1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
DRUG SAFETY AND RISK MANAGEMENT
ADVISORY COMMITTEE
IN JOINT SESSION WITH
THE
DERMATOLOGIC AND OPHTHALMIC
DRUGS
ADVISORY COMMITTEE
Hilton
2
PARTICIPANTS
Peter Gross, M.D., Chair
Kimberly Topper, M.S., Executive
Secretary
CONSULTANTS (VOTING)
Wilma F. Bergfeld, M.D.
Michael E. Bigby, M.D.
Margaret Honein, Ph.D.
Arthur H. Kibbe, Ph.D.
Sarah Sellers, Pharm.D.
Amarilys Vega, M.D., Ph.D.
Jurgen
Venitz, M.D., Ph.D.
DRUG SAFETY AND RISK
MANAGEMENT ADVISORY COMMITTEE
Michael R. Cohen, R.Ph., M.S.,
D.Sc.
Stephanie Y. Crawford, Ph.D.,
MPH
Ruth S. Day, Ph.D.
Jacqueline
S. Gardner, Ph.D., MPH
Arthur
A. Levin, MPH (Consumer
Representative)
Robyn S. Shapiro, J.D.
Brian
L. Strom, M.D., MPH
DERMATOLOGIC AND OPHTHALMIC
DRUGS ADVISORY
COMMITTEE
Roselyn E. Epps, M.D.
Robert Katz, M.D.
Paula Knudson (Consumer
Representative)
Sharon S. Raimer, M.D.
Eileen W. Ringel, M.D.
Kathleen Y. Sawada, M.D.
Jimmy D. Schmidt, M.D.
Elizabeth S. Whitmore, M.D.
Michael G. Wilkerson, M.D.
FDA STAFF
Jonca Bull, M.D.
John Jenkins, M.D.
Sandra Kweder, M.D.
Paul Seligman, M.D., MPH
Anne Trontell, M.D., MPH
Jonathan Wilkin, M.D.
3
C O N T E N T S
PAGE
Call to Order
Peter Gross, M.D. 4
Conflict of Interest Statement:
Kimberly Topper, M.S. 4
Effectiveness of the Isotretinoin
Risk Management
Program for the Prevention of Fetal
Exposure to
Accutane and its Generic Equivalents
and
Consideration of Whether
Changes to this
Isotretinoin Risk Management
Program would be
Appropriate
Open Public Hearing
Representative Bart Stupak 8
Gordon Day 21
LaDonna Williams 25
Boni Elewski, M.D. 29
Paul L. Smith 35
Debbie Banner 40
Carter Crosland 46
Lisa Crosland 51
Jeffrey Federman 57
Responses from Slone Epidemiology Center
Allen A. Mitchell, M.D. 66
Introduction of Questions:
Paul Seligman, M.D., MPH 101
Committee Discussion 106
FDA Presentation:
Kathleen Uhl, M.D. 183
Carl Kraus, M.D. 192
Anne Trontell, M.D., MPH 205
Hoffmann-La Roche Presentation:
Martin H. Huber, M.D. 208
Committee Discussion 243
4
1 P R O C E E D I N G S
2 Call to Order
3
DR. GROSS: We would like to begin
by
4
reading the Conflict of Interest Statement
5 Conflict of Interest
Statement
6
MS. TOPPER: The following
announcement
7
addresses the issue of conflict of interest with
8
respect to this meeting and is made a part of the
9
record to preclude even the appearance of such at
10
this meeting.
11
The topics to be discussed at today's
12
meeting are matters of broad applicability. Unlike
13
issues before a committee in which a particular
14 sponsor's
product is discussed, issues of broad
15
applicability involve many sponsors and their
16
products.
17
All FDA participants have been screened
18 for
their financial interests as they may apply to
19 the
products and companies that could be affected
20 by
the committee's decisions. Based on this
21
review, it has been determined that there is no
22
potential for an actual or apparent conflict of
5
1
interest at this meeting with the following
2
exception:
3
In accordance with 18 U.S.C. 208(b)(3),
4 Dr.
Ruth Day has been granted a waiver that permits
5 her
to participate fully.
6
A copy of the waiver statement may be
7
obtained by submitting a written request to the
8
Food and Drug Administration's Office of Management
9
Programs, Division of Freedom of Information HFI-35
10 at
5600 Fishers Lane in Rockville, Maryland 20857.
11
Because issues of broad applicability
12
involve many sponsors and their products, it is not
13
prudent to recite all potential conflicts of
14
interest as they apply to each member, consultant,
15 and
guest speaker.
16 There will be no industry
representative
17 at
today's meeting. As you are aware, the
Food and
18
Drug Administration has appointed industry
19
representatives who currently serve on each of
20
these committees, but Annette Stemhagen, the
21
industry rep from the Drug Safety and Risk
22
Management Committee, and Peter Kresel, the
6
1
industry rep from Dermatologic and Ophthalmic Drugs
2
Advisory Committee, work with sponsors that are
3
directly impacted by the matter before the
4
committee.
5
FDA has contacted three other industry
6
representatives from other Center for Drug
7
Evaluation and Research Committees that have
8
experience in risk management and with the FDA
9
Advisory Committee process, however, none were
10
available to participate in this meeting.
11
Dr. Stemhagen and Mr. Kresel are present
12 in
the audience and attending as interested
13
observers. Further, we would like
to note that Dr.
14 Lou
Morris, a member of the Drug Safety and Risk
15
Management Advisory Committee, has been recused
16
from participating in today's meeting.
Dr. Morris
17 is
also present in the audience and attending as an
18
interested observer.
19
We would like to remind the FDA
20
participants not to discuss issues at hand outside
21 the
advisory committee meeting.
22
In the event that the discussions involve
7
1 any
other products or firms not currently on the
2
agenda for which FDA participants have a financial
3
interest, the participants involvement and
4
exclusion will be noted for the record.
5
With respect to all other meeting
6
participants, we ask in the interest of fairness
7
that they address any current or previous financial
8
involvement with any firm whose product they may
9
wish to comment upon.
10
Thank you.
11 Open Public Hearing
12
DR. GROSS: We will begin with the
open
13
public hearing.
14
Both the Food and Drug Administration and
15 the
public believe in a transparent process for
16
information gathering and decisionmaking. To
17
ensure such transparency at the open public hearing
18
session of the Advisory Committee meeting, FDA
19
believes that it is important to understand the
20
context of an individual's presentation.
21
For this reason, FDA encourages you, the
22
open public hearing speaker, at the beginning of
8
1
your written or oral statement to advise the
2
committee of any financial relationship that you
3 may
have with the sponsors of any products in the
4
pharmaceutical category under discussion at today's
5
meeting. For example, this
financial information
6 may
include the sponsor's payment of your travel,
7
lodging, or other expenses in connection with your
8
attendance at the meeting.
9
Likewise, FDA encourages you at the
10
beginning of your statement to advise the committee
11 if
you do not have any such financial
12
relationships. If you choose not
to address this
13
issue of financial relationships at the beginning
14 of
your statement, it will not preclude you from
15 speaking.
16
The first speaker in the hearing will be
17
Representative Bart Stupak.
18
MR. STUPAK: Good morning. I do not have
19 any
financial interests with anyone,
20
pharmaceuticals or any of the sponsors here today.
21
Thank you for the opportunity to allow me
22 to
address this Accutane Advisory Committee.
I
9
1
have submitted a written statement, so let me
2
highlight some parts of it.
3
The FDA has documented 366 pregnancy
4
exposures since the inception of the S.M.A.R.T.
5
program. Because the reporting of
the pregnancy
6
exposures to isotretinoin is voluntary, there is no
7 way
of knowing how many pregnancies have actually
8
occurred. In fact, Dr. Graham of
the FDA has
9
actually estimated the yearly exposure rate may be
10 as
high as 2,000, and that has recently been
11
revised, may be as high as 3,500 per year. This,
12 of
course, does not include abortions.
13
It seems clear that the only way to
14
dramatically reduce the rate of pregnancy exposures
15 in
Accutane patients is to regulate like the FDA
16
regulates Thalidomide.
17
A toothless, voluntary registry does not
18
work, and we all know it. The
registry should be
19
mandatory for all female and male patients, for all
20
prescribers and dispensers of Accutane.
There
21
should be real consequences for refusal to
22
participate in a program. I plan
to introduce that
10
1
legislation in the coming weeks.
2
For 22 years, we have seen the harm
3
Accutane can do to pregnant women and to our
4
children. How many more babies
have to be born
5
with serious birth defects, how many more women
6
need to have miscarriages, and how many more
7
children have to die before the FDA implements
8 meaningful protections and restrictions on
the use
9 of
Accutane?
10
The risk of severe birth defects caused by
11
Accutane is undisputed. Let's
take a look at the
12
history of this drug a little bit, because I don't
13 think anyone has ever focused on the full
history
14 of
this drug.
15
Go back to the Advisory Committee hearings
16 of
1988, 1989, and 1990. Roche had assured
17
Advisory Committees that Accutane would be
18
prescribed only to women with severe recalcitrant
19
cystic acne and pregnancy exposure rates would
20
dramatically decrease because the average
21
dermatologist would only see less than one female
22 per
year that would require Accutane therapy.
11
1
Therefore, they concluded it would be
2
limited to 5,000 new patients per year, and Roche's
3
advertising would focus, not on Accutane usage, but
4
future ads would, quote, "dramatically" focus on
5
"contraindication and proper use of pregnancy
6
prevention."
7
With those assurances, even the 1988
8
Advisory Committee, by consensus, considered
9
limiting the use, prescription and distribution in
10
four ways, but this consensus was never acted upon
11 and
the committee concerns were largely forgotten
12 as
Roche went on to make Accutane their second
13
highest selling drug.
14
Ten years later, the FDA and Roche
15
implemented the Pregnancy Prevention Program after
16
continued pregnancy exposures. In
this program,
17
pharmacists, patients, and physicians were to work
18
together to decrease the pregnancy exposures to
19
Accutane.
20
Despite the PPP, the red stickers, the
21
voluntary consent form, and the NO pregnancy symbol
22
with the red line through it, Accutane pregnancy
12
1
exposures continued at unacceptable levels. In
2
fact, many patients, when they saw that pregnancy
3
with the line through it, the women actually
4
thought that Accutane was a form of birth control.
5
Not only did the number of female patients
6
receiving Accutane dramatically increase, so did
7 the
off-label use of Accutane. It is
estimated
8
that 90 percent of Accutane use is for off label,
9 and
the FDA is of the opinion that many of the
10
prescribing physicians do not understand the
11
teratogenic effects of Accutane.
12
At the end of the September 2000 Advisory
13
Committee hearing, the Advisory Committee
14
recommended five conditions, and I am sure you are
15 all
familiar with them.
16
The FDA agreed with the Advisory Committee
17
recommendations. FDA and Roche
then began their
18
discussions on how to implement these
19
recommendations.
20
While the focus of these negotiations
21 centered
on a pregnancy risk management program,
22 the
U.S. House of Representatives became involved
13
1
after the death of my son. In
October of 2000, my
2
family and I went public with our concerns that
3
Accutane was associated with suicides in some
4
patients. Back then, Roche and
the FDA claimed
5
there were 37 suicides. I believe
there were at
6
least 54 associated with Accutane use.
7
Congressional hearings were
held in
8
December of 2000 and again on December 11, 2002.
9 The
December 2002 congressional Oversight and
10
Investigation Subcommittee hearing was attended by
11 12
members of the Energy and Commerce Committee.
12
The answers we sought were to the numerous
13
issues relating to Accutane, but included the
14
continued pregnancy exposure and the psychiatric
15
effects of Accutane. Committee
members were
16
appalled when they learned that the FDA had
17
reversed its position and decided it was not
18
necessary to implement the September 2000 Advisory
19
Committee recommendations.
20
The FDA excuses of privacy and HIPAA
21
concerns for not implementing these recommendations
22
rang hollow with congressional committee members.
14
1
In the meantime, Roche continued to
2
aggressively market Accutane, growing to 1.51
3
million prescriptions in 2001.
4
The FDA negotiations with Roche produced
5 an
agreement called the S.M.A.R.T. program.
6
S.M.A.R.T. did not fulfill the recommendations made
7 by
the Advisory Committee. The S.M.A.R.T. program
8
began five months before the December 11, 2002
9
hearing.
10
Witnesses from the March of Dimes and the
11
Organization of Teratology Information Services,
12
OTIS, as we call them, testified that the
13
S.M.A.R.T. program would not achieve its
14
objectives, and the S.M.A.R.T. program did not go
15 far
enough.
16
The OTIS representative further testified
17
that a partial review of their organization had
18
already revealed 17 cases of pregnancy exposure to
19
Accutane and that there was a lot of slippage in
20 the
system.
21
At the hearing, the Chairman of our
22
committee asked the FDA, "What is your fallback
15
1
position if the S.M.A.R.T. program doesn't improve
2
things with the pregnancy exposures?"
3
Dr. Woodcock answered that for a variety
4 of
reasons, FDA would evoke its authority under the
5
Food, Drug, and Cosmetic Act only as a last resort.
6
Members of the committee also learned
7
firsthand the FDA was dragging its feet.
The FDA
8
failed to provide relevant documentation until the
9 day
of the hearing, when they dropped off a number
10 of
boxes filled with information requested by the
11
committee.
12
The FDA had evidence of the failings of
13 the
S.M.A.R.T. program from its inception.
Doctors
14
were pre-dating yellow stickers that signify the
15
female patient had received a negative pregnancy
16
test. Medical clinics were
pre-dating
17
prescriptions so the patient could fill more than
18 one
prescription within the seven-day limit of the
19
negative pregnancy test.
20
At least one patient was purchasing
21
Accutane with no pregnancy test, no prescriptions,
22 no
consent forms. Some health care plans,
who
16
1
electronically dispense their prescriptions, were
2 not
using the yellow negative pregnancy sticker.
3
Pharmacies were not giving out the Med
4
Guides for Accutane, and that compliance with these
5
toothless regulations were not working. In fact,
6
approximately 50 percent of the doctors were not
7
using the informed consent forms because it's
8
voluntary.
9
The FDA withheld this information from our
10
committee at the December 11th hearing.
11
Now, Roche said they will
support a
12
mandatory registry and submit a proposal. Please
13
understand my and a number of committee members
14
skepticism after going through the numerous
15
Advisory Committee hearings. I
still do not
16
believe the FDA and Roche will ever institute a
17
registry and certification program similar to that
18 of
S.T.E.P.S. for Thalidomide.
19
Equivalent effects call for equivalent
20
restrictions. There must be a
mandatory
21
isotretinoin registry for patients, doctors, and
22
pharmacists. Pregnancies will
continue to occur if
17
1 any
element is left out of the registry.
There
2
must be consequences for failure to comply with any
3
part of the program.
4
FDA complains that if we do this, we will
5
send this drug to a black market.
