
2
[Slide]
3
These would be the main elements of the
4
restrictions in an IND:
Photographic proof of
5
severe cystic acne confirmed by an independent
6
group of dermatologists. Digital
cameras make this
7
kind of process relatively easy to set up.
8
Secondly, a written record for each
9
patient that there, in fact, is adequate previous
10
treatment of the disease with antibiotics and other
11
treatments and that there is recalcitrance to it.
12
Third, a written statement of
13
contraceptive practices and provision of a copy of
14
this and a negative pregnancy test in order for the
15
drug to be dispensed each time.
16
[Slide]
17
In summary, the S.M.A.R.T. program is
18
clearly a failure. Without these
proposed IND
19
restrictions, this administration and this advisory
20
committee will continue to put its imprimatur on
21 the
reckless use of a drug that each year causes
22 the
need for hundreds of abortions and many
82
1
seriously deformed infants with birth defects
2 and/or mental retardation. This is one of the two
3
worst epidemics of preventable serious birth
4
defects ever seen in the U.S. I
would just point
5 out
the other one is two defects where there is
6
deficiency of folic acid, as you know.
The odds of
7
neural tube defects are a couple of orders of
8
magnitude lower than the odds of a birth defect
9
with a live birth. Of course, it
is different not
10 to
have enough folic acid as opposed to be
11
administering one of the more potent teratogens we
12
have ever seen. It is time to end
the more than 20
13
years of voluntary restrictions and some mandatory
14
ones that have failed to reduce its prescribing for
15
more than 20 times as many women as would be using
16 the
drug if it were limited to the approved
17
indications. Thank you. I would be glad to try
18 and
answer any questions.
19
DR. GROSS: Thank you very much,
Dr.
20
Wolfe. The final speaker in the
open public
21
hearing will be Dr. Sherri Shubin, who will read a
22
letter from Dr. Furberg, which is in your packet.
83
1
DR. SHUBIN: Thank you. I have no
2
financial conflicts of interest.
As a member of
3 the
public, I would like to read the statement that
4 was
written by Dr. Curt Furberg, a member of this
5
committee who could not be here today:
6
Due to an unexpected family health
7
problem, I will not be able to attend the upcoming
8
advisory committee meeting on Accutane risk
9
management. Based on long
observation and careful
10
study, I feel very strongly about this issue and
11
regret that I will not be there to express my views
12 and
participate in the committee's discussion and
13
deliberation. As a member of the
committee, I
14
would ask that the following be read aloud at the
15
meeting after all testimony has been presented but
16
before the committee begins its consideration and
17
discussion of the issue and the questions presented
18 it
by the agency.
19
To be candid, the history of Accutane is
20 an
example of inadequate and ineffective risk
21 management
by the FDA and the manufacturer of
22
Accutane to the detriment of thousands of women.
84
1
Examples are numerous. Although
Accutane was a
2
known animal teratogen and a suspected human
3
teratogen at the time of its approval, the company
4 did
not recommend and the FDA did not insist upon
5
labeling that emphasized the importance of
6
contraception or abstinence while under treatment
7 with
the drug. The consequences of this
omission
8
become more apparent when one understands that five
9
women became pregnant while taking Accutane during
10
pre-approval clinical trials despite following the
11
contraception requirements of the study.
12
In 1988, a highly publicized FDA advisory
13
committee meeting was held to discuss the high
14
level of pregnancy exposure to Accutane and the
15
overuse of the product and its contribution to the
16
pregnancy exposure problem. The
Pregnancy
17
Prevention Program, PPP, emerged following this
18
meeting as the primary means of managing Accutane's
19
teratogenic risks. Several
advisory committee
20
meetings were held to monitor the progress of the
21 PPP
between 1989 and 1991. It was clear from
these
22
meetings that the majority of women taking Accutane
85
1
were not volunteering to participate in the PPP,
2 that
even in the group that did volunteer pregnancy
3
testing was infrequently performed and that
4
pregnancy exposure to Accutane was still occurring
5 at
a high level.
6
Remarkably, no advisory committee meeting
7 on
the Accutane pregnancy exposure and the
8
performance of the PPP was convened until
9
September, 2000. At this meeting,
it was shown
10
that enrollment in the PPP was low and falling,
11
that pregnancy testing was still often not being
12 performed and that recommendations about
13
contraception or abstinence were often not adhered
14
to. Even more alarming, the use
of Accutane in
15
women had increased three-fold during the preceding
16
ten-year period when one would have expected it to
17
decline substantially because of successful
18
treatment of prevalent cases of severe nodular
19
acne. The committee's response to
this evidence
20 was
to declare the PPP a failure and to recommend
21
that a comprehensive risk management program that
22
included patient and physician registration, as
86
1
well as mandatory pregnancy testing, be
2
established. None of these has
been implemented.
3
Instead, the S.M.A.R.T. program was
4
introduced. It is an effort that
added yellow
5
stickers to the existing PPP, but had no means of
6
determining if pregnancy testing was actually
7
performed or of how many pregnancy exposures
8
actually occurred. Unfortunately,
S.M.A.R.T. had
9 the
same basic design limitations as the PPP and
10
this should have been recognized.
Now, after
11
almost four years and thousands more of unnecessary
12 pregnancy
exposures to Accutane, this committee is
13
once again asked to advise the FDA.
14
Simply put, I believe that the system is
15 not
safe and cannot be used in a safe manner.
