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