Since 1999,
6
myself and other members of Congress have tried to
7
address this issue on the Internet.
We have asked
8 for
the FDA to comment on our legislation, where
9 can
we improve upon it. To date, FDA has not
10
answered.
11
The manufacturer of Accutane, Hoffmann-La
12
Roche, is just as culpable as the FDA in allowing
13
Internet and mail order of Accutane in the country.
14
Roche hides behind the FDA's inaction to complain
15 of
Internet sales. Yet, their product
coding
16
allows them to determine the exact location of
17
where products are shipped, to whom, and when.
18
We can cut down on these illegal sales, it
19 can
be done. In fact, our committee has
convinced
20
Purdue Pharma to stop shipping oxycotin to Mexico
21 as
it is being brought back across the U.S. border.
22
Yet, when we pointed this out, what we have been
18
1
able to do in Mexico, and that Mexico does not have
2 the
same regulatory scheme for Accutane as we have
3 in
this country, Roche has refused to stop the
4
shipment of Accutane to Mexico.
5
Answers as to why Roche isn't really
6
serious about entering into a mandatory registry
7 for
Accutane for patients is very clear.
Roche did
8 all
it could to defeat the registry for Accutane as
9
recommended by the September 2000 Advisory Panel.
10
In fact, the recommendations or the defeat
11 of
those recommendations was a cause to celebrate
12
because, as Roche says, there is no psychiatric
13
registry.
14
Not only did Roche view the defeat of the
15
registry as a cause to celebrate, and they
16
protected their $450 million sales in Accutane,
17
Roche does not want any form of registry that would
18
provide insight into the psychiatric effects on
19
patients.
20
Roche is so fearful that a registry may
21
provide evidence of Accutane causing psychiatric
22
injury to young, developing brains that it will
19
1
stop at nothing to prevent the registry.
2
If you go back and take a look at the
3
history of this drug, Roche, in its initial
4
application to the FDA, they forgot to submit a
5
study, a study which was uncovered, which shows
6
that Accutane does adversely affect the central
7
nervous system in mice.
8
The committee has uncovered three more
9
studies, subsequent studies, that also suggest
10
Accutane does have some effect on the central
11
nervous system. Even the FDA,
which has been
12
working with the National Institute of Mental
13
Health and the National Institute of Health has
14
kept from the Advisory Committee and the American
15
people their preliminary studies which do suggest a
16
causation between Accutane and psychiatric
17
injuries. Both the FDA and Roche
have misled and
18
failed to protect the American people, unborn
19
children, and young adults from the devastating
20
effect of this drug.
21
I hope this time the FDA does not allow
22 the
manufacturers of Accutane and its generics to
20
1
come in and water down the recommendations that may
2 be
made by this Advisory Committee.
3
I am not sure Congress is willing to let
4
them do that anymore. As I said
earlier, I will be
5 introducing
legislation to establish a mandatory
6
registry of patients, doctors, and pharmacists,
7
similar to that of the Thalidomide registry.
8
Within the documents provided by the FDA,
9
there is a statement provided by an exasperated FDA
10
investigator who cries out, how could the FDA grant
11 a
patent extension on Accutane for use in young
12
patients with the devastation this drug has caused?
13 One
begins to ask, what special powers or charm
14
does Roche have over the FDA?
15
It is time to put restrictions on the
16
users, prescribers, dispensers and marketers of
17
Accutane and its generics.
18
Thank you and if there is any questions, I
19
will be pleased to answer them.
20
DR. GROSS: Thank you very much,
21
Representative Stupak.
22
The second speaker is Gordon Day, who is
21
1
President-Elect of the Society of Dermatology
2
Physician Assistants.
3
MR. DAY: Good morning, Advisory
Members.
4
My name is Gordon Day, and I am a
5
certified physician assistant, and I practice
6
dermatology in Sandy, Utah, a suburb of Salt Lake
7
City.
8
I am the President-Elect of the Society of
9
Dermatology Physician Assistants.
The SDPA is a
10
national medical association of 900 members whose
11
mission is to improve patient care by providing
12 additional education and training for our
members.
13
Physician assistants are but one group of
14
physician providers that prescribe isotretinoin.
15 We
are an integral component of the medical team.
16 The
collegial and dependent relationship we have
17
with dermatologists contributes
directly to the
18
quality of diagnostic and
therapeutic care
19
furnished to our patients.
20
The uniqueness of our position allows us
21 to
spend more time with patients, providing
22
education on the therapeutic options for acne
22
1
treatment including the risks and benefits of
2
isotretinoin therapy. This also
includes
3
contraceptive counseling.
4
Our Society firmly believes it is
5
necessary to assure the public that our members who
6
prescribe medications such as isotretinoin are
7
qualified to do so. Continuing
medical education
8 and
other life-long learning opportunities offered
9 by
our Society include compliance with the
10
manufacturer-developed and FDA-approved risk
11
management program for fetal exposure.
12
It is also essential that medical
13
providers using isotretinoin be proactive in ways
14
that guarantee the continued availability of this
15
drug for qualified patients, and that is why I am
16
here today.
17
There are few other therapeutic options
18
available to us to effectively treat nodulocystic
19
acne. Additionally, it is
important to the
20
dermatology health care team that patients be
21
compliant in all aspects of isotretinoin therapy,
22
including adherence to contraceptive practices
23
1
which are in place to minimize the likelihood of
2
adverse outcomes.
3
The importance of isotretinoin cannot be
4
emphasized strongly enough for our patients with
5
severe acne, who can avoid scarring and
6
disfigurement by use of this medication.
7
As a physician assistant in dermatology, I
8 see
older patients on a daily basis who would have
9
benefited from isotretinoin, but whose bouts of
10
this severe acne occurred before this wonder drug
11 was
approved for sale in the United States.
They
12
will be scarred forever.
13
I have observed firsthand how patients
14
with severe cystic acne may be so concerned with
15
their appearance that it affects their daily
16
living, self-concept and quality of life. There
17 are
patients I care for who will not go swimming
18
because of the severe cystic acne lesions and
19
scarring on their backs and shoulders.
20
I have female patients that have limited
21
outings socially because of their severe cystic
22
acne, and I have those patients who suffer from low
24
1
self-esteem and required psychiatric treatment
2
because of their severe acne.
Isotretinoin is an
3
important tool for helping these patients when all
4
other options fail to improve their condition.
5
In the dermatology practice where I
6
provide care, in an attempt to avoid adverse
7
outcomes, I not only employ the S.M.A.R.T. program,
8 but
also have developed a protocol that I and my
9
supervising physician, and other members of our
10
health care team use to make sure that all the
11
necessary risk management program components are
12
documented when using isotretinoin.
13
This enhanced protocol encompasses review
14 of
side effect profiles, pregnancy testing,
15
contraceptive counseling, the completion of
16
time-specific laboratory testing, a thorough review
17 of
the patient's own responsibilities,
18
participation in the survey, and completion of the
19
informed consent process.
20 It is an unfortunate fact that a
small
21
number of fetal exposures still occur in female
22
isotretinoin patients, relative to the overall
25
1
number of female patients taking this drug.
2
Therefore, the Society of Dermatology
3
Physician Assistants would like to collaborate with
4 the
American Academy of Dermatology Association and
5 the
FDA on improving the effectiveness of the
6 current risk management program in ways that
lead
7 to
fewer adverse outcomes and safeguard patient
8
confidentiality and rights in the health care
9
system.
10
This process, once completed, should serve
11 as
an educational tool for the patients, the
12
prescribers, and the pharmacists.
13
Thank you.
14
DR. GROSS: Thank you, Mr. Day.
15
The third speaker is LaDonna Williams,
16
Executive Director, Inflammatory Skin Disease
17
Institute.
18
MS. WILLIAMS: Good morning. I am LaDonna
19
Williams, and I am the Executive Director of the
20
Inflammatory Skin Disease Institute, a patient
21
advocacy group that provides education, public
22
awareness, and support to those patients with
26
1
inflammatory skin disease and their families.
2
Inflammatory skin disease is a broad
3
category of conditions ranging in severity. As you
4 can
imagine, these diseases are very distressing to
5
those who have them, causing great discomfort and
6
real emotional distress.
7
You can learn more about inflammatory skin
8
disease by visiting our web site
9
www.isdi.online.org.
10
I feel it is important to be here today on
11
behalf of the patients who suffer from the
12
inflammatory skin disease acne.
Severe acne is
13
characterized by papules, pustules and inflamed
14
nodules. Acne is a common skin
disease and can be
15 a
very serious medical condition.
16
For many Americans it is more than a
17
temporary cosmetic problem that can be treated by
18
over-the-counter lotions and creams.
19
For many Americans it is more than a
20
condition that can be treated by antibiotics, oral
21
contraceptives, or steroids.
Indeed, for thousands
22 of
unfortunate Americans, acne can be a
27
1
life-altering and a socially terminal medical
2
condition for which isotretinoin is the only
3
effective method of treatment.
4
I am representing hundreds of acne
5
patients who cannot be here today.
These patients
6 are
both male and female, teenagers and adults who
7
have contacted me to express their strong support
8 for
continued access to isotretinoin. This
drug
9
literally worked wonders for them and they want to
10
make certain that it remains available for other
11
severe acne sufferers.
12
You have already reviewed reams of
13
briefing material and listened to hours of
14
testimony about the current risk management effort
15 to
reduce fetal exposure to isotretinoin.
16
The Inflammatory Skin Disease Institute
17
agrees it is necessary to provide and improve a
18
program and reduce the number of pregnancies
19
associated with this drug keeping in mind I have
20
received numerous letters from teenagers and adults
21
stating how isotretinoin saved their skin and their
22
self-esteem.
28
1
Many parents have written to me on behalf
2 of
their children. One grateful mother told
me how
3
isotretinoin improved her daughter's skin, and not
4
only made positive changes in her teenager's life,
5 but
made positive changes in the whole family
6 because
they could go out in public and do social
7
things together again.
8
I have received calls in my office from
9
patients and their parents explaining how academics
10 in
high school has improved dramatically because
11 attendance became 100 percent after
isotretinoin
12
cleared up their student's acne.
13
One patient had to consider to leave her
14 job
that she loved very much because her acne was
15 so
severe that her face was in a constant state of
16
being red, swollen, and painful, with disfiguring
17
pustules. Children were afraid of
her, which in
18
turn made her withdrawn and depressed.
She took
19
isotretinoin and she feels it saved her job, her
20
relationships, and her life.
21
I could go on and on with personal
22
accounts from patients for whom isotretinoin made a
29
1
positive difference in their lives.
It is on their
2
behalf that I speak with you today.
3
I thank you for your time and your
4
attention in listening to these stories, and I hope
5 you
will keep these testimonies in mind as you
6
debate the future direction of the isotretinoin
7
risk management program.
8
If I may close with somewhat of a cliche -
9 the
effectiveness of isotretinoin goes beyond skin
10
deep. I hope that I have
impressed upon this
11
committee how absolutely essential it is for this
12
drug treatment for acne to remain on the market,
13 and
I hope I have impressed upon you how essential
14 it
is for the qualified patients
15
Thank you.
16
DR. GROSS: Thank you.
17
The next speaker is Dr. Boni Elewski,
18
President of the American Academy of Dermatology,
19 the
fourth speaker.
20
DR. ELEWSKI: Good morning,
everyone.
21
My name is Dr. Boni Elewski. I am
a
22
practicing dermatologist and Professor of
30
1
Dermatology in the Department of Dermatology at the
2
University of Alabama in Birmingham.
3
In addition to my medical duties, I am
4
also President of the American Academy of
5
Dermatology Association. On
behalf of the 14,000
6
members of the Association, and our hundreds of
7
thousands of acne patients, I thank you for the
8
chance to speak with you about the current
9
pregnancy risk management program for isotretinoin.
10
The health, safety, and welfare of our
11
patients is of paramount importance to
12
dermatologists, as is the integrity of the
13
doctor-patient relationship.
Indeed, because of
14
these concerns, our organization is committed to
15
optimizing the safety of our patients taking this
16
drug, as well as ensuring continued access to
17
isotretinoin for all qualified prescribers.
18
Education and communication with our
19
members and their patients about isotretinoin
20
compliance is essential to the safe use of this
21
drug.
22
The current risk management program has
31
1
been promoted in numerous education and
2
communication efforts, such as CME activities,
3
Member Alerts, articles on our web site, in our
4
official publication Dermatology World, and will be
5
augmented by new initiatives.
6
In addition, the Association hosted a
7
scientific consensus conference on the safe and
8
optimal use of isotretinoin to which key
9
decisionmakers in the FDA and the scientific
10
community were invited. The
proceedings will be
11
published next month.
12
Recently, the Association sent a letter to
13 the
FDA Commissioner with a list of web sites that
14
sell isotretinoin on line. We
hope this
15
information will assist the agency with addressing
16 the
problem of illicit sales of this powerful drug.
17
You have just heard a number of compelling
18
stories about the benefits of isotretinoin therapy.
19 I
myself have treated hundreds of patients whose
20
quality of life has improved tremendously because
21 of
this drug.
22
This is because acne is not simply a
32
1
cosmetic problem. In 1948,
renowned dermatologist
2 Dr.
Marion Sulzberger said, and I quote, "There is
3 no
single disease which causes more psychic trauma,
4
more maladjustment between parents and children,
5 and
general insecurity and feelings of inferiority
6 and
greater sums of psychic suffering than does
7
acne." More than a half
century later, his
8
observation still rings true.
9
When all other treatment options fail,
10
isotretinoin is the miracle drug that clears away
11 the
redness, painful swelling, and lesions of
12
severe, nodulocystic acne, which may lead to
13
painful and disfiguring scars.
14
Unfortunately, a small number of women are
15
pregnant or become pregnant while taking this drug.
16 As
always, our goal is to ensure both patient
17
safety and continued access to isotretinoin for all
18
qualified patients. For this reason, we would like
19 to
offer the following recommendations for
20
improving the current risk management program.
21
First, the survey of female patients
22
should be mandatory, not voluntary.
We propose
33
1
that isotretinoin therapy be prescribed for
2
qualified female patients only if they participate
3 in
the survey. Data generated by this
mandatory
4
survey would be more complete. Of
course, it is
5 the
ultimate responsibility of the female patient
6 to
comply with the birth control requirements of
7 the
program and to avoid pregnancy.
8
Second, a single questionnaire and vendor
9 for
the female patient survey should be designated.
10 The
present situation with the generic
11
manufacturers using one questionnaire and vendor,
12 and
Hoffmann-La Roche using another questionnaire
13 and
vendor, is confusing to prescribers and
14
patients alike.
15
Furthermore, differences in the surveys
16
make it difficult to compare data.
A single
17 questionnaire
and vendor would minimize this
18
confusion, improve data gathering, and promote
19
patient safety and education, and ultimately
20
improve the health, safety, and welfare of our
21
patients taking this drug.