To
16
minimize the number of pregnancy exposures to
17
isotretinoin an IND-like process could be
18
implemented that ensures universal pregnancy
19
testing, registration of all pregnancy test results
20 and
incorporates a mechanism whereby the drug
21
cannot be dispensed without a negative pregnancy
22
test. This coupling of a negative
pregnancy test
87
1
with dispensing of the drug would be analogous to
2 the
policy that has been successfully employed with
3 the
antipsychotic clozapine and has been summarized
4 as
"no blood, no drug." An added
benefit of such
5 an
approach would be that we would have more
6
accurate information regarding the actual number of
7
pregnancy exposures to the drug.
The numbers we
8
have now, coming from a relatively small and
9
self-selected group of volunteers, is undoubtedly a
10
gross underestimate of reality.
11
Other features of this IND-like approach
12
could include limiting the number of
13
isotretinoin-dispensing centers, mandatory
14
pregnancy avoidance counseling at each visit and
15 the
proviso that dispensing centers would be
16
audited periodically. An
important objective of
17 our
risk management should be to reduce the overuse
18 of
isotretinoin. Therefore, I would
recommend that
19 the
IND-like process I have briefly described
20
include some means of documenting the presence of
21
severe nodular acne in patients being considered
22 for
isotretinoin treatment. In clinical
trials for
88
1 the
approval of Accutane only patients with severe
2
cystic acne were enrolled, and photographs of at
3
least some of these patients were taken and used in
4
advertisements and at professional meetings.
5
Perhaps a photograph, documenting the patient's
6
severe cystic acne, could be required prior to
7
approval for treatment.
8 The S.T.E.P.S. program for
thalidomide has
9
been talked about as a possible model for
10
isotretinoin risk management, but it would not be
11
adequate. If my understanding is
correct, there is
12
actually no current coupling of a negative
13
pregnancy test with dispensing of the drug and
14
there is no central registry of the pregnancy test
15
results. Under this system,
thalidomide
16
prescribers answer several questions over the
17
telephone in response to automated prompts in order
18 to
receive a number authorizing use of the drug for
19 the
next month. This system is very similar
to the
20
yellow sticker system under S.M.A.R.T. in that it
21
relies on prescriber self-attestation.
There is no
22
validation that what the prescriber has answered is
89
1
true and there is no comprehensive or reliable
2
means of knowing how many pregnancy exposures have
3 occurred.
4
The occurrence of pregnancy exposures with
5 the
original Accutane pre-approval clinical trials
6
and, more recently, within a clinical trial for
7
another formulation of isotretinoin raises an
8
uncomfortable question, should this drug have ever
9
been released on the open market?
I think it was
10 and
is unethical to allow isotretinoin to be
11
available for use outside of the protections that
12
would be afforded by a controlled and documentable
13
process of distribution.
14
I do have copies of this statement for
15
anyone who would like one.
16
DR. GROSS: Yes, there are copies
of the
17
statement in the committee's folders.
Thank you
18
very much, Dr. Shubin. Shalini
Jain has a comment
19 she
would like to make now.
20
MS. JAIN: I just want to make a
comment
21 for
a point of clarification with regards to Dr.
22
Furberg's letter. Dr. Shubin was
reading the
90
1
letter on behalf of Dr. Furberg.
In functioning as
2 an
FDA committee member representative, he has not
3
been cleared for this meeting for purposes of
4
conflict of interest but solely as a representative
5 of
the public today. Thank you.
6
DR. GROSS: Thank you. We will now move
7 on
to the next set of presentations. From
8
Hoffmann-La Roche, Joanna Waugh, Group Director for
9
Regulatory Affairs, is first; Dr. Martin Huber,
10
Vice President, Global Head, Drug Safety Risk
11
Management; and Dr. Susan Ackermann Shiff, Global
12
Head, Risk Management, Drug Safety Risk Management.
13
Hoffmann-La Roche, Inc. Presentations
14 Introduction
15
MS. WAUGH: Good morning.
16
[Slide]
17
I am Joanna Waugh, from the Regulatory
18
Affairs Department at Hoffmann-La Roche, Nutley,
19 New
Jersey. Thank you to the FDA and the
committee
20 for
giving us the opportunity to present today.
21
[Slide]
22
What I would like to do first is to just
91
1
give you an overview of the framework of our
2
presentation today. Having heard
the FDA
3
presentation, there is some overlap with our
4
presentation so we will go fairly rapidly through
5
some of the areas where there is duplication.
6 Following myself, Dr. Martin Huber
will
7
provide a brief overview of the risk/benefit
8
profile for isotretinoin. I will
then briefly
9
summarize a regulatory overview, focusing on risk
10
management milestones for Accutane since its launch
11 in
the U.S. in 1982. Dr. Susan Ackermann
Shiff
12
will then provide an overview of the S.M.A.R.T.
13
program, comprising a description of what that
14
program entails, as well as an assessment of some
15 of
the data with particular reference to metrics
16
which were predetermined in agreement with FDA.
17 Dr.
Martin Huber will then review the pregnancy
18
data from the S.M.A.R.T. program and move on to
19
discuss our recommendations for program
20 modification.