22
Third, the survey questionnaire should be
34
1
re-evaluated and simplified to obtain the pertinent
2
information to assess the risk management program.
3
Ultimately, this will improve the health, safety,
4 and
welfare of our patients taking isotretinoin.
5
Fourth, the current risk management
6
program must be clarified and simplified to address
7
ongoing issues of concern for doctors and patients
8
alike.
9
And finally, it is crucial that program
10
materials warn patients to avoid Internet sales,
11
avoid re-use, or sharing of isotretinoin.
12
Let me close by saying, the preservation
13 of
the doctor-patient relationship is crucial, and
14 may
I add, an integral component to the risk
15
management system. As we strive
to improve the
16
current risk management program for isotretinoin,
17 the
American Academy of Dermatology Association's
18
guiding principle has always been, and will
19
continue to be, the health, safety and welfare of
20 our
patients.
21
Thank you.
22
DR. GROSS: Thank you, Dr.
Elewski.
35
1
The next speaker, the fifth speaker, is
2
attorney Paul Smith.
3
MR. SMITH: Good morning. My name is Paul
4
Smith and I am an attorney practicing law in
5
Austin, Texas.
6
My practice relates
exclusively to
7
pharmaceutical litigation and for the past two
8
years I have worked nearly full time on behalf of
9
families and individuals who have experienced
10
devastating and catastrophic side effects from
11
Accutane.
12
In connection with this privilege, I have
13
personally seen and known dozens of individuals and
14
families whose lives have been horribly altered as
15 a
result of this powerful and dangerous drug.
16 The tragedy of a parent who has lost
their
17
child to suicide and the tragedy of these parents
18 and
babies who have to live with serious and
19
permanent birth defects is beyond description.
20
I understand that as my role, I am charged
21
with the responsibility to seek redress for these
22
people in the court system.
However, today, I am
36
1
stepping out of my role as a legal advocate, today,
2 I
come before you as a member of the public who has
3
talked to and seen many who have been harmed by
4
Accutane.
5
Today, I am asking you to take a serious
6 and
deliberate look at risk presented by this drug,
7
which has not, in my opinion, been fairly and
8
accurately examined.
9
You are fortunate to have the ability to
10
suggest and ensure that the tragedies that I have
11
seen in connection with this drug are substantially
12
reduced.
13
For over 20 years now, the FDA has made an
14
effort to regulate this product by adding warnings
15 and
warnings in connection with this drug.
This is
16 a
laudable goal to try to ensure some safe use of
17 this
product, however, as has been well established
18 and
is beyond dispute today, the various programs
19
that have been instituted have failed miserably.
20
The admission and concession by Roche that
21 a
registry is needed is too late for many.
If
22
there is a registry, however, there are two
37
1
components which must be incorporated.
2
The first involves paternal exposure, that
3 is,
where the father takes Accutane when the mother
4
conceives the fetus. This is
limited to treatment
5 of
the father with Accutane.
6
The second is the incredible failure of
7
Roche to consider the known psychiatric component
8 of
the drug to impair complete compliance with any
9
rational program aimed at preventing fetal
10
exposures.
11
The dangers and risk of paternal exposure
12 is
something that must be better studied and
13
understood. I point you to the
Thalidomide
14
warnings which strongly advised male patients
15
taking Thalidomide to use contraceptive measures.
16
This is in dramatic contrast to the Accutane,
17
which suggests that there is no risk to the fetus
18 as
the result of paternal exposure.
19
I have with me recently released documents
20
that indicates that Roche's own internal experts
21
has, in reviewing 13 potential paternal exposures,
22
found that in 5 of those cases, a possible
38
1
relationship could not be excluded.
2
This is a document that Roche fought hard
3 to
keep from the public. I have it here
with me.
4 It
is sitting here for your review. I would
5
welcome and request that you get a copy of this and
6
review it thoroughly.
7
Carter Crosland, who is here with his
8
mother and father, is, in fact, one of the five
9
whose medical records were examined by the Roche's
10
internal geneticist. The Roche
consultant
11
concluded that Carter's difficulties could very
12
well be related to Accutane embryopathy.
13
Roche's response to this phenomena and the
14 risk
associated with paternal exposure is
15
inadequate. The public should be
aware the
16
potential exposure does exist, and there should be
17
warnings specifically advising that there is
18
problem with paternal exposure.
19
We would strongly urge a registry
that
20
includes males using Accutane that specifically
21
tracks their sexual activities.
22
The second issue for your consideration is
39
1 the
inability of certain patients to comply with
2
warning and instructions as a direct result of
3
known psychiatric side effects presented by this
4
drug.
5
Only Roche disputes that Accutane may
6
cause depression and behavioral changes.
It seems
7 to
be well accepted within the rest of the
8
scientific community that there is a strong
9
relationship between Accutane and psychiatric
10
adverse events and depression.
11
I have seen nothing publicly which
12
suggests that Roche has even considered this
13
foreseeable and predictable phenomenon of pregnancy
14
secondary to impaired capacity as a result of
15
depression.
16
Debbie Banner is here to explain to you
17 how
she got depressed and was unable to comply with
18 the
program in effect at the time to prevent her
19
pregnancy.
20
I thank you for your attention and your
21
kind consideration and again the paternal exposure
22
study itself that was submitted to the FDA is here
40
1 for
your review.
2
Thank you very much.
3
DR. GROSS: Thank you, Mr. Smith.
4 The sixth speaker is Debbie Banner.
5
MS. BANNER: Good morning. My name is
6
Debbie Banner. I am here with my
husband Kevin. I
7
have known my husband since I was 17, and we have
8
been married for seven years. I
appreciate this
9
opportunity to share with the members of this
10
honorable committee my horrifying experience with
11 the
drug Accutane.
12
Starting today, we will offer one of the
13
answers to this question, why are girls continuing
14 to
become pregnant while on Accutane despite the
15
warnings that Accutane causes birth defects?
16
I am afraid that one of the answers I will
17
propose today is one that neither the FDA, this
18
committee, or Hoffmann-La Roche has adequately
19
studied or considered.
20
I am also here to describe the nightmare
21 of
having a child who has been born with Accutane
22
birth defects.
41
1
I became pregnant while on Accutane.
I
2
survived this nightmare by the grace of God, strong
3
faith, a loving husband, and an overwhelming
4
commitment to my son.
5
I was devastated that I played a role in
6
causing my own child to be deformed.
So, I vowed
7 to
sacrifice everything to give him the best life I
8
could possibly give. Because I
accepted my fate
9
humbly, I believe that is why God finally revealed
10 the
other side of the story to me, the missing
11
piece of the puzzle.
12
On October 4th, 1996, my son Deven was
13
born. There is no medical doubt
that his birth
14
defects are due to the effect of Accutane on him as
15 a
developing fetus. He has been seen by
the best
16
physicians and was diagnosed with Accutane
17
embryopathy.
18
Deven was diagnosed with an underdeveloped
19
cerebellum resulting in cerebral palsy and
20
hypotonia. At the age of 7, he is
fed through a
21
feeding tube that is surgically inserted into his
22
stomach, he suffers from seizures.
42
1
After four eye surgeries, he has visual
2 perceptual
problems. He has sensory integration
3
problems which manifest as autistic-like behaviors.
4 He
has verbal expressive disorder, speech problems,
5 and
requires physical therapy, occupational
6
therapy, and speech therapy.
7 He has a chronic history of
pneumonia. He
8
requires special education services in school and
9
special accommodations. Along
with these and other
10
medical problems, as well as fine motor and gross
11
motor impairments, it is likely that he will be
12
unable to take care of himself as an adult.
13
I was on Accutane in 1995 when I was 24
14
years old. I was an aerobics instructor and
15
attending school. I was working
two jobs. I was
16 of healthy
mind, body, and spirit, so when I first
17
visited the dermatologist, I was a happy person
18
although I had an acne problem.
19
Days after ingesting Accutane, I began to
20
react as if I were poisoned. I
developed severe
21
headaches and sharp, piercing head pains. I was
22
nauseous day and night. I was
weak, dizzy,
43
1
confused, forgetful, suffering from hypersomnia and
2
severe crying spells.
3
Eventually, I developed suicidal thoughts.
4 I
just wanted to sleep and never wake up again.
I
5 was
too sick when I was awake.
6
At the initiation of treatment, I had
7
chosen abstinence as my method of birth control. I
8
chose this for religious reasons and did not plan
9 to
be sexually active again until I was married.
10
However, once in a state of severe
11
depression, I became mentally incapable of making
12 appropriate
decisions. My thoughts were filled with
13
thoughts of suicide and death, which eventually
14
required psychiatric intervention.
15
At the time of conception, I was no longer
16 a
patient that was reliable and capable of
17
complying with mandatory pregnancy prevention
18
procedures and reliable in carrying out
19
instructions.
20
The missing piece of the puzzle was given
21 to
me when I learned that the psychiatric problems
22
that led to my pregnancy were a side effect of
44
1
Accutane.
2
Through my research, I have now met other
3
mothers who became pregnant on Accutane.
I have
4
learned that depression was a factor in their
5
inability to comply with the warnings that, like
6 me,
led to a nightmare of birth defects.
7
I have spoken to one mother who actually
8
attempted suicide while on Accutane and became
9 pregnant weeks later. To this day, there is
no
10
instruction, education, or warning on how
11
psychiatric side effects of this drug may prevent
12
you, despite the best intentions, from complying
13
with the pregnancy prevention program.
14
It seems fundamental to me now, but how
15 can
you educate someone that may not be able to
16
protect themselves. How can anyone including the
17
doctors who prescribe it believe that the drug
18
could do this when Roche refuses to admit that
19
there is a psychiatric component to the drug?
20
I am here to tell you from my own
21
experience, and experience told to me by other
22
mothers admitted in a cloud of shame and stigma
45
1
that depression can and does interfere with
2
pregnancy prevention even when patients have chosen
3
other forms of birth control.
4
Because women and girls are continuing to
5 become pregnant, I plead with this committee
to
6
require that females of childbearing potential
7
receive an initial psychiatric evaluation and are
8
then monitored by a psychiatrist throughout
9
treatment.
10
To leave this decision to patients who may
11 be
in denial and cannot protect themselves is to
12
guarantee more birth defects and abortions.
13
Because Accutane is such a powerful drug, it is
14
worth the extra effort and expense to save children
15
from a lifetime of deformity and pain and to
16
finally bring an end to the outrageous number of
17
Accutane abortions.
18
Warning is simply not enough when
19
psychiatric side effects are involved.
20
In conclusion, I want to express my
21
sympathy for people suffering from acne, but even
22 in
the very worst cases of acne, their suffering
46
1
cannot compare to the suffering endured daily by
2
children born with Accutane birth defects.
3
Thank you.
4
DR. GROSS: Thank you, Debbie, and
Kevin
5
Banner.
6
The seventh speaker is Carter Crosland.
7
MR. CROSLAND: Good morning. My name is
8
Carter Crosland.
9
Today, you will hear my story.
Not only
10 do
I speak for myself, but also for the hundreds,
11
perhaps thousands of children whose voices will
12
never be heard. Those dreams and hopes will never
13 be
realized. Today, I am their voice.
14
I was born January 22, 1985, in a small
15
rural town in central Utah, the first child of my
16
parents. As a young boy, I was
told that I was a
17
miracle and that I had something important to share
18
with the world. I have been
blessed with the
19
health, strength, and mental faculties to speak
20
before you today. Perhaps that is
my purpose.
21
As a young boy, I dreamed of being a
22
wrestler. I loved sports and had
an unusual talent
47
1 for
learning statistics. I played T ball
with my
2
friends and they ran the bases for me while I
3
stopped the ball with my wheelchair tires.
4
And then the boys moved on to minors and
5
majors and I stayed behind. I
became the batboy
6 and
then the base ump. Then the coach,
manager, or
7
anything else just to stay involved.
The same was
8
true with football and wrestling.
As I matured, I
9
realized I would be left behind again.
Not only in
10
sports, but in every single aspect of my life.
11
My parents sacrificed to get me where I
12 am,
and because they worked hard, we didn't qualify
13 for
disability funding from the government.
I was
14 too
smart. I passed all the cognitive tests,
15
despite missing a third of my brain to a cyst.
16
I passed all the skills and vocabulary
17
tests. I could even pick up the
blocks with my
18
mouth and put them in the holes quickly.
19
Therefore, by their standards, I wasn't disabled,
20 and
I was at the end of the waiting list without
21
assistance.
22
I had generous people who helped me get
48
1
arms as a young boy, but we couldn't keep up with
2 the
constant re-fitting and trips to the city.
My
3 mom
worked full time to keep insurance for me, but
4 she
couldn't keep leaving work for sick kids and
5
trips to the prosthetic specialist, so I gave up on
6 the
arms. They were too costly.
7
When I entered first grade, my mom quit
8
work, so that I could go on field trips, birthday
9
parties, and to the library with my friends. Where
10 I
went, my chair went, and also my parents and my
11 van
went. That made our financial situation
even
12
worse, but I appreciated having my mom around.
13
I took drivers ed at 15 and passed with
14
flying colors, well, all except for the driving
15
test. You see, I can't afford the
car for me to
16
drive and the school district can't provide it. I
17
completed high school and graduated with my class.
18 I
was voted most preferred senior probably because
19 I
had the gift of gab and I like to visit with
20
everyone.
21
My school built a ramp so that I could
22
participate in pomp and circumstance with my peers.
49
1 I
now attend college and I am studying
2
communications. I hope to be a
sports broadcaster
3 or
work for some firm as a public relations guy.
4
My voice is the only asset I have that
5
puts me on the same playing field as those around
6
me. It is literally the only
thing I can do on my
7
own. This is what I have
accomplished so far in my
8
life against all odds. Now I
would like to tell
9 you
what I cannot do.
10
I room with a friend at college.
I pay
11 him
to help me bathe, get dressed, cook my meals,
12
charge my wheelchair, get my books, help me on
13
dates, drive my car, and anything else I want to
14
do. My friends lift me up the
stairs to their
15
place or to any other place that is not accessible.
16
I have to plan for bathroom breaks because
17 I
need help. My friend will get married
soon, and
18 I
will find another person and then another, and
19
another. My parents travel to
bring me home and
20
back on weekends because I cannot afford a car that
21 I
can drive on my own. My buddies take me
shopping
22 and
help prepare and eat my meals. They
clean up
50
1 for
me and do my wash.
2
Because I have all my mental faculties, my
3
dreams are the same as every other young man my age
4 - a
car, a job, a girlfriend, and someday a wife
5 and
family. I hope for these things, but I
take it
6 one
day at a time, and I don't know what the future
7
holds for me.
8
I keep being determined to make the best
9 of
it and to find happiness in every small thing
10
around me. Some of these dreams I
can realize now
11 if
I could afford it. Money is a tremendous
12
limitation, nearly as limiting as my disability.