21
[Slide]
22
In addition to the team of presenters
92
1
which are listed on the left-hand side of this
2
slide, Roche does also have available, for
3
responding to questions in the question and answer
4
session, some additional colleagues, Miss Kay Bess
5
from our Drug Safety Risk Management Department,
6 Dr.
Karen Blesch, from the same department, Miss
7
Tammy Reilly, Vice President of Dermatology and
8
Oncology, and Dr. Susan Sacks, from the Drug Safety
9
Risk Management Department.
10
[Slide]
11
Additionally, we have available the
12
following outside experts for responding to
13
questions, Dr. Diane Berson, from Cornell
14
University; Dr. Judith Jones, from the Degge Group;
15 and
Dr. Victor Strecher, from the University of
16
Michigan School of Public Health.
17
[Slide]
18
As this slide shows and was referred to by
19 the
FDA in their presentation, the S.M.A.R.T. risk
20
management program was approved in 2001 and it was
21
subsequently implemented early in 2002.
Since 2002
22
generic isotretinoin has also been available on the
93
1
U.S. marketplace and this slide shows the
2
respective manufacturers' products and risk
3
management programs, which are all equivalent to
4 the
Accutane S.M.A.R.T. risk management program.
5
[Slide]
6
The conditions for the approval of the
7
S.M.A.R.T. risk management program included the
8
requirement to develop a backup program for a
9
mandatory registry, as well as the understanding
10
that a follow-up advisory committee would be
11
convened when more data was available to discuss
12 the
effectiveness of the program, which is why we
13 are
here today. When more data was
available,
14
Roche evaluated that data and developed a specific
15
proposal for program enhancement based on the data
16 we
saw emerging.
17
[Slide]
18
In December of 2003, the FDA, Roche and
19 the
generic companies reviewed the data across our
20
respective risk management programs.
Roche and the
21
generic companies subsequently worked together on
22
recommendations for program modification. All
94
1
companies agree on the need for one single program
2 and
the recommendation that you will hear put
3
forward today is generally agreed to by all the
4
companies. The details of the
implementation
5
require some further refinement and discussion and
6 we
look forward to the discussion from the advisory
7
committee today on the proposal that we will put
8
forward to you.
9
I will now hand over to Dr. Martin Huber.
10 Benefit/Risk
11
DR. HUBER: Good morning.
12
[Slide]
13
What I would like to briefly review for
14 you
is the benefit/risk. As a first step in
any
15
risk management approach there needs to be an
16
assessment of both the benefit and the risk that we
17 are
addressing.
18
[Slide]
19
Just to remind you, isotretinoin is
20
indicated for severe recalcitrant nodular acne. It
21 is
indicated only for patients who are unresponsive
22 to
conventional therapy, including systemic
95
1
antibiotics. Finally, it is
indicated only for
2
those females who are not pregnant and agree to not
3
become pregnant.
4
[Slide]
5
The medical need for isotretinoin is
6
because it is a serious disease with profound
7
consequences. Inadequately
treated severe
8
recalcitrant nodular acne can lead to disfiguring
9
scarring. Fortunately, it is a
uniquely
10
efficacious therapy for this condition and there
11 are
currently no alternative therapies for these
12
patients.
13
[Slide]
14
To briefly remind you, this is the
15 concern.
Inadequately treated SRNA can lead to
16
disfiguring scarring which is life-long.
17
[Slide]
18
However, there is a specific challenge for
19
isotretinoin, as has been indicated by the previous
20
speakers. Isotretinoin is known
to be a human
21
teratogen. The majority of the
female patients who
22 use
this drug are of childbearing potential.
96
1
Therefore, pregnancy prevention measures, including
2
proactive risk management, are essential. But the
3
specific challenge of this program is that we must
4
change the behavior of patients in order to have
5
them comply better with these risk management
6 programs.
7
[Slide]
8
The public health goals, as previously
9
stated, remain the same. Our
vision is that no
10
woman who is pregnant should receive isotretinoin
11
therapy; no woman should become pregnant during or
12 for
one month after receiving isotretinoin therapy.
13
[Slide]
14
I will now turn it over to Miss Waugh who
15
will review the regulatory history and the risk
16
management program to date.
17
Regulatory Overview
18
[Slide]
19
MS. WAUGH: The teratogenic risk
of
20
Accutane has been known since the approval of the
21
drug in 1982 in the U.S. Because
of this known
22
risk, we have taken a variety of risk management
97
1
steps throughout the product life cycle with the
2 aim
of reducing pregnancies as far as possible.
3 The
proposed program that you will hear today
4
includes risk management enhancements in response
5 to
data that we have seen in the S.M.A.R.T. risk
6
management program.
7
[Slide]
8
This slide provides an overview of some
9
examples of steps Roche has taken throughout the
10
product life cycle to minimize pregnancies. Since
11
product launch in 1982, the product had a pregnancy
12
category X, i.e., it was contraindicated in
13
pregnant women. In 1984 a black
box warning was
14
introduced to increase the prominence of warnings
15
surrounding pregnancy.
16
In 1988 the Pregnancy Prevention Program
17 was
introduced which FDA alluded to in the earlier
18
presentation. This was the first
risk management
19 program
of its kind which used mechanisms over and
20
above labeling as tools for risk management. Some
21
components of the Pregnancy Prevention Program are
22
listed on this slide and I will just go through
98
1
them briefly, the requirement for two forms of
2
contraception to be used simultaneously for one
3
month before, during and after Accutane treatment.
4
Additionally, the requirement for negative monthly
5
pregnancy testing; the addition of an "avoid
6
pregnancy" symbol in the packaging.
Educational
7
materials were introduced regarding contraceptives
8 and
pregnancy avoidance, and a female informed
9
consent form was introduced.
10
Further evaluation tools to assess the
11
effectiveness of this program were introduced which
12
included the Accutane survey.
This survey was
13
developed by the Slone Epidemiology Center at
14
Boston University and provided information about
15
women's understanding of the risk issues related to
16
teratogenicity, as well as some information about
17 the
pregnancy rate based on the number of women
18
enrolled in the survey.
19
[Slide]
20
in 1990 we added information to the U.S.
21
product information concerning a description of
22
birth defects that could occur, as well as a
99
1
recommendation that prescribing should be limited
2 to
a one-month supply.
3
In 1994 the patient informed consent form
4 was
updated to include additional requirements.
In
5 May
of 2000, amongst additional requirements, one
6 of
the requirements was to have two negative
7
pregnancy tests prior to the initial prescription.
8
In September of 2000, as has been
9
mentioned earlier, an advisory committee was
10
convened which discussed pregnancy prevention. I
11 will come back to that in a little bit more
detail
12
later. Subsequent to that
advisory committee,
13
Roche worked in collaboration with the FDA to
14
determine how best to implement their
15
recommendations. The result of
these discussions
16 was
the ultimate approval for the S.M.A.R.T. risk
17
management program in October, 2001.
18
[Slide]
19
As I mentioned, the 2000 advisory
20
committee discussed pregnancy prevention. The
21
recommendations from that advisory committee, as
22
mentioned by the FDA, included the recommendation
100
1 for
the introduction of patient and prescriber
2
registry. In subsequent discussions
with the
3
agency, Roche put forward various proposals which
4
included mandatory patient and prescriber
5
registration. In discussions with
the agency about
6 the
best way to implement these recommendations and
7 in
view of some of the issues that FDA alluded to
8
earlier, Roche and FDA agreed that the critical
9
issue was to link a negative pregnancy test with
10
each prescription and dispensing of Accutane.
11
[Slide]
12
The S.M.A.R.T. program introduced a link
13
between dispensing and negative pregnancy testing
14 via
the Accutane qualification sticker.
15
Additionally, the S.M.A.R.T. program included
16
enhanced education, enhanced informed consent, and
17 the
requirement for prescribers who wish to
18
prescribe Accutane to be registered into a
19
database.
20
[Slide]
21
Dr. Susan Ackermann Shiff will now provide
22
more details about the S.M.A.R.T. program.
101
1 Overview of the S.M.A.R.T.
Program
2
DR. ACKERMANN SHIFF: Thank you.
3
[Slide]
4
What I would now like to briefly do is
5
overview the S.M.A.R.T. program or the System to
6
Manage Accutane-Related Teratogenicity.
The
7
program was developed with and approved by the FDA,
8 and
went into effect on April 10 of 2002.
9
[Slide]
10
This high level overview slide provides
11 two
important features, first that the registered,
12
qualified physician, the qualified patient and the
13
pharmacist work together in the dispensing of the
14
product. Second, the
qualification sticker is the
15 one
area where the negative pregnancy test and the
16
dispensing of the product is linked.
17
[Slide]
18
Different from the Pregnancy Prevention
19
Program, all prescribers must be enrolled in the
20
program in order to prescribe the product. A
21
prescriber will read the guide to best practices,
22
sign a letter of understanding and receive the
102
1
qualification stickers.
2
[Slide]
3
When the prescriber signs the letter of
4
understanding they attest to the fact that they
5
know the risk and severity of fetal injury and
6
birth defects; that they know how to diagnose and
7
treat various forms of acne; that they know the
8
risk factors of unplanned pregnancy and they will
9
properly follow the S.M.A.R.T. procedures. In this
10
case, it includes education, pregnancy testing,
11
contraception, informed consent and offering of the
12
Accutane survey.
13
[Slide]
14
Once the prescriber has been registered
15
within the system, they can educate the patient on
16 the
appropriate use of the product. The
"Be Smart,
17 Be
Safe, Be Sure" educational brochure that is
18
shown on this slide contains elements of education
19
about the product; contraceptive information; the
20 two
informed consents, the all-patient informed
21
consent and the female patient informed consent; an
22
enrollment card for the Accutane survey; and
103
1
educational reinforcement. The
purpose of this
2
brochure is that it be used at the initial office
3 visit
and all subsequent office visits.
4
[Slide]
5
As Roche understands that patients learn
6 in
different ways, we have also provided a variety
7 of
other educational materials. There are
story
8
boards in both English and Spanish and two
9
educational videos, one about contraception and one
10
about the risks of unplanned pregnancy.
There are
11 two
1-800 lines, one for Accutane information and
12 one
for contraception. In addition, there is
an
13
"avoid" blister pack pregnancy symbol and a
14
medication guide that is now packaged in the
15
blister pack that has information about the product
16 and
is patient friendly.
17
[Slide]
18
There is also a patient education brochure
19 for
men that contains product information, informed
20
consent and educational reinforcement.
21
[Slide]
22
The qualification sticker signifies that
104
1
there is a qualification date that, in this case,
2 is
the date of the last negative pregnancy test,
3 not
the date that the pregnancy test was received.
4 The
pharmacist must dispense within seven days of
5 the
qualification date and can't dispense more than
6 a
30-day supply. No refills are
allowed. Both
7
males and females have a qualification sticker
8
attached to their prescription.