13
Please do not make money a factor in your decision
14 to
research and regulate this drug.
15
They say that I don't fit into any
16
category or syndrome because of my intelligence. I
17
feel that my mental abilities are a gift from God
18 and
are for a purpose. Today, I hope that
purpose
19 is
to bring this matter before you to your
20
attention.
21
I hope that you will look deep into your
22
heart and do everything you can to study, research,
51
1 and
take every step possible to prevent this from
2
happening to one more child. Most
are not as
3
fortunate as I am. Their voices
will never be
4
heard. Please hear mine.
5
I thank you for your time.
6
DR. GROSS: Thank you, Mr.
Crosland.
7
The eighth speaker will be Lisa Crosland.
8
MRS. CROSLAND: Ladies and
gentlemen, good
9
morning. I am Lisa Crosland, and
I am here with my
10 husband
Russell and my son.
11
A first pregnancy is supposed to be a
12
happy time filled with anticipation and excitement,
13 but
mine was neither. For me, I was a
19-year-old
14 in
college, in love. We had big plans, big plans
15 and
dreams that included marriage and children, but
16
things changed when Russell began using Accutane.
17
Our relationship became a disaster filled
18
with unkept promises and unpredictable behavior.
19 An
engagement was broken and so was my heart, and
20
then I found out I was pregnant and alone.
21
Things went from bad to worse. I
had
22
recurring nightmares that the baby inside me was
52
1 not
right. I didn't grow enough, the baby
banged
2
back and forth. An ultrasound at
almost six months
3
confirmed my worst nightmare.
4
We were told that our baby had no arms and
5
legs, no sex organs. The child had
a third of its
6
brain covered with fluid that was increasing. They
7
felt his eyes were too big and his head too large.
8 A
large growing hernia and funny-shaped mouth was
9
also evident.
10
Most doctors felt the child would abort
11
itself. Others said that if it lived, it would be
12 on
life support, unable to suck, and
13
institutionalized. I was
devastated and so was
14
Russell. We prayed for a miracle
that our child
15
would not suffer.
16
Our miracle was not what we expected, our
17
child lived, and today we are telling his story.
18 As
parents, our first concern was why did this
19
happen, what did I do. Parents
need to know why
20
this has happened to them.
21
I had lived what I thought was a clean and
22
healthy life. I did not smoke, I
did not drink or
53
1 use
drugs. Every effort was made to
determine what
2 I could
have done to prevent this as a mother.
3
Yet, we turned up empty-handed.
4
The first time I heard the word Accutane
5
embryopathy was from a genetics counselor at the
6
University Hospital in Salt Lake City.
Carter was
7
almost three months old and had just had his second
8
surgery. The doctor felt Carter's
symptoms were
9 too
similar to maternal Accutane exposure to
10
ignore.
11
I told her that I had never used the drug,
12 but
his father had before, during, and after I
13
became pregnant. Carter has been
worked up by the
14
best doctors and the best facilities.
Everyone
15
wanted to know whether Russell or I carried some
16 odd
genetic code that would cause this in the
17
future.
18
We looked everywhere, but there was
19
nothing else but Accutane. We
reported an adverse
20
reaction to Hoffmann-La Roche, who responded that
21
this could not be the cause of our child's
22
deformities. A few years later I
spoke directly to
54
1 a
doctor at Hoffmann-La Roche who told me that
2
there were a few other reports of paternal
3
exposure, but all could be attributed to another
4
cause.
5
I even asked for and received films and
6
study materials from Roche. You
see, as we have
7 now
learned from Roche's internal documents made
8
public only after Roche fought and lost the battle
9 to
keep it private. Carter has all the
clinical
10
signs of Accutane embryopathy.
11
Roche initially agreed that paternal
12
exposure to Accutane could not be ruled out. Why
13
then hasn't this been researched?
Are kids like
14
Carter not worth it?
15
Since this time, I have seen warning
16
labels and adverse reports increase, more children
17
aborted and affected. I have
studied and found
18
more and more similarities to things Carter was
19
experiencing in his life that other children whose
20
mothers were exposed were experiencing.
21
His mouth, his dental problems, his
22
problems with temperature regulation are just a few
55
1 of
the less visible problems. Some children
whose
2
only link is a mental I.Q. of under 85 have been
3
attributed to Accutane. I find it
impossible not
4 to
include Carter in this category simply because
5 his
father was the user and he is normal in
6
intelligence.
7
Of course, it may very well be that women
8 who
become pregnant from a father who has taken
9
Accutane may never put the issue together. The
10
possibilities of hundreds and thousands of
11
abortions simply attributed to poor development or
12
unwanted pregnancy may have occurred, with the
13
public being kept in the dark of these risks.
14
The fact that there has not been more
15
reporting of this issue does not mean that there is
16 not
a serious risk and danger. It only means
that
17
Roche has been successful in keeping this from the
18
public.
19
This drug Accutane has devastated my
20
family emotionally, physically, and financially.
21 It
has been carelessly over-prescribed and
22
under-regulated. It has destroyed
our dreams and
56
1
shattered our lives, yet we stand before you today
2
united in our efforts to demand a change.
3
We want adequate research and funding into
4 the
possibility of paternal exposure of retinoids.
5 We
want the prescription of this drug for
6
dermatological reasons restricted to dermatologists
7 who
are forced to prescribe it only as a last
8
resort for both men and women.
9
We want those greedy individuals who
10
facilitate unprescribed Internet sales of this drug
11 stopped
and prosecuted.
12
Most of all, we want answers, not only for
13
ourselves, but for the hundreds of babies aborted
14 who
may very well be exactly like Carter, but
15
discarded.
16
I cannot stand before you today and tell
17 you
exactly how Accutane is responsible for my
18
son's disabilities, only that we know that it is.
19 Our
family and many others have suffered long
20
enough at the hands of Hoffmann-La Roche. We urge
21 you
to take a stand and ensure the safety of this
22
drug.
57
1
Thank you for your time.
2
DR. GROSS: Thank you, Mrs.
Crosland.
3
Is there anyone from the public who wants
4 to
speak at this point?
5
[No response.]
6
DR. GROSS: Hearing none, we will
declare
7 a
recess at this point, and we will reconvene at
8
9:15.
9
[Break.]
10
DR. GROSS: While we had closed
our public
11
hearing, we are going to reopen it briefly. The
12
tenth speaker from earlier today, Jeffrey Federman
13
will speak.
14
MR. FEDERMAN: Good morning. My name is
15
Jeff Federman, and I am President of Paragon Rex, a
16
company that provides services to the
17
pharmaceutical industry.
18
For purposes of disclosure, we are not
19
engaged with the manufacturers involved in today's
20
meeting. In addition, my
colleagues and I authored
21 a
book about pharmaceutical risk management.
22
Let me begin my proposing that today's
58
1
proceedings provide two insights about what can
2
reasonably be expected about the design and
3
improvement of risk management programs.
4
The first focus is on the expectations of
5
rigor and precision. We are all
associated with a
6
pharmaceutical industry that is famous for the
7
rigor and precision of its well-controlled clinical
8
trials. We expect to be able to
determine drug
9
efficacy using scientific and statistical methods,
10 and
would hope to bring a similar level of rigor to
11 pharmaceutical
risk management.
12
Our colleagues in other risk-intensive
13
industries, such as nuclear energy and aerospace,
14
have much to teach us about applying a similar
15
degree of rigor to risk assessment and program
16
design. Validated
well-established methodologies
17
exist to guide the design of risk management
18
programs in these industries.
19
Research of these practices, as well as
20 the
disease management and adult learning
21 disciplines,
suggest that effective drug risk
22
management may have several key elements.
59
1
1. Evidence-based assessment and
design
2
process, perhaps such as failure mode and effects
3
analysis, or FMEA, that targets interventions to
4
address specific process-related causes of failure.
5
2. Redundancies that back up the
6
inevitable human failures.
7
3. Collaborative design with
practicing
8
physicians to help program elements fit seamlessly
9
into their day-to-day practice of medicine.
10
4. Predictive modeling or
pre-testing to
11
determine the likely effectiveness of any proposed
12
program and anticipate where program weaknesses may
13
exist.
14
5. Innovative implementation
approaches,
15
perhaps such as scenario-based learning, that build
16 on
the way clinicians and patients learn.
17
Finally, ongoing monitoring and
18
measurement with the anticipation that initial
19
programs change over time.
20
Certainly, rigorous design is achievable,
21
yet, in the world of every-day clinical practice,
22
where care is delivered based on the judgments and
60
1
knowledge and motivations of well-meaning men and
2
women, high precision in terms of predicting
3
program compliance and use may be an unrealistic
4
expectation at the time of program introduction.
5
This key difference between the controlled
6
clinical trial environment to which we are
7
accustomed and the realities of clinical practice
8
lead to a second expectation.
9
I suggest that expecting a definitive
10
precise or final design at the time of risk
11
management program introduction may not be
12
reasonable. Quality improvement
standards in other
13
industries are built on the foundation of
14
continuous quality improvement, or CQI.
15
The concept of intervening with an initial
16
program, then, monitoring and measuring for early
17
opportunities to improve the program may be a more
18 achievable
expectation.
19
The approach of showing continuous
20
movement towards a goal may require a frequency of
21
analysis and potential redesign occurring in
22
intervals of months, not years.
61
1
Today's discussions are another step in
2 the
ongoing improvement of Roche's pioneering PPP
3 and
enhanced S.M.A.R.T. programs. We support
these
4 FDA
initiatives and believe these hearings today
5
will help lead to the next generation of effective
6
pharmaceutical risk management programs that
7
incorporate both rigorous evidence-based program
8
design, as well as continuous quality improvement
9 to
provide the degree of product we are all seeking
10 to
achieve.
11
Thank you.
12
DR. GROSS: Thank you, Mr.
Federman.
13
At this point, we will close the open
14
public hearing again, and we will move on to some
15 other orders of business.
16
Allen Mitchell, Director, Slone
17
Epidemiology Center, Boston University, will have a
18 few
minutes to comment on some questions that were
19
raised yesterday.
20
DR. MITCHELL: Thank you very
much, Dr.
21
Gross, and committee, I really appreciate your
22
offer of a few minutes to respond to some of the
62
1
concerns raised in the FDA review.
2
Yesterday, I mentioned that I
was not here
3 on
behalf or speaking for the FDA, and then this
4
morning's remarks, I just want to point out that
5 not
only is that the case for these remarks, but I
6 am
not speaking on behalf of the generic sponsors
7 or
Hoffmann-La Roche. I guess that leaves
me
8
speaking on behalf of the Slone Epidemiology
9
Center, which I think they will allow me to do.
10
This presentation has not been shared with
11
anyone other than our own group.
12
[Pause.]
13
DR. GROSS: We have a few
questions from
14
yesterday. I would like to start
with Dr. Day.
15
DR. DAY: Thank you. I did have questions
16
yesterday, however, I would like to defer that
17
comment and use it for an additional comment on the
18
questions today.
19
Would that be all right, Dr. Gross?
20
DR. GROSS: That's fine.
21
Dr. Bigby.
22
DR. BIGBY: I have a couple of
questions.
63
1 The
first is to Hoffmann-La Roche.
2
The question was asked I think yesterday
3
about annual sales, and you found the number, but
4 didn't say what it was, the number of 450
million
5
came out today.
6
What are the annual sales of Accutane?
7
MS. REILLY: What year, sir?
8
DR. BIGBY: Last year.
9
MS. REILLY: In 2003, our U.S. net
sales
10
were $144 million.
11
DR. BIGBY: Do you have any idea
sort of
12
what you have spent in terms of legal fees and
13
lawsuits around the issue of teratogenicity?
14
MS. REILLY: No, sir, I do not.
15
DR. BIGBY: Is that an obtainable
figure?
16
MS. REILLY: I would defer to our
counsel.
17
DR. GROSS: Dr. Cohen, Michael,
did you
18
have a question from yesterday?
19
DR. COHEN: No, I will hold it
until a
20
discussion later.
21
DR. GROSS: Dr. Katz.
22
DR. KATZ: I wanted to ask Dr.
Huber, on
64
1 the
people who enroll, what percentage of those,
2 how
soon do they get a notice that they have
3
enrolled do they get a questionnaire, and what
4
percentage of the people that enroll fill out those
5
questionnaires, the two or three questionnaires
6
they get?
7 On the enrollment form, it says you
will
8 get
two or three questionnaires through the
9
treatment. So, what percentage of
the people that
10
enroll get the questionnaires and answer them, and
11 how
quickly do they get them?
12
DR. HUBER: I will refer to Dr.
Blesch who
13
will answer your question.
14
DR. BLESCH: The Accutane survey
is
15
divided into two sections. Eighty
percent of the
16
patients who enroll, 80 percent get questionnaires
17
immediately upon enrollment. The
other 20 percent
18 get
a questionnaire approximately six months after
19
they enroll, and then a final questionnaire six
20
months after they finish treatment.
21
All Accutane-surveyed patients are
22
followed, continue to receive questionnaires until
65
1 six
months after their treatment has stopped.
2
DR. KATZ: What percentage of
patients who
3 you
send that questionnaire to fill out the
4
questionnaire?
5
DR. BLESCH: I don't have that
exact
6
number, but I believe it is about 80 percent.
7
DR. KATZ: Thank you.
8
DR. GROSS: Then, the last
question from
9
yesterday was from Mr. Levin.
10
MR. LEVIN: I will defer questions
until
11
later, but I do have one.
12
I am just curious what the sales for
13
Accutane for Roche were in 2002, prior to generic
14
entry into the market.
15
MS. REILLY: In 2002, that year to
date
16
figure was 380 million.
17
DR. GROSS: Thank you.
18
Before proceeding, I would like to read a
19
comment that Dr. Jackie Gardner suggested I read,
20 and
I concur.
21
We would like to publicly thank the people
22 who
came forward during the open public hearing
66
1
with their personal stories and acknowledge how
2
difficult that was.
3
Thank you.
4
Allen Mitchell.
5
Responses from Slone Epidemiology Center
6
DR. MITCHELL: Thank you. I think we have
7
things working.
8
[Slide.]
9
If I can follow up on Dr. Katz's question
10
from our survey, which is a similar design, the
11
response rate to the during and after treatment
12
questionnaires, the questionnaires that are sent to
13
women at the onset of therapy and the midst of
14
therapy is about 97 percent in our survey. It is
15
extremely high. That is both with
mail and
16
telephone responses included.
17
I wanted to speak about the limitations of
18 the
voluntary isotretinoin survey and perhaps some
19 of
the non-limitations because it seems to us that
20
this is a critical issue in interpreting the data.
21
[Slide.]
22
Quickly, to review some of the questions,
67
1 and
these are questions that we have posed as
2
potential limitations to this or any other survey
3
since 1988 when we first designed it, what is
4
success. The committee is
struggling with this.