9
[Slide]
10
The qualification criteria or what the
11
sticker represents on actual presentation is that
12 the
female patient has had the negative pregnancy
13
testing, two at the start of therapy and one every
14
month during therapy. In
addition, she has
15
selected and committed to use two safe and
16
effective forms of contraception.
She has signed
17
all-patient informed consent and the female
18
informed consent, and has been offered the
19
opportunity to participate in the Accutane survey
20 and
knows of its importance.
21
[Slide]
22
Again, the qualification sticker is the
105
1
actual sticker that links the dispensing of the
2 product with the negative pregnancy test. The
3
pharmacist will allow no more than a 30-day supply;
4
will dispense within seven days of the
5
qualification date or the date of the last negative
6
pregnancy test; and no refills are allowed. In
7
addition, no telephone, computerized or mail order
8
prescriptions are allowed. The
pharmacist also has
9 the
opportunity to verify that the physician has
10
been entered into the system by calling a 1-800
11
number.
12
[Slide]
13
What I would like to do now is to review
14 the
data from S.M.A.R.T. year one, or April 1 of
15
2002 through March 31, 2003. In
some cases I will
16 be
comparing these data to the year previous to
17 S.M.A.R.T. or the last year of the Pregnancy
18
Prevention Program which is April 1, 2001 through
19
March 31, 2002.
20
[Slide]
21
We used three specific data sources to
22
evaluate the S.M.A.R.T. program in year one. The
106
1
first is the prescription compliance survey; the
2
second, the Accutane survey; and, three, pregnancy
3
reports. I will be reviewing the
first two data
4 sources
and Dr. Huber will be reviewing the
5
pregnancy reports in addition to the corresponding
6
failure analyses.
7
[Slide]
8
The prescription compliance survey is a
9
quarterly survey of a random sample of pharmacies
10
pertaining to the use and completion of the
11
qualification stickers. In
addition, Roche
12
conducted a quarterly audit of anonymous Accutane
13
prescriptions from a random sample of these
14
participating pharmacies. While I
will not be
15
discussing the quarterly audit, what I can say is
16
that the results are consistent with the quarterly
17
sample of the random sample of pharmacies.
18
[Slide]
19
There is one major objective of the
20
prescription compliance survey, that is, to assess
21
prescribers' and dispensing pharmacists' compliance
22
with the appropriate use of the qualification
107
1
sticker.
2
[Slide]
3
During our discussions with the FDA, we
4 had
decided on two specific sets of metrics with
5
regard to the prescription compliance survey. The
6
first is that by the end of S.M.A.R.T. year one 90
7
percent of all physicians would use the
8
qualification stickers. The
secondary metrics
9
included that 90 percent of all physicians would
10
completely and correctly fill out the stickers, and
11
that 90 percent of all prescriptions would be
12
dispensed with a medication guide.
In October of
13
2002 Roche started packaging the medication guides
14
within the blister packs so the secondary metric is
15 no
longer applicable.
16
[Slide]
17
The results of the
prescription compliance
18
survey are as follows: Over the
six waves of the
19
survey an average of 97 percent of all
20
prescriptions had a qualification sticker affixed.
21 Of
those, 96 percent were correctly or completely
22
completed. There were no
differences between the
108
1
survey waves and there were no differences between
2 the
age of patient, the gender of patient, the
3 location
of the dispensing of the prescription or
4 the
payer type. In conclusion, we have met
and
5
exceeded our metrics for stickers and the mechanics
6 of
the stickers are working well. [Slide]
7
Now I would like to review some of the
8
high-level results from the Accutane survey.
9
[Slide]
10
As Ms. Waugh noted previously, the
11
Accutane survey was developed by Slone Epidemiology
12
Center of the Boston University School of Public
13
Health. It was initially
implemented with the
14
Pregnancy Prevention Program in 1989 and, to date,
15
Roche has had two vendors for the survey. From
16
1989 to the presentation of these data, Slone
17
Epidemiology Center was our primary research
18
organization. In October, 2002 we
switched
19
research organizations to SI International and the
20
Degge Group.
21
While I won't go into detail about the
22
methodology of the survey, and I know that Dr.
109
1
Mitchell is presenting later, what I do want to
2
note is that there are two specific arms within the
3
Accutane survey, the Accutane after treatment arm
4 and
the during and after treatment arm. The
5
presentation of these data deal only with the
6
during and after treatment arm.
In addition, I
7
would also like to note that the research
8
organization SI/Degge did implement the
9
questionnaire that was modified to include
10
components of S.M.A.R.T.
11
[Slide]
12
There are four specific objectives of the
13
Accutane survey. It was a
voluntary survey to
14
determine female patient awareness of the
15
teratogenic risks of Accutane. In
addition, it is
16
used to measure compliance with key components of
17
S.M.A.R.T., in this case informed consent, the
18
medication guide, pregnancy testing, contraceptive
19 use
and the qualification sticker.
Historically,
20 we
have used data from the Slone Epidemiology
21
Center to calculate a rate of pregnancy among
22
female Accutane users and to identify risk factors
110
1
that occur with pregnancy.
2
[Slide]
3
Again, during our discussions with the FDA
4 we
had agreed upon a variety of primary and
5
secondary metrics, the primary metric being that 60
6
percent of all women would enroll in the Accutane
7
survey by the end of S.M.A.R.T. year one. We have
8
several data specific secondary metrics including
9
female patient representativeness; recall of
10
qualification sticker; recall of pregnancy test;
11
medication guide; the use of two forms of safe and
12
effective forms of contraception; and enrollment in
13 the
Accutane survey via the prescriber's office,
14
from the blister pack or by calling a toll-free
15
number.
16
[Slide]
17
Before I go on to specific review of the
18
data, I would like to give you a high-level
19
overview of our findings. We were
successful in
20
increasing enrollment in the Accutane survey by
21
approximately 10 percentage points but missed the
22 60
percent metric.
111
1
We found that females recalled the use of
2 the
qualification sticker and that percentage was
3 almost
100 percent. In addition, almost 100
4
percent of all women knew the risks of taking
5
Accutane while pregnant and were told to avoid
6
pregnancy during Accutane.
However, they did not
7
receive the pregnancy testing or were not using
8
contraception according to the package insert.
9
With regard to the enrollment rate, we
10
calculated an enrollment rate by dividing the
11
number of enrollees by the number of new patient
12
female starts. The result for the
first year of
13
S.M.A.R.T. is 28.2 percent of enrollment of all
14
female Accutane users, which was up from 17 percent
15 in
pre-S.M.A.R.T. year one. While, again,
we
16
increased the enrollment rate, we did not succeed
17 in
meeting the 60 percent metric.
18
[Slide]
19
However, when you look at the method of
20
enrollment, we were very successful in shifting the
21
method of enrollment from the blister pack to the
22
physician's office. Again, if you
remember, the
112
1
enrollment card is within the "Be Smart, Be Safe,
2 Be
sure" educational brochure and we see this as a
3
marker that education was occurring within the
4
physician's office.
5
[Slide]
6
When we asked females at the start of
7
therapy what might Accutane do if it is taken
8
during pregnancy, and did your doctor tell you the
9
importance of avoiding pregnancy while on Accutane,
10
almost 100 percent of all women indicated that it
11
causes birth defects and that their physician told
12
them the importance of avoiding pregnancy while on
13
Accutane.
14
[Slide]
15 However, when we look at two
important
16
components of the S.M.A.R.T. program, pregnancy
17
testing and contraceptive compliance, we found that
18
only 64 percent of all women at the start of
19
treatment indicated that they had received two
20
pregnancy tests. We were
successful in reducing
21 the
women that reported no pregnancy tests from 18
22
percent to approximately 9 percent, but a large
113
1
proportion of women did not receive the pregnancy
2
testing according to the package insert.
3
[Slide]
4
When we looked at the risk category at the
5
start of treatment, we found that 50 percent of all
6 women
were not sexually active but 44 percent of
7 all
women reported some sort of sexual activity.
8
[Slide]
9
When we looked at sexual activity by use
10 of
two forms of contraception, we found that 41
11
percent of these women indicated that they were not
12
using two safe and effective forms of contraception
13 at
the start of their treatment.
14
[Slide]
15
When we looked at non-compliance with
16
contraception by age, we noticed that females 12-19
17
reported the highest percent of not sexual
18
activity. However, women 20-29,
30-39 and 40-44
19 who
were sexually active reported high levels of
20 not
using two forms of contraception, 20 percent,
21 35
percent and 40 percent respectively.
22
[Slide]
114
1
We noted previously from the prescription
2
compliance survey that a large percentage of
3
prescriptions had the sticker affixed.
In this
4
case, the percentage is similar, 97 percent of all
5
women indicated that a qualification sticker was
6
affixed to their prescription.
However, when we
7
asked them about baseline pregnancy testing,
8
receipt of two or more pregnancy tests and sexual
9
activity by using two safe and effective forms of
10
contraception, the percentages were no different
11
between those women who reported a qualification
12
sticker affixed to their prescription and those
13
women who did not. In fact, when
we look at the 22
14
cases of pregnancy, 20 of those cases of pregnancy
15
occurred in women who claimed to have a
16
qualification sticker attached to their
17
prescription.
18
[Slide]
19
Further, when we looked at these same data
20
during treatment, 21 percent of all women during
21
treatment indicated that they had not received a
22
pregnancy test. Only 63 percent
of these women
115
1
indicated that they had received two or more
2
pregnancy tests. Again, during
this time in the
3
course of their treatment they should have received
4 at
least three pregnancy tests.
5
[Slide]
6
Forty percent of all women indicated they
7
were sexually active during treatment.
However, 52
8
percent of these women indicated that during
9
treatment they were not using two safe and
10
effective forms of contraception as outlined in the
11
S.M.A.R.T. materials.
12
[Slide]
13
However again, we found that almost 100
14
percent of all women said that they had seen a
15
qualification sticker on their prescription during
16 the
course of their treatment.
17
[Slide]
18
In summary, we believe we were successful
19 in
increasing the enrollment of the Accutane survey
20 by
10 percentage points, however, we did not meet
21 the
60 percent metric set out. We increased
the
22
proportion of patients enrolling vis-a-vis the
116
1
prescriber's office. For us, that
was an
2 indication
that education is occurring within the
3
prescriber's office. And, we
believe that the
4
mechanics of the sticker are working well.
5
[Slide]
6
In addition, from the percentages in the
7
Accutane survey, women do understand the need to
8
avoid pregnancy and the consequences of becoming
9
pregnant while on Accutane.