5
Of course, there were no pre- and
6
post-comparisons possible, and here we are talking
7
about the data up until the onset of S.M.A.R.T.
8
These are the 14 years of data preceding S.M.A.R.T.
9
What are the critical events that one
10
judges success by, is it pregnancies, live born
11
infants, infants with birth defects?
Is the
12
critical outcome a rate of pregnancy, or is it an
13
absolute number?
14 One could imagine different scenarios
with
15
very different responses to that final question.
16
[Slide.]
17
Two other limitations that we have
18
identified is that survey participation may provide
19 an
unintended intervention and also that recall of
20
risk management may be biased among women who
21
become pregnant.
22
We were well aware of those two concerns
68
1 going into it, and to deal with those
concerns, the
2
design, which is admittedly complicated, includes
3 two
arms, the AT arm, which is the after therapy
4
only interview, if you will, and the DAT arm, which
5 is
the during and after therapy interview with a
6
number of contacts with patients throughout the
7
course of therapy.
8
Those have varying degrees of patient
9
contact, and information in those arms is collected
10
either prospectively or retrospectively with
11
respect to some of these behaviors. So, we think
12
that we have been able to deal with those issues.
13
[Slide.]
14
There is another point about whether the
15
reporting of pregnancies among survey participants
16 is
credible. We are, of course, concerned
about
17
that. If women are avoiding
pregnancy during
18
treatment, one would expect a rebound in pregnancy
19
rates following treatment. That
seemed to us to be
20 an
indirect measure of whether reports may be
21
accurate.
22
[Slide.]
69
1
We have lifted this figure from our 1995
2 New
England Journal paper, which summarized the
3
survey experience to date at that point, to
4
describe the pregnancy rates and outcomes during
5 and
after isotretinoin therapy.
6
I think it becomes fairly clear that
7
during treatment now, which is lumped together, the
8
pregnancy rate is somewhere approximately 9 per
9
1,000 person years. We are using
person years
10
here.
11
And as you can also see, elective
12
termination represents about 70 percent roughly of
13
those pregnancies. In the one
month after
14
treatment, where the risk of malformation is
15
considerably reduced, and in our data doesn't show
16
much increase at all, but in that one month of
17
therapy, you begin to see the pregnancy rates
18
increase, and in the two months, three months, and
19
four months after therapy--and we only go out to
20
four months--what you find is a considerable
21
rebound in the pregnancy rates, which is what one
22
would expect if women are trying to avoid pregnancy
70
1
during the course of therapy.
2
But it is also interesting to point out
3
that by the time you get to the fourth month, the
4
proportion of pregnancies that result in elective
5
termination approximates what we see for the U.S.
6
population.
7
So, this provides some indirect assurance
8
that reporting is not terribly inaccurate.
9
[Slide.]
10
But what I want to focus on is the issue
11 of
whether voluntary enrollment may compromise
12
representativeness, and, of course, one always
13
worries about that.
14
The response to that concern is to
15 maximize
enrollment. We all know that, that is
16
basic epidemiology.
17
[Slide.]
18
The second approach is to compare the
19
survey population to the target population, and to
20 do
that, using demographic characteristics, on the
21 one
hand, and ideally, the risk factors in the two
22
groups, on the other hand.
71
1
[Slide.]
2
I think we should make the point and
3
understand clearly that enrolling 60 percent or
4
more of the target population does not, in itself,
5
assure that that population is representative.
6
Conversely, enrolling less than 60 percent
7 of
the target population does not assure that the
8
sample is unrepresentative, and I think that there
9 has
been a fair amount of assumption that because
10 the
enrollment rates are below 60 percent,
11
therefore, the sample population is
12
unrepresentative.
13
[Slide.]
14
It is very difficult to make direct
15
comparisons in trying to respond to the question
16
about is the survey population a biased sample, and
17 we
could spend days, as we have, we have spent
18
months over the past 14 years struggling with how
19 to
evaluate this, the best we can do, and this is
20
based, not only in our own considerations, but
21
suggestions from FDA and from advisory committees
22 and
our own advisory committee that we have, is to
72
1 do
some indirect comparisons.
2
These are necessarily limited and
3
imperfect, and I wish to make that very clear.
4
[Slide.]
5
Two parts of data that I want to present
6
were alluded to in the FDA review document. One
7 was
a comparison we did using United Health Care
8
data, which is a large plan that had I think 14
9
different prescription plans under one umbrella.
10
What we were able to do through a
11
complicated process was to compare women who had
12
received a prescription for Accutane through that
13
plan, and look at those who enrolled in our survey
14 and
those who didn't enroll.
15
[Slide.]
16
There were very few variables that we
17
could identify for comparison, but one of them was
18
age, and what we found was that the age among the
19
Accutane participants was somewhat younger by about
20 two
years than it was in the population that didn't
21
enroll in the survey. This was
actually compatible
22
with some anecdotal reports which we frankly didn't
73
1
believe from one of our colleagues at Roche at the
2
time.
3
This was back in the beginning of the
4
survey, in the '90s, who had said that in his
5
conversations with providers, he was finding a
6
number of them reporting to him that they tried to
7
have women participate in the survey if they felt
8
that woman was at increased risk, that they felt
9
that the survey would provide some additional
10
intervention or a component that would help
11
encourage compliance. It might do
that indirectly,
12 but
it certainly isn't the purpose of the survey.
13
[Slide.]
14
So, this was compatible in that one would
15
expect that women who are older would be at less
16
risk for pregnancy, and, indeed, when you stratify
17
these findings according to age, and now we are
18
looking at this time the participation rate in the
19
survey was estimated to be about 40 percent, what
20 we
found was that that 40 percent rate was fairly
21
consistent across the three youngest age strata.
22
Where the participation rates were lowest were in
74
1 the
oldest group of women, and, in fact, among the
2
women 50 to 59 years old, only 14 percent
3
participated, which would be compatible with the
4
either subselection or doctor's selection of women
5 at
low risk saying don't both participating in the
6 survey, you are not at risk for pregnancy.
7
[Slide.]
8
The other data alluded to in the FDA
9
review, and that we have cited, and these are again
10
previously presented data, is a consumer survey
11
that was conducted by Roche identifying a number of
12
women who had been prescribed Accutane, and asking
13
them whether they enrolled in the survey or not,
14 and
interestingly enough, the age difference was
15
again about two years, that the enrolled women
16
tended to be about two years younger than those who
17
didn't enroll in the survey.
18
Median education wasn't terribly
19
different, the source of their prescription wasn't
20
terribly different, indeed, the women in the
21
survey, 10 percent more than the women who weren't
22 in
the survey reported being sexually active, and
75
1 not
surprisingly, along with that, higher rates of
2
contraception use.
3
Now, one of the things cited in the FDA
4
report was that, well, gee whiz, if you look at
5
this population, use of the birth control pill was
6
reported by 40 percent of the women enrolled in the
7 Slone survey, but only 16 percent among the
women
8 who
did not enroll.
9
On the face of it, there is no question
10
there is a difference there. It
is not accounted
11 for
by condom use or other barrier methods, but it
12 is
striking that the surgical sterilization rates
13
were compensatorily different among the enrolled
14 and
unenrolled women, and if you add up the highly
15
effective contraceptive methods as a percent, what
16 you
find is that they are virtually identical in
17
terms of highly effective contraception use among
18 the
women in the survey and the women who chose not
19 to
participate in the survey.
20
[Slide.]
21
But again, even within this analysis,
22
there is about three times as many women--two and a
76
1
half times as many women on the pill in the survey,
2
suggesting that again, if anything, the survey
3 population
may be at higher risk for pregnancy
4
since surgical sterilization is a highly effective
5 and
more effective method than the pill.
6
[Slide.]
7
Finally, bringing us to the most recent
8
data, we compared the survey data, as did FDA,
9
versus isotretinoin users according to age--and
10
this is in the one year before S.M.A.R.T., and we
11
used the FDA data presented for advanced PCS as
12
representing the base population, the target
13 population, and we have provided the survey
age
14
distributions on the left.
15
I think most observers would say that this
16 is
actually, until you get to the older age groups
17 for
sure, pretty representative, and while there is
18 a
decrease in the proportion of participants who
19 are
15 years of age or under, that decrease is
20
relatively small, where again we see a deficit of
21
participation that is fairly consistent is again in
22 the
older women who are less at risk for pregnancy
77
1 by
and large.
2
[Slide.]
3
And, indeed, when you compare the
4
pregnancies-- this is again in the year
5 pre-S.M.A.R.T.--reported
by our survey, and the
6
total reported by FDA including the spontaneous
7
reports, we see striking similarities in the
8
distributions.
9
[Slide.]
10
So, in answer to the question is the
11
survey population a biased sample, to us, the
12
evidence does not suggest that the survey
13
population is biased towards women at low risk of
14
pregnancy.
15
Indeed, the indirect evidence, and I
16
stress it is indirect, suggests that, if anything,
17 the
survey disproportionately includes women at
18
relatively high risk of pregnancy, and this pattern
19 has
been observed consistently at various points in
20 the
survey's history.
21
[Slide.]
22
That brings us back to this figure that we
78
1
showed in our presentation yesterday, where we
2
observed, again in the pre-S.M.A.R.T. era, 14 years
3 experience,
a decrease in the pregnancy rate from
4
roughly 4-fold to a little bit over 1-fold, a
5
rather striking and consistent decrease over time.
6
[Slide.]
7
Well, if the survey has any value, we need
8 to consider
what this means, and we think this
9
trend is unlikely to be explained by enrollment
10
biases, which would have to have changed over the
11
14-year period.
12
We have done all sorts of models as to how
13 one
might account for this trend through biases,
14 and
it is very difficult to come up with one.
15
[Slide.]
16
Rather, we think it may reflect continuing
17
improvements in the implementation of the risk
18
management program via its incorporation into
19
routine practice and I might add residency training
20
programs and the dermatology programs, so that our
21
summary view is that without respect to S.M.A.R.T.
22
specifically, we do think that the 14 years
79
1
experience preceding S.M.A.R.T. does reflect
2
incorporation of risk management elements to the
3
point where they have actually appeared to result
4 in
a fairly substantial decrease in the pregnancy
5
rates.
6
I will be happy to take questions, and
7
thank you for your consideration.
8
DR. GROSS: Are there any
questions? Yes.
9
DR. KIBBE: My question deals with
the
10
characteristics of the individuals in the two
11
groups, those that undergo therapy and don't get
12
pregnant, and those that undergo therapy and end up
13
having either been pregnant when they start or end
14 up
getting pregnant during the time frame.
15
I guess we could say that 99 percent of
16 the
women who enroll in therapy are successful in
17 not
having a pregnancy occur during that, and 1 or
18 2
percent do, but what characterizes the
19 differences
between those two groups, because if we
20
want to improve what we do, we don't have to change
21 it
for the 98 percent who go through the process
22
effectively, but if we could find some handle that
80
1
would help our clinicians identify individuals that
2
needed an additional activity or procedure, it
3
would help us a lot.
4
DR. MITCHELL: Actually, it is
obviously a
5
relevant question. First of all,
from these data
6 in
the most recent years preceding S.M.A.R.T., the
7
pregnancy rate would be 99.9 percent, it's roughly
8 1
in 1,000. I don't mean to quibble, but
it is
9
useful to keep that in mind.
10
What we would call the
analysis you are
11
describing is a risk factor analysis.
What one of
12 the
public speakers called it was a failure mode
13 and
effects analysis.
14
We are in the midst at the present time
15 frankly
in doing a detailed analysis of exactly
16
that consideration. We have
certainly identified
17
crudely that there are no gross characteristics
18
that appear to predict an increased risk of
19
pregnancy.
20
As one might expect, we have seen the
21
chosen method of birth control is directly related
22 to
the risk of pregnancy. We have seen that
the
81
1
typically effective methods are effective and the
2
typically ineffective methods are ineffective.
3
We have also seen and published in this
4
paper in 1995, our experience which indicates that
5 for
any given mode of contraception, we provide
6
data to suggest considerably higher efficacy than
7 the
generally published data on efficacy, and that
8 is
because we think the motivation of this
9
population is unusually high.
10
What we are doing now is looking at all
11 the
elements in the Pregnancy Prevention Program,
12 the
pre-S.M.A.R.T. Pregnancy Prevention Program, to
13 see
if we can identify any elements that do exactly
14
what you are describing, that characterize the
15
women who become pregnant and distinguish those
16
women from the women who did not become pregnant,
17 so
that interventions could be targeted to that
18
population, and we are hoping to have that
19
completed--Dr. Trussel, James Trussel is going to
20 be
joining us in that analysis as he has in the
21
past--and we hope to have completed in the next few
22
months.
82
1
DR. KIBBE: A second question has
to do
2
with my interest in the international experiences,
3 if
you will, with this medication. Roche
has said
4
that they have never had a country ask them to take
5 it
off the market, but I can't imagine that there
6
aren't countries that are interested in eliminating
7 the
risks.
8
Do you have any access to any data that
9
would help us understand how their interventions
10
differ from ours and how their risk ratios might
11
differ from ours, and how that might impact our
12 decisionmaking?
13
DR. MITCHELL: The short answer is
no, we
14
don't have any data and we have certainly tried to
15
find such data. One of the concerns that we have is
16
that the way drugs are managed philosophically in
17 some
other countries, and particularly one
18
scandinavian country with which I am aware, is very
19
different culturally from the U.S.
20
In one country, the attitude was that we
21 do
what we do and after that it is not our concern,
22 and
they don't track the outcomes of exposures, not
83
1
pregnancy exposures, but even pregnancy rates.
2
I think the U.S. is frankly, uniquely
3
providing information that has a denominator.
4
Other countries have not, to our knowledge, taken
5
this concern nearly as seriously as it has been
6
taken in the U.S., and the result is that there is
7
very little data.
8
DR. GROSS: Thank you, Dr. Kibbe,
for your
9
questions.
10
The next question comes from Dr. Honein.
11
DR. HONEIN: Yes. Dr. Mitchell, you
12
mentioned 38 to 45 percent survey enrollment based
13 on
the United Health Care survey for 1990 to 1996.
14
Yesterday, the FDA presented data suggesting a 19
15
percent survey enrollment for the year prior to
16
S.M.A.R.T.
17
Was there that much decline in enrollment
18 in
the survey over that time period, or is this a
19
different methodology for calculating the estimated
20
survey participation?
21
DR. MITCHELL: The methodologies
by which
22 you
calculate participation requires that you know
84
1
what the denominator is, and the denominator is the
2
number of unique women taking the drug.
3
The difficulty in establishing that
4
denominator, the difficulties are considerable, and
5 we
have had a lot of debates over the years about
6
what is an appropriate denominator.
7
I mean if you simply divide the total
8
number of female scripts by 3.7, as the FDA used
9 the
figure from one experience in the Seattle area,
10 you
come up with one estimate of a denominator.
If
11 you
divide that by 4 prescriptions or 2
12
prescriptions, you get very different denominators.
13 The
Kaiser data I think were closer to what we use.
14
But the fact is that we do suspect, based
15 on
indirect evidence, that participation rates
16
declined over time, and it was really because of
17 our
concern that we focused a lot of attention on
18
does the decline also reflect some differences in
19 the
way women are enrolling.
20
What we think, although we can't prove, is
21
that the $10 incentive, which we identified at the
22
outset of the survey back in '89 as an incentive to
85
1 get
women to participate in the survey through the
2
medication package which we came up with the idea
3 of
putting the enrollment form in the medication
4
package to bypass the physicians who may not want
5
women to participate or may not encourage them.
6
So, we said, you know, make it like a
7
toaster rebate coupon and encourage women who might
8 be
noncompliant to participate. But that
was a $10
9
incentive back in 1989, and one of the reasons for
10
increasing the incentive in the most recent efforts
11 was
to adjust, if you will, for inflation that $10
12
incentive. So, we do think that
there has been a
13
decline.
14
DR. GROSS: The next question is
from Dr.
15
Wilkerson.
16
DR. WILKERSON: Considering best
practices
17
once again, considering the women that we have, the
18
ages, the methods of birth control that they have
19
employed and reasonable rates of success of those
20
programs, what would be your calculated rate of
21
pregnancies per 1,000 cases if everybody did
22
exactly what they were supposed to do and they used
86
1 the
methods which are they using, what would this
2
rate actually look like? Instead
of being 1 per
3
1,000 courses of therapy, how much would it go down
4 to?
5
DR. MITCHELL: Can I turn your
question a
6 little
bit?
7
DR. WILKERSON: It depends.
8
DR. MITCHELL: I can't give you
the
9
answer. Okay, I can't give you
the answer, but I
10
want to understand the question, so we could give
11 you
the answer.
12 DR. WILKERSON: In other words, if you
13
take the current women and their methods of birth
14
control that they are currently using, use
15
optimally as real, everyday life people use them,
16
what would be the predicted rate of pregnancy per
17
1,000 courses or however you want to express this.
18 We
know that methods fail, we know that.
19
That zero is not obtainable in this
20
process short of females not taking this drug right
21
now, but I mean best practices in normal settings,
22
what would be the predicted rate of pregnancy in
87
1
this setting.
2
DR. MITCHELL: I think I can parse
that
3
question, to use an old term. One
question is in
4
efficacy in the normal use of the method, and, in
5
fact, what our data suggests is that efficacy is
6
better than normal data would suggest.
We can
7
spend a lot of time on defining on how best
8 efficacy was defined some years ago.
9
In the population we have observed, what
10 we
see is roughly 1, 1.2 per 1,000. If all
women
11
were on the pill, I could actually get you some of
12
those estimates, it's in the paper, but I think the
13
real question is what is the efficacy if women are
14 on
two methods of contraception, which is what is
15
specified in the risk management program.
16
The difficulty in assessing that is trying
17 to
find out whether women who report two methods
18
were reporting two simultaneous methods.
Those
19
kinds of questions become extremely, not only
20
invasive, but they become extremely difficult to
21
ask, because you essentially have to understand if
22 a
woman is on the pill, did she take a pill every
88
1
day, if she was using the pill and the condom, did
2 she
use the condom with every act of sexual
3
intercourse with the male partner.
4
One of the concerns is that women may be
5
interpreting the two methods, may be using two
6
methods, but forgetting the simultaneous. It is
7
conceivable, this is sort of the law of unintended
8
consequences that Dr. Trontell mentioned yesterday.
9 A
concern we have, although we don't have data to
10
support it, is there going to be a fraction of
11
women who say, okay, I have got to use two methods,
12 I
will use the pill a couple days a month and I
13
will use the condom when I think of it.
14
I don't mean to dodge your question.
We
15 can
give you contraceptive efficacy rates for any
16
single method that was reported, and it's in the
17 paper,
in the New England Journal paper from '95,
18 but
we can't answer the question any more directly
19
than that.
20
DR. GROSS: Dr. Kweder, do you
want to
21
comment on that?
22
DR. KWEDER: Yes, basically, it is
similar
89
1 to
what Allen had to say. We have some
slides that
2
display contraceptive method effectiveness rates as
3
generally understood, but there really are not data
4 that help us with the two methods
simultaneously
5
used, and Allen's point is exactly what we have
6
struggled with, as well, does it mean, you know,
7 how
many women actually interpret use of two
8
methods as simultaneous all the time.
That, we
9
don't know.
10
DR. GROSS: The next question is
from
11
Sarah Sellers.
12
DR. SELLERS: I am wondering if
you have a
13
regional distribution of the study participants.
14
DR. MITCHELL: We do, and it is
compatible
15
with the sales. I could get the
slide out, I would
16 be
happy to provide you. It will take me a
couple
17
minutes to find it, but it is similar.
18
DR. SELLERS: Just one more
follow-up, and
19 we
may have addressed this yesterday, but has the
20
survey been validated at all with any medical
21
records or exam data?
22
DR. MITCHELL: Specifically, how
would
90
1
you--
2
DR. SELLERS: To confirm in
particular any
3 way
to validate voluntary reporting on pregnancies.
4
Primarily, that would be the only thing that we
5
could look at.
6
DR. MITCHELL: I think the concern
is
7
false negatives, in other words, women who fail to
8
report pregnancies, and we have not done that.
9
That raises some privacy issues that are a little
10
tricky to get around.
11
Pregnancies that are reported are followed
12 up,
and any pregnancy that is identified with any
13
suggestions of malformations, the records are
14
obtained if the woman will allow us to.
15
DR. TRONTELL: I would like to try
and
16
address Dr. Sellers' question. I
just wanted to
17
point one challenge in assessing pregnancy. Many
18
health plans do not cover termination of pregnancy,
19 so
individuals who self-diagnose pregnancy and
20
elect to terminate outside their usual medical care
21
system will never be captured or ascertained.
22
DR. MITCHELL: Which is one of the
reasons
91
1
that we rely on voluntary reporting from
2
participants.
3
DR. GROSS: Thank you, Dr.
Trontell.
4
Dr. Strom.
5
DR. STROM: I wanted to follow up
on Dr.
6
Kibbe's question with a comment and then a question
7 to
the company in follow-up. You were
asking about
8 the
international experience in particular.
9
Anecdotally, my colleagues in other
10
countries tell me that Accutane is seen as a
11
uniquely American problem, but that is not because
12 we
are the only ones looking, but because we are
13 the
only ones using it so widely, that other
14
countries don't use it anywhere nearly as widely as
15 we
use it, so use is much less.
16
What I wonder about from the company is
17
whether you could give us sales data by population
18 for
some selected countries, so, for example, to
19 try
to nail down whether that anecdotal experience
20 is
correct, in other words, what is the rate of use
21 in
the U.S. population, how does that compare to
22
perhaps the English population or the Swedish
92
1
population or otherwise.
2
DR. HUBER: We do not have the
data on
3
sales broken down by country here.
That would take
4 us
a little time to compile and we don't keep those
5
here in the U.S., so it would take us some time.
6
DR. STROM: But I think that is
why you
7 are
not seeing the sensitivity from other
8
countries.
9 DR. KIBBE: I think there is an underlying
10
social issue, too, and that general acceptability
11 of
birth control methods in Sweden and some other
12
countries in Europe are going to be quite a bit
13
different than the United States.
I am trying to
14
figure out what factors are out of the direct
15
control of the system that we have are impacting
16 it,
that's all.
17
DR. GROSS: Thank you, Dr. Kibbe.
18
Dr. Whitmore has the last question.
19
DR. WHITMORE: Can you clarify,
you had a
20
graph up there talking about the number of
21
pregnancies during Accutane and then for the
22
subsequent months after therapy, and I thought it
93
1 was
10 per 1,000 person years, is that correct?
2
DR. MITCHELL: It was about 9
during
3
therapy, 9 per 1,000 during the course of therapy
4 at
that time.
5
DR. WHITMORE: So, just to
clarify, that
6
would be 1 in 100 essentially as opposed to 1 in
7
1,000.
8
DR. MITCHELL: Well, yes, but I am
sorry,
9 I
accept your correction. I am confusing
10
different--our usual rate estimators per course,
11 per
1,000 courses, correct.
12
DR. WHITMORE: And that was person
years,
13 and
therapy can range anywhere from 24 to 48 weeks
14
depending how dosing is done essentially. I think
15
that is a point that need to be re-emphasized as
16
opposed to if birth control pills and a second form
17 of
contraception were used effectively, maybe more
18
like 1 in 1,000 rate of pregnancy.
I mean those
19
numbers are not correct, but I think just to give
20 us
a ballpark idea.
21
One more question about your survey.
22
There is incentive to fill out the survey. For
94
1
teenagers, their parents probably make them fill it
2
out. For adults, there is a
monetary reward for
3
doing it, and also there are probably some adults
4 who
think oh, if I don't fill this out, something
5 bad
is going to happen, or think that it is part of
6 all
the program or something they need to do
7
particularly with all the PR about Accutane and
8
everything else.
9
So, I would say that a lot of people would
10
probably fill out the survey, fill it out because
11 of
incentive reasons of some sort, and then I would
12 ask
you, these women are signing a form that says I
13
will be abstinent or I will use two forms of
14
contraception throughout therapy.
15
What makes you think that a non-anonymous
16
survey is going to capture any information about
17
people actually not doing these things, they have
18
signed on a document saying they are going to do?
19
Also, reports about abortions, what makes
20 you
think that these women who have signed this
21
document, if they do get an abortion, if they are
22 not
going to tell their doctor, what makes you
95
1
think they are going to report it to you?
2
DR. MITCHELL: Probably the fact
that we
3 are
dealing with human beings would be a large part
4 of
that answer. We were similarly skeptical
going
5 in,
and remain somewhat skeptical, but less so.
6
What is very interesting is how often we
7
find women telling us things they have not told
8
their doctor. In fact, we
did--and, Dr. Katz, you
9 had
asked the question yesterday and I couldn't
10
remember what it was when we bumped into each
11
other, but it comes to mind now--and that question
12 is
really how accurately do the data reflect what
13 the
physician is doing.
14
We identified back in I think it was the
15
early '90s, a group of women who reported to us
16
that they had not had pregnancy testing prior to
17 the
prescription of Accutane. From their enrollment
18
forms, we were able to identify the physicians who
19
were in that loop.
20
We called those physicians' offices to ask
21
sort of an anonymous survey question about we are
22
just calling from Boston University, we are
96
1
querying physicians about their practices with
2
respect to Accutane, and typically, very often the
3
person responding would be an office manager or the
4
office nurse rather than the physician.
5
We asked whether they routinely did, in
6
fact, do pregnancy testing as one of a number of
7
questions, and a surprising number--not a
8
surprising number--a large number of physicians
9
indicated that they routinely do pregnancy--I mean
10 the
office nurse said oh, we always do pregnancy
11
testing, but a number of offices said to us we
12 don't.
13
Now, would you expect a physician's office
14 to
tell a survey that they don't do pregnancy
15
testing? The converse is also the
case, that when
16 we
identify a woman who reports that she is
17
sexually active and does not use contraception, we
18
consider that woman at such great risk for
19
pregnancy that the design of the survey calls for
20 us
to call that woman.
21
We call it reading the riot act.
We call
22
that woman and say to her that the behaviors you
97
1
reported to us put you at high risk for pregnancy,
2 and
we urge you to immediately call your physician,
3
stop taking the drug. Incidentally, would you also
4 be
willing to allow us to talk to your doctor.
5
When the woman gives us permission to call
6 her
doctor, you would assume that the doctor would
7
give you some response that would be compatible
8
with what the woman is reporting, and, in fact, I
9
can't give you the quantitative response, but there
10
were a disturbing number of times where the
11
physician would get on the phone with us, once the
12
woman gave us permission, and would go to the
13
medical record and read us from the medical record
14
that the woman said she was actively--so here was a
15
woman inviting us to find out, and what she was
16
doing was telling the survey--this is a long answer
17 to
your question, but I think it deserves that--she
18 was
telling us something that she wouldn't tell the
19
doctor.
20
So, the survey is actually in a position
21 to
find out things that a woman wouldn't tell the
22
doctor.
98
1
DR. WHITMORE: I had no idea that
you
2
called patients. I think that is
absolutely
3
fantastic.
4
DR. GROSS: Dr. Mitchell, thank
you very
5
much for your presentation.
6
DR. MITCHELL: Thank you.
7
DR. GROSS: Dr. Katz.
8
DR. KATZ: I want to clarify. You call
9 the
doctor's office, and you said some said they
10
didn't do any pregnancy testing, but you talked to
11 the
office manager and most doctors' offices--I
12
happen to draw blood in the office, but most don't
13
draw blood in the office--so, the office manager
14
says no, we don't do pregnancy testing.
They send
15 them
to the laboratory, but they don't do it.
16
DR. MITCHELL: First of all, let
me
17
explain this was a very biased sample.
This was a
18
sample of women, a small sample of women who had
19
told us they had not gone through a compliant
20
process, so we are already dealing with a subset
21
that is hopefully small.
22
When we called--Dr. Katz, I can't remember
99
1 the
specific questions, but we can get them for
2
you--we asked a series of questions of someone who
3
would be familiar with the offices practices, it
4
often was the nurse, but it represents only a very
5
small fraction, and we did incidentally try to
6
reach those doctors subsequently and get them
7
informed of what the appropriate practices were. I
8
don't mean to suggest that was a widespread
9
phenomena.
10
DR. GROSS: Thank you again, Dr.
Mitchell.
11
We will now move on to Dr. Trontell, who
12 had
some information to present to us that will be
13
helpful in our consideration of the questions.
14
DR. TRONTELL: There were some
questions
15
yesterday about the specifics of the clozapine
16
program and also of the S.T.E.P.S. program. I am
17
thankful to the representative from Celgene who
18
came and provided information, which I will repeat,
19 and
I will also invite that individual to come to
20 the
microphone to supplement it.
21
But relative to the registration of
22
patients in the S.T.E.P.S. program, patients are
100
1
registered by their Social Security number. In the
2
event that that number is not unique, a second
3
unique number is assigned to those individuals.
4 So,
the provision of patient anonymity in
5
S.T.E.P.S. it isn't truthfully there.
If you have
6
their Social Security number, that can be readily
7
linked to an individual's name.
8
The other question that was asked was
9
about clozapine and the mechanism that led to its
10
institution. In fact, information
provided to me
11 by
one of the members of the Division of
12
Neuropharmacologic Drug Products told me, in fact,
13
that some of the experience that I cited with
14
agranulocytosis related to post-marketing
15
experience abroad where the product was marketed
16
with recommended monitoring for white counts and
17
prevention for agranulocytosis.