However, there was
10
incomplete compliance with both pregnancy testing
11 and
with contraception. In fact, we found little
12
relationship between the qualification sticker,
13
pregnancy testing and contraception.
14
[Slide]
15
Dr. Huber?
16 Evaluation of S.M.A.R.T.
Program
17
[Slide]
18
DR. HUBER: I would now like to
briefly
19
review the pregnancy case reports that we have
20
received at Roche and put them in perspective--as
21 Dr.
Crawford was asking earlier, the case value
22
analysis basically.
117
1
[Slide]
2
First, I would like to go briefly through
3 the
methodology. These reports come from
multiple
4
sources. These are exposed
pregnancies that are
5
reported via either of the vendors for the Accutane
6
survey or via spontaneous reports from healthcare
7
professionals or consumers.
8
[Slide]
9
In order to compare the pregnancy numbers
10
from S.M.A.R.T. and the pre-S.M.A.R.T. year we set
11 up
the following metrics so that the numbers would
12 be
somewhat comparable. What we refer to
here as
13
pre-S.M.A.R.T. is that treatment was started so
14
isotretinoin or Accutane was started between April
15 1,
2001 to March 31, 2002. But, because
there are
16
delays in receiving some of these reports, we
17
allowed that the report was received by August 15,
18
2002. The S.M.A.R.T. data is
essentially these
19
same definitions but one year later.
20
The other issue we have to deal with in
21 the
analysis of these data is that there are
22
numerous reports that come in, in which there is no
118
1 therapy
date stated on the report. We don't know
2
when the therapy started. In
fact, when you review
3
these, in some of these it is fairly explicit that
4 the
therapy was years ago. So, we include
this
5
category of therapy start dates unknown and,
6
because we don't have a therapy start date, we
7
assign them to the period in which the report was
8
received.
9
[Slide]
10
To give some context to these
11
reports--there have been numerous questions about
12
rates, etc.--what I would like to do is remind you
13 of
the overall use of the product. First,
the
14
majority of these reports are from spontaneous
15
reporting sources, not from the survey.
Also,
16
overall Accutane use has been declining since 2000.
17 I
would like to focus on the estimated number of
18
females treated. This is female
patients in total,
19 not
just childbearing, and this is Accutane.
So,
20 you
see 278,000, 253,000, 218,000. I would
like to
21
note that generics were introduced in 2002. So,
22
when you see 2003 here, the 128,000 reflects purely
119
1 the
Accutane, not isotretinoin, data.
2
[Slide]
3
These are the pregnancy case reports we
4
have received according to the cut-offs I defined
5
earlier. For pre-S.M.A.R.T. there
was a total
6
number of 150 pregnancies; for S.M.A.R.T., 183. If
7 we
focus on those in which there is a treatment
8
initiation date known to occur in the period, it is
9
essentially 94 and 94. Where the
biggest increase
10 has
been is in this group of patients, these 89
11
with treatment initiation date unknown.
I will go
12
into a little more explanation of why we think this
13
occurred in the next few slides.
14
[Slide]
15
We think it is unlikely that the true
16
number of pregnancy case reports is a true
17
increase. In other words, we
don't believe it is
18
possible that an increased educational program,
19
with increased monitoring and with the
20
qualification sticker actually led to more exposed
21
pregnancies. Rather, as has been
noted by several
22 of
the previous speakers, in a spontaneous
120
1
environment there is a percentage of reports that
2 you
receive and a percentage you don't know about.
3 We
believe that this is most likely what is
4
occurring here and that with the first year of
5
S.M.A.R.T. we have actually seen an increased
6
proportion of reporting.
7
Why did that occur? Of note,
there was
8
increased awareness among physicians with
9
S.M.A.R.T. There was also, as Dr.
Ackermann noted,
10
increased participation in the survey.
Finally,
11
there is increased education and awareness among
12
patients.
13
[Slide]
14
To go through the details of these cases
15
now, I will start with what is the source of these
16
reports. We follow the convention
of this in
17
pre-S.M.A.R.T. with a known therapy start date;
18
S.M.A.R.T. with a known therapy start date; this is
19
pre-S.M.A.R.T. and S.M.A.R.T. with an unknown
20
therapy start date cases. This
bottom color here
21 is
those cases that came in via the Accutane survey
22
from either vendor. The green is
direct to Roche
121
1
from a healthcare professional.
This orange is
2
direct to Roche from consumers or others.
3
What you see here is that the most
4
substantial increase in number of pregnancy reports
5 is
this 10 to 33 in association with the Accutane
6
survey. Also consistent with
increased awareness
7
from consumers, while we didn't see an increase
8
here, what we did see was a substantial increase
9
from 19 to 30 of these cases coming to Roche from
10
consumers that had this unknown therapy start date.
11
[Slide]
12
When we start looking at this, as has been
13
noted, there are really two issues here.
There are
14
those patients who are pregnant prior to starting
15
Accutane therapy and then those patients who become
16
pregnant on Accutane therapy.
These data try to
17
break this down. We looked
specifically at the
18
patients who were pregnant prior to starting
19
Accutane therapy. For the
pre-S.M.A.R.T., of the
20 150
pregnancies, 28 or 19 percent occurred in the
21
pre-S.M.A.R.T. year; S.M.A.R.T. year one, 24 of 183
22 or
13 percent occurred prior starting Accutane
122
1
therapy. If we look at the number
that became
2
pregnant while on Accutane therapy, 51 percent, 41
3
percent with approximately the same numbers.
4
Patients becoming pregnant within 30 days after
5
stopping, 44 or 29 percent, 58 and 31 percent. The
6
biggest increase is in this unknown category but,
7 as
I stated earlier, this does include a large
8
number of cases that had unknown treatment
9
initiation and they also had unknown pregnancy
10
date.
11
[Slide]
12
Looking at the demographics of these
13
patients, these are the same patients, 153
14
S.M.A.R.T., 183 S.M.A.R.T., broken down by age. Of
15
note, when you look at the 16-19 group or from
16
19-29, 12-15 percent. What is
interesting is the
17 age
group 20-29 declined from 41 percent to 24
18
percent but please note that 20-29 remains the
19
largest category of patients, and 30-39 is
20
essentially similar, 16 and almost 15 percent and
21
once again a large number of unknown in S.M.A.R.T.
22
year one. The mean or median did
not shift
123
1
significantly.
2
[Slide]
3
Now coming to why are these people getting
4
pregnant, we looked for evidence of educational and
5
compliance understanding of patients.
These are
6 not
a linkage of survey data to these case reports.
7
Rather, this information is gathered as part of our
8
follow-up procedure for the pregnancy case reports.
9
The green is yes, the orange is no and the
10
light, pale color here is unknown.
What I would
11
like to do is focus on the signed female informed
12
consent, received a spiral notebook and enrolled in
13 the
Accutane survey. The axis here is the
number
14 of
pregnancy case reports that qualified for each
15
category. These are now the
S.M.A.R.T. year one
16 cases only.
17
What we see here is that only three
18
patients stated no to recall of a signed female
19
informed consent. Only five
patients stated no to
20
receiving a spiral notebook and this is in the
21
group that is our worst outcome group in that they
22 got
exposed pregnancy, and seven said no to
124
1
enrolling in the survey. So, of
those that
2
answered, the interpretation of the data is they
3 are
getting the educational materials. This
is
4
also consistent with what Dr. Ackermann talked
5
about in the survey where 99 percent of the
6
patients know they are not supposed to get
7
pregnant. They do receive the educational
8
materials.
9
[Slide]
10
The problem, as we see it, is linking it
11 to
compliance with the behaviors in the program.
12
Using the same format, this is once again
13
S.M.A.R.T. year one, the number of pregnancy case
14
reports are on this axis, two baseline pregnancy
15
tests, monthly follow-up pregnancy tests, used two
16
forms of contraception, and was the qualification
17
sticker attached.
18
I will start on the right first and 58
19
versus zero recalled the qualification sticker and
20
this is among the patients who became pregnant.
21
What is most disturbing is that 16 said no to the
22
question of baseline pregnancy tests; 8 said no to
125
1
monthly follow-up pregnancy tests; and 6 said no to
2
using two 2 forms of contraception.
So, what we
3
detect in this data is a pattern of failure to
4
comply with the educational materials that they
5
received.
6
[Slide]
7
I would like to review briefly the methods
8 of
contraception in these cases. Now we are
9
pre-S.M.A.R.T. and S.M.A.R.T. and these were
10
focusing on the 94 with the known start date in
11
both groups. Of note, 10 were
pre-S.M.A.R.T.; 11
12 of
S.M.A.R.T. were using abstinence as a primary
13
method of contraception. Of note,
of these 11
14
cases that reported abstinence, 4 did report
15 additionally
using condoms.
16
For the two forms of contraception, 17
17
pre-S.M.A.R.T., which increased dramatically to 30
18 in
the S.M.A.R.T. reports, reported using two
19
forms, one primary and one secondary.
No one
20 reported
in either year using two forms of
21
secondary contraception. With
regards to one form
22 of
primary, 18 and 18; one form secondary, 14 and
126
1
11. Unknown declined from 27 to
19.
2
[Slide]
3
To put these numbers in perspective I am
4
going to use some data from the Accutane survey.
5 Dr.
Mitchell will talk in more detail about these
6
later. But this is the one set of
data we have in
7
which we have a numerator--the number of
8
pregnancies via the survey, and a denominator--the
9
number of patients who enrolled in the survey.
10
However, this applies only to the Slone Accutane
11
survey participants. We have not
calculated this
12
rate for year one of S.M.A.R.T. in the SI because
13
there is an issue with the follow-up necessary to
14 get
the patients in and sufficient follow-up is not
15
there yet.
16
The other thing is that pregnancy rates
17 get
reported in multiple ways. So, you are
going
18 to
see some numbers potentially through the course
19 of
this day kind of flying around. I would
like to
20
show you two ways to try and help you understand.
21 One
approach has used Accutane exposed pregnancies
22 per
1,000 of the 140-day Accutane treatment
127
1
courses. Given that the normal
treatment course is
2 140
days, one approach has been to analyze the
3
exposed pregnancies by treatment courses. So, when
4 you
see the 140-day treatment course, this is what
5 we
are referring to. The other way which
you will
6 see
used is the number of Accutane exposed
7
pregnancies per 1,000 patients per year.
8
[Slide]
9
On this slide we are looking at these data
10 by
both methods. On the left vertical axis
here,
11
this is the number per treatment courses. This is
12 when we refer to the 140; zero on the bottom,
4 on
13 the
top. This is the blue line, over time
within
14 the
survey and enrollment date year 1989 to 2002