18
That rate was on the order of 1 to 2
19
percent, and that had been described in the era of
20 the
clozapine national registry in practice with
21
mandatory monitoring of white count to be less than
22 1
percent, specifically 0.38 percent.
101
1
If there are additional questions, I would
2
invite the individuals who know each of those
3
registries to come to the microphone to address
4
them.
5
DR. GROSS: Hearing none, we will
move on
6 now
to Dr. Paul Seligman, Director of the Office of
7
Pharmacoepidemiology and Statistical Science at the
8
FDA, who will introduce the questions to us.
9 Introduction of Questions
10
DR. SELIGMAN: Good morning. I have been
11
asked to present the issues and questions for
12
consideration by the committee this morning and
13
this afternoon.
14
Please note that these questions are part
15 of
the agenda that was distributed for the meeting
16 and
can be found after the agenda.
17
Before I begin, I just want to take a
18
brief moment on behalf of myself and my colleagues
19 at
the FDA to also thank the members of the public
20
this morning who were here to share their testimony
21 and
their personal experiences.
22
The issues and questions fall into the
102
1
following sort of broad categories.
We are asking
2 the
committee today to evaluate the performance of
3 the
current program and the data that have been
4 presented both yesterday and today, to
consider
5
options for improvement of this current risk
6
management program, to consider how best to monitor
7 any
recommended changes, and to consider benchmarks
8 for
success as noted yesterday morning.
9
I think it was the first question out of
10 the
gate by Dr. Bigby, as well as others this
11
morning, who have focused on how best to determine
12
whether subsequent changes or any program that
13
comes out of these deliberations should be
14
determined to be successful.
15
[Slide.]
16
The first issue that we ask the committee
17 to
consider this morning is that based on the
18
reports and patient surveys, there does not appear
19 to
be a meaningful decrease in the number of
20
pregnancies reported in women taking a course of
21
isotretinoin since implementation of the current
22
risk management program.
103
1
We would ask you then to discuss the
2
measurement and implementation factors that may
3
have contributed to these findings.
4
[Slide.]
5
The second issue is based on prescription
6 audits and patient surveys, use of the
7
qualification sticker is high.
Patient surveys
8
suggest an inconsistent link between monthly
9
pregnancy testing and use of the stickers.
10
Reported pregnancies and patient surveys indicate
11
incomplete or inadequate birth control measures
12
among females.
13
Again, we ask you to please comment on
14
measurement and implementation aspects of the
15
current program that may have contributed to these
16 findings.
17
[Slide.]
18
Question 3. FDA's goals for the
19
Isotretinoin Pregnancy Prevention Risk Management
20
Program are that: no woman who is
already pregnant
21 be
prescribed and dispensed isotretinoin, and that
22 no
pregnancies should occur while on this therapy,
104
1 and
that effective pregnancy prevention occur
2
throughout the course of treatment.
3
[Slide.]
4 In recommending any changes to the
risk
5
management program, we ask the committee to
6
consider the potential tools and strategies in
7
light of the likelihood of effectiveness in further
8
reducing fetal exposure, the practical impact on
9
health care providers who prescribe and dispense
10 the
product, and the impact on patients who must
11
navigate any such program.
12
[Slide.]
13
Given these factors, we are asking the
14
committee to consider the following options:
15
(a) Continue the current risk management
16
program without additional tools, and if this is
17 the
recommendation, if so, what approaches do you
18
recommend to improve adherence with the program by
19
patients, physicians, pharmacists and others, such
20 as
health educators?
21
[Slide.]
22
(b) Or to consider modification of the
105
1 current program with additional risk
management
2
tools to reduce fetal exposure.
3
We list a number of them here, such as
4
programs to enhance education and interaction with
5
patients to identify and minimize high risk
6 behaviors; to tighten the linkage of
prescriptions
7
dispensed by pharmacists with required check of
8
pregnancy test results; the registration of
9
patients, pharmacists, physicians and/or others
10
such as health educators; limiting the access or
11
distribution of the drug, or other tools. In
12
recommending the other tools, we would ask you to
13
describe them.
14
I should note that in the course of our
15
discussions and deliberations, other tools have
16
also been mentioned, but not listed here.
17
[Slide.]
18
Question 4. In order to
adequately
19
monitor the risk management program, we ask the
20
following:
21
(a) Would it improve monitoring of risk
22
management program performance to register
106
1
patients, pharmacists, physicians, and other
2
relevant participants?
3
(b) If participants in such a risk
4
management program are registered, how can this be
5
more effectively done in a multi-source
6
environment, so that individuals are not registered
7
multiple times or double-counted?
8
[Slide.]
9
Finally, we are asking the committee to
10
identify critical benchmarks for determining the
11
success or failure of the
pregnancy risk
12
management program, and suggest, for example, such
13 as
reducing to zero the number of women who are
14
pregnant at the initiation of isotretinoin
15
treatment, and others.
16
I am happy to answer any questions about
17
these issues and provide any clarification as need
18 be.
19
DR. GROSS: Thank you, Dr. Seligman.
20 Committee Discussion
21
As Chair, I am going to make a suggestion
22
that we consider Question 3 last because that is
107
1 the
recommendation of the committees on what the
2
program should be in the future.
3
Question 4, I suggest be considered before
4 3
because it talks about whether or not registers
5
would be helpful, and that may be part of the
6 ultimate
plan that we come up with in Question 3,
7 and
assessing success and failure is something that
8 we
can also consider beforehand.
9
Is that okay with the committee if we do
10 it
in that order, Question 1, 2, 4, 5, then 3?
11
Does anybody have any objections to that? Okay.
12
Why don't we begin with Question No. 1.
13
Based on the reports and patient surveys, there
14
does not appear to be a meaningful decrease in the
15
number of pregnancies reported in women taking a
16
course of isotretinoin since implementation of the
17
current risk management program.
18
Data has been presented on that.
Please
19
discuss measurement and implementation factors that
20 may
have contributed to these findings. If I
may
21 be
so bold as to say that insufficient data has
22
been presented to answer that part of the question,
108
1 but
let's hear what committee members think on
2
those issues.
3
Dr. Gardner.
4
DR. GARDNER: As a non-clinician,
it would
5
help me greatly to understand what happens in the
6
clinician's office in terms of the implementation
7 of
these processes both from the standpoint of
8
physician and patient burden, and also the
9
logistics we heard yesterday, a scenario of trying
10 to
get a pregnancy test, is it the result or a new
11
request, and so on.
12
Could the clinicians comment
on how these
13
processes are implemented in practice for example?
14
DR. GROSS: Any dermatologist want
to--Dr.
15
Katz.
16
DR. KATZ: We will walk you
through it
17
from the beginning. First of all,
the patient has
18
been seen multiple times previously, on every other
19
treatment we know, different antibiotics starting
20
with the least risk of inducing and most used for
21
decades, and then antibiotics with a high risk
22
profile.
109
1
Then, the patient is evaluated, and if it
2 is
a minor, the parent is in the office initially,
3 a
complete discussion of all side effects are done,
4 and
then the female patient, one can't portray in
5
this meeting the doctor-patient contact and the
6
validity of patient response, reliability of
7
patient, we can't project that here, but the
8
physician assesses that, as well.
9
Then, you give the patient a choice of
10
having a parent leave the room, so you can discuss
11 the
contraception end. We ask them if they
are
12
using contraceptives, and it is burdensome going
13
through this entire thing, then, of all the side
14
effects involved.
15
All risks are mentioned and if it is
16
decided to go ahead with the Accutane, in female
17
patients, baseline bloodwork is done, CBC, hepatic
18
profile, lipids, and HCG pregnancy test, and they
19 are
told to come back at the time of the next
20
period for another pregnancy test, or they can get
21
that done, since they are not coming, that might be
22 in
10 days, they wouldn't have to come back to the
110
1
office, they can go to the lab and get the
2
laboratory test. They will often fax it, and then
3
they can come by and get a prescription with the
4
yellow stickers.
5
They are told to come back in two weeks
6 and
then every four weeks through the course of
7
treatment. Bloodwork is obtained
each time, and
8
then they are given a prescription again. They are
9
reminded each time about the necessity of two means
10 of
pregnancy.
11
They are asked about the side effects, how
12
they are feeling as far as generally, and once
13
again you can't project everything.
You are
14
looking at their face to see how they are doing.
15
With all this said and done, you remind the patient
16
each time about the necessity of two means of
17
contraception.
18
A lot of times people say yes, it happened
19 to
me, to bear on this question further, how can
20
these adverse effects be reduced, it can't be to
21
zero because a patient says that she is not
22
sexually active, and each time she remarks a little
111
1
bit, she said I told you that last time, and each
2
time I remind her, she reminds me that, doctor, I
3
told you I am not sexually active, and then two
4
weeks later she calls me and says she missed her
5
period. This happens. So, how do
you eliminate
6
that?
7
Now, it so happens, then, we got a
8
pregnancy test, she wasn't pregnant, she had just
9
missed a period. But she was
concerned because
10
obviously, she wasn't sexually inactive.
So, these
11 are
the problems that face us, and that is why this
12 is
going to happen anyway.
13
Does that answer your question?
14
DR. GARDNER: Thank you.
15
DR. GROSS: Dr. Crawford has a
question.
16
DR. CRAWFORD: A follow-up either to Dr.
17
Katz or any other member of the committee. Other
18
than actual pregnancy testing, what would be
19
different with the male patient prescribed
20
isotretinoin?
21
DR. KATZ: No, except that
contraception
22
isn't discussed, which might bring up some points
112
1
that came up with the male patients, but, no, that
2 is
not discussed.
3
DR. GROSS: That is an issue we
will need
4 to
consider later on, whether male contraception
5
should be recommended.
6
At this point, I would like to encourage
7 the
committees to specifically stick to the
8
question.
9 The first part of the Question 1,
does
10
anybody disagree with the statement, the statement
11
being there does not appear to be a meaningful
12
decrease in the number of pregnancies?
Does
13
anybody disagree with that? Yes.
14
DR. BERGFELD: I would like to
speak to
15
that. This was a new program, the
S.M.A.R.T.
16
program for the dermatologists, and when they were
17
asked to participate, the American Academy of
18
Dermatology put in place very intensive teaching
19
courses at all of their meetings to inform the
20
dermatologists of their behaviors.
21
We were also visited by the company in our
22
offices in which the S.M.A.R.T. programs were
113
1
introduced to us. We then had
didactic sessions to
2 go
through what our responsibilities were to be in
3
this program, and we were requested, and it was
4
inferred, that unless we signed up, we would not be
5
prescribing this drug and that we would be out of
6
order to prescribe this drug.
7
So, in my practice at the Cleveland
8
Clinic, we did abide by what we felt was the best
9
thing for our patients, we became informed, we
10
abided by the sticker qualifications, and we did
11
somewhat what you did, Dr. Katz.
We used the forms
12
that are given to us to go over with the patients.
13
But what I would like to say about this is
14
that what happened was that the compliance of the
15
dermatologists went up with informed consent and
16
education of the patient.
17
I think that is reflected by the fact that
18 you
have decreased numbers of prescriptions being
19
written overall, but a constant number of
20
pregnancies, and I think there has just been an
21
increased reporting that has gone on because of the
22
educational program.
114
1
I think when you open or begin a new
2
program, this is what you would expect, and I would
3
think that what we here do today would be to
4
enhance this program to make it more efficient and
5
improve it, so the reporting continues and the
6
education continues, with the ultimate objective to
7
reduce the pregnancies to zero if possible.
8
DR. GROSS: Okay. I am still trying to
9
answer Question No. 1. Let me
take the prerogative
10 of
the Chair and say there does not appear to be a
11
meaningful decrease in the number of pregnancies.
12
Would anybody disagree with that?
Dr.
13
Whitmore.
14
DR. WHITMORE: The one thing that
you
15
asked was are there contributing factors.
16
DR. GROSS: That is the second
part of the
17
question. Let's do the first part
first.
18
Otherwise, we are never going to get through the
19
day.
20
Does anybody disagree? Dr.
Ringel.
21
DR. RINGEL: I think the real
honest
22
answer is that we really don't know.
We don't know
115
1 if
Dr. Bergfeld's comment about the number being
2 artificially high because of increased
reporting is
3
true.
4
On the other hand, if that number really
5
reflects the actual rate, that is problematic
6
because the rate should have decreased, in fact,
7
because there were decreased numbers of
8
prescriptions written.
9
I think the only thing that this shows is
10 we
don't have the answer to that, and we really
11
need a registry.
12
DR. GROSS: So, we have one
dissenter.
13 Does
anybody else dissent on the statement there
14
does not appear to be a meaningful decrease in the
15
number of pregnancies? Dr. Bigby.
16
DR. BIGBY: The suggestion has
been raised
17
should we consider as an objective, the rate or the
18
absolute number, so if, in fact, you could show,
19 and
you could probably do this, that the rate had
20
actually decreased and the absolute numbers in the
21
hundreds, is that a success. That is the point I
22
think we should think about, so maybe rate isn't
116
1
what we should be looking at.
2
DR. GROSS: Could I see a show of
hands on
3 the
question there does not appear to be a
4
meaningful decrease in the number of pregnancies?
5 We
are never going to get through the program.
We
6 are
going to be stuck on Question 1 until 5:00 p.m.
7 To
me, the answer seems obvious. Yes.
8
DR. SCHMIDT: Yesterday, on page
70 in
9
this Pregnancy Rate and Accutane Survey, this, I
10
thought was meaningful that it decreased, that
11
there was almost like a 2- to 4-fold decrease in
12
some of the slides that were shown in the decrease
13 in
pregnancy rate.
14
I want to add one other thing to back up
15
Wilma. You know, people are very,
very anal about
16
doing these different things in the offices.
17
At least in Houston, I mean we really bend
18
over backwards to do everything and cross out t's
19 and
dot our i's on these, and from a clinical
20
experience, I took a straw vote at one of our major
21
meetings, our Thursday morning conference, and
22
since this S.M.A.R.T. program started, I could only
117
1
identify in this group one pregnancy that had
2
occurred at least in our group, which probably
3
includes a lot of people doing a lot of Accutane.
4
DR. STROM: To bring it to resolution, I
5
think the problem is an issue of terminology and
6
people are confusing numbers and rates.
The
7
question is there does not appear to be a
8
meaningful decrease in the number of pregnancies
9
reported. I think it is very
clear that is the
10
case. That is based on
spontaneous reports, the
11
numbers are roughly even.
12
All of the issues everybody is raising are
13
correct in terms of issues of reporting that maybe
14
that the rates have gone down despite the fact that
15 the
numbers haven't, and I think those are the two
16
things that people have confused.
17
But the question says not a meaningful
18
decrease in the numbers, and those numbers are
19
based on spontaneous reports, that is clearly the
20
case. The numbers are roughly the
same.
21
MR. LEVIN: I just want to add to
Brian's
22
comment that I think what people are responding to
118
1 is
the second part. I mean the issue of
whether we
2 are
seeing better reporting, more accurate
3
reporting or actually that things are remaining the
4
same is a question of measurement, and that is in
5 the
second part of the question.
6
DR. GROSS: So, a show of hands on
the
7
first part of the question.
8
DR. DAY: Excuse me. Could I ask a
9
clarification? I know these questions have been set
10 for
some time, but is there a way for us to ever
11
modify it, so that we could have a second part that
12 we
could vote that the number has not decreased,
13 but
that we do not have sufficient evidence about
14 the
rate or the rate has or has not? Can we
15
address number and rate in this question?
16
Otherwise, some of us will be uncomfortable in
17
voting quickly one way or another to get it off our
18
agenda.
19
DR. GROSS: Sure, there is no
reason. I
20
think we should answer the question, then, if you
21
want to put another statement, there is no reason
22 we
can't do that.
119
1
DR. TRONTELL: May I offer some
2
clarification from the Agency? We
do our best to
3
express the questions clearly, but our intent in
4
this question was, in fact, to engage the committee
5 is
some discussion on the issue of ascertainment of
6 pregnancy, some of which have already been
raised
7 in
some of the remarks around the table.
8
We would appreciate some discussion or
9
closure around it, not so much an issue of debating
10
whether or not the numbers have changed.
We can
11
make our assessment of that, but the issue of
12
ascertainment, as well as implementation are what
13 we
would like the committee to address.
14
DR. GROSS: So, ascertainment
really
15
relates to the second part of the question.
16
A show of hands on the number of
17
pregnancies. Do all people think
the number of
18
pregnancies appear not to have decreased
19
meaningfully? A show of hands
that they agree that
20 is
the case.
21
[Show of hands.]
22
DR. GROSS: Those who disagree?
120
1
DR. KIBBE: Abstentions? I think the data
2 is
inconclusive and I will not vote one way or the
3
other when the date is unreliable.
4
DR. GROSS: Fine. So, the majority agree
5 and
there is one abstention.
6
DR. KWEDER: Dr. Gross, if there
is a
7
vote, we would appreciate it if you could record it
8 for
the record in the instances when you do vote.
9
Thank you.
10
DR. GROSS: For the record, the
group
11
agrees there does not appear to be a meaningful
12
decrease.
13
Do you want to go around the room, is that
14
what you mean by record?
15
MS. TOPPER: For the record, we
are
16
required to go around the room individually and
17
have each person record their vote.
If you will
18 say
your name and you agree or disagree, we will
19
need to have that. Thank you.
20
DR. GROSS: Art, do you want to
start?
21
MR. LEVIN: Arthur Levin. I agree.
22
DR. SAWADA: Kathy Sawada. I agree.
121
1
DR. VENITZ: Jurgen Venitz. I agree.
2
DR. STROM: Brian Strom. I agree.
3
DR. BERGFELD: Wilma
Bergfeld. I agree
4
with the number, but I do not agree with the rate.
5 I believe
the rate has gone down.
6
DR. GROSS: You believe the rate
has gone
7 up?
8
DR. BERGFELD: Down.
9
DR. RAIMER: Sharon Raimer. I am going to
10
abstain. I don't think we have
good enough data.
11
DR. GROSS: So, that is an
abstention?
12
DR. RAIMER: Abstention.
13
MS. KNUDSON: Paula Knudson. I agree.
14
DR. BIGBY: Michael Bigby. I agree with
15 the
statement that there hasn't been a meaningful
16
decrease in the number of pregnancies reported. I
17 do
think that there is information that the actual
18
rate has decreased.
19
DR. HONEIN: Peggy Honein. I agree.
20
DR. COHEN: Michael Cohen. I agree.
21
DR. WHITMORE: Beth Whitmore. I agree
22
there has not been a meaningful decrease.
122
1
MS. SHAPIRO: Robyn Shapiro. I agree and
2
also observe that by asking for numbers as opposed
3 to
rates, there seems to be an implied goal about
4
what we should be looking for, whether intended or
5
not.
6
DR. EPPS: Roselyn Epps. I agree.
7
DR. SCHMIDT: Jimmy Schmidt. I agree.
8
DR. CRAWFORD: Stephanie
Crawford. I
9
agree there has not been a meaningful decrease in
10 the
absolute number.
11
DR. GROSS: Peter Gross. I agree.
12
DR. WILKERSON: Michael Wilkerson. I
13
agree with the question.
14
DR. RINGEL: Eileen Ringel. I agree also.
15
DR. VEGA: Amarilys Vega. I think that we
16
don't have sufficient data.
17
DR. GROSS: So, that is an
abstention?
18
DR. VEGA: Yes, sir.
19
DR. DAY: Ruth Day. I agree with the
20
decrease in number reported and make no claims
21
about anything else, numbers that may have
22
occurred, as well as changes in rate.
123
1
DR. KIBBE: Arthur Kibbe. I abstain on
2 the
basis that the data is not conclusive, nor is
3
this an appropriate question.
4
DR. GARDNER: Jackie Gardner. I agree.
5
DR. KATZ: Robert Katz. I agree.
6
DR. SELLERS: Sarah Sellers. I agree.
7
DR. GROSS: Thank you all.
8
Now, for the more difficult part--that was
9
easy, believe it or not--please discuss measurement
10 and
implementation factors. This is really
where
11 the
expertise of the committee could be enormously
12
helpful.
13
Any suggestions, comments?
14
Robyn Shapiro.
15
MS. SHAPIRO: I agree with your
earlier
16
comment that there is insufficient data to weigh in
17 on
that.
18
DR. GROSS: Anyone else? Art.
19
MR. LEVIN: I guess I am just
confused by
20
what the rate, when talking about rates, where we
21
are. If I look at P70 of the
Roche presentation,
22
which is sourced at Slone and tracks the number of
124
1
pregnancies per 1,000 Accutane treatment courses
2 and
the number of pregnancies per 1,000 patients
3 per
year, there does seem to be a decrease, but
4
where we get down to is around the number 3, and we
5
have just heard from 4 to 3. Over
the period of
6
1989 to the year 2002, and if we sort of track
7
into, you know, sort of approximate on this graph
8
where the first prevention program came into effect
9 and
then where S.M.A.R.T. came into effect, which
10 is
probably not on this graph actually. You
know,
11 we
see recent history.
12
But we just heard of a rate of 1, I think,
13 in
the presentation from Slone. So, I am
just
14
personally somewhat confused as to the different
15
presentations of what the rate issue is, whether it
16 is
in the course of treatment or per patient year
17
what we are discussing here.
18
DR. GROSS: Sarah.
19
DR. SELLERS: I would just like to
remind
20
everyone that we are talking about a reporting
21
rate, we are not talking about an incidence rate,
22 and
the primary objective of the risk management
125
1
program is to decrease the number of pregnancies,
2 not
to decrease the reporting rate.
3
These are reported pregnancies and the
4
number of reported cases are small in comparison to
5
what we believe are the overall number of
6
pregnancies that may be occurring and exposures
7
during pregnancy.
8
So, a meaningful decrease in a reporting
9
rate, in my opinion, has very little validity in
10 the
discussion of decreasing pregnancy exposures.
11
DR. GROSS: Thank you.
12
So far we have been talking about
13
measurement on this question. How
about
14
implementation factors, implementation factors that
15 may
have contributed to a lack of a decrease in the
16
number of pregnancies? Dr. Katz.
17
DR. KATZ: Just to take one second
to
18
reiterate an anecdote--I won't reiterate it--but to
19
remind you we don't have part of not being able to
20
improve on it although we have to keep trying and
21 use
every effort is the human fallibility and that
22 was
my only point in mentioning that little
126
1
anecdote. You can't completely
control human
2
behavior, nor can we unfortunately 100 percent
3
control physician behavior and how much time
4
somebody is spending with a patient, and so forth.
5
So, some of it, we are not going to be
6
able to reduce it to zero.
7
DR. GROSS: A point well taken.
8
DR. KATZ: It was also pointed out
9
yesterday, with all the stringent requirements that
10 one
might consider adding, that still doesn't
11
eliminate pregnancies. It will
capture the numbers
12
better and it may be a reminder, an education
13
reminder, but if somebody is going to tell the
14
doctor that they are sexually inactive, you can't
15
force them to take birth control pills.
There is a
16
certain limit to what we can do.
17
DR. GROSS: Exactly. There is going to be
18 a
limit to what we can do, but does that mean we
19
shouldn't try to make the program stricter. I mean
20
that is going to be one of the things we have to
21
consider.
22
Dr. Venitz has a comment?
127
1
DR. VENITZ: Yes. My comment is with
2
those survey instruments in general.
We just had a
3
preview I think of our discussion when we looked at
4 the
reported numbers, and you stated that we are
5
dealing with reported numbers.
6
I would make the observation that in my
7
mind, the only number that has any validity is the
8
fact that 28.2 percent of the patients participated
9 in
the survey, which means the remainder, 70-plus
10
percent did not participate in the survey.
11
We are looking at pregnancies, which is an
12
event that presumably is rare with or without the
13
implementation or the appropriate implementation of
14 a prevention
program, so we are looking at in my
15
mind bias, at least potentially biased survey
16
sample.
17
So, any of the numbers that follow from
18
that point on, to me, cannot be interpreted whether
19
they are made or reported, they do not reflect any
20
interventional effects. So, the
observation I am
21
making is one of the limitations and anything that
22 I
have heard over the past day and a half is the
128
1
fact that only 28 percent of the patients post-
2
S.M.A.R.T. participate in the survey.
So, all the
3
numbers from that point on, to me are meaningless.
4
DR. GROSS: An important point.
5
Dr. Strom.
6
DR. STROM: I would like to
address the
7
measurement issues and to limit it, to some degree
8
this may be duplicative and I think is expressing
9
what everybody is saying, and then move on to the
10
implementation factors.
11
For a measurement issue, I think to a
12
large degree we are looking at spontaneous
13
reporting data. The problem there
is we have an
14
incomplete numerator, we have an incomplete
15
denominator, and given that, we can say something
16
about numbers.
17
In this case, the numbers are unusually
18
important perhaps because they are telling us there
19 are
still people being affected, but we can say
20
nothing about the rates, you can't calculate rates
21
based on spontaneous reporting data.
22
You have got again uncertain numerators
129
1 and
uncertain denominators. I think the only
place
2 we
have rates are the survey data, but as Dr.
3
Venitz said, and as Dr. Mitchell has talked about,
4 as
well, there are obviously limitations that have
5
been well recognized in the survey, and as much as
6 it
could be designed to address it, it has, but it
7 is
an intrinsic problem when you are dealing with a
8
voluntary system, and the enrollment is voluntary
9
accordingly.
10
In terms of implementation factors, I
11
think what we are hearing is an extraordinarily
12
complex system that it was certainly hard for us to
13 be
explained to us, no less harder yet for
14
clinicians to implement. I am a
general internist,
15 not
a dermatologist, so I don't prescribe Accutane,
16 and
I haven't been subject to it, and the more
17
details I hear about it, the gladder I am to that
18
effect.
19
I think there is a very substantial burden
20
here on physician and on pharmacist.
I think there
21 is
an enormous obviously lack of reporting as we
22
talked about, and I think there is a huge lack of
130
1
ability to enforce I think is the key issue.
2
I think to the degree we are talking about
3 a
system where you are trying to drive things
4
towards zero. You will never
achieve zero for the
5
reasons everybody is saying, but we are trying to
6
drive it towards zero.
7
You are not going to be able to get this
8
complex health care system with all of the enormous
9
heterogeneity and hundreds of thousands of
10
providers when you are dealing with physicians and
11
pharmacists, and try to ask the health care system
12 to
enforce it in a voluntary way.
13
It is just never going to happen, and I
14
think as long as we are relying on a voluntary
15
system in terms of the implementation, we can't
16
expect it to go as low as it can.
17
I am struck and impressed by how well it
18 has
done given all of that. I think there
has been
19
enormous compliance on pharmacy part, I think there
20 is
enormous compliance on dermatologists' part.
21
I think the answer isn't to keep hitting
22
people on the head, because we can't expect more
131
1
from a voluntary system than we have already
2
gotten. I think the problem is
the implementation
3 has
been voluntary and has been diffuse, and has
4
been totally decentralized.
5
DR. GROSS: So, zero is a laudable
goal
6 and
we can try to design a program to reach that
7
goal, but not expect that we will ever get there.
8 Dr. Vega.
9
DR. VEGA: I just want to concur
with Dr.
10
Strom, that in terms of the implementation factors,
11 I
think that the weakest of the links here is the
12
voluntary nature of this program, as he so nicely
13 described.
I think that is the best we can get
14
from this type of voluntary program.
15
DR. GROSS: Dr. Epps.
16
DR. EPPS: Just a few things I
wanted to
17
say. Although I know this is a risk management,
18 part
of the risk-benefit ratio, also to say
19
something about the benefits, and that it does
20
benefit a lot of patients, and those of us who use
21 it
or some of us who may have taken it, I feel that
22 I
should say something for them, because I think it
132
1 is
a very useful drug, I think it is a very
2
important drug.
3
Dermatologists, in general, are not very
4
cavalier about prescribing it. Most
of us are very
5
careful. I have treated a lot of
minor patients or
6
young people, and if either the parent or the child
7
does not agree, you just don't give it.
8
If the child is involved in risk-taking
9
behavior, they are the ones that are smoking and
10
underage drinking, they are probably having
11
unprotected sex, you don't give it to them. So,
12
patient selection is also very important.
13
Dermatologists, in general, quite a few
14 are
solo practitioners, kind of an independent
15
group, and to get over 90 percent participation,
16
anything isn't a miracle.
17
Also, I agree with Dr. Katz, it is very
18
difficult to control for human behavior or for
19
human biology, and there are some patients who will
20 say
or do, your history is only as reliable as your
21
informant, and you have to, you know, you take what
22
your patient says, you can look for signals for
133
1
other things.
2
When we deal with minors, however,
3
certainly you have to involve the parent and get
4
their consent. With adults, you
can't control
5
adult behavior. You can make
recommendations, you
6 can
make suggestions, but we don't go home with
7
them and we can't control. We can
advise, and we
8 can
withdraw the medication if they aren't doing
9
what they are supposed to do.
10
There have been questions about
11
international patients. I guess
it should be said
12
that different ethnicities have different
13
experiences with acne. It is not
the same in all
14
cultures. Some cultures are more
severe than other
15 people,
so I am not sure the emphasis on other
16
countries is that meaningful.
17
Also, if the survey is voluntary and
18
complete, it doesn't mean that it is necessarily
19
truthful. A couple of questions
might need
20
modification for minors, such as did
you sign the
21
consent. Well, a concrete young
person might say
22 no,
I didn't, my mother did, but I didn't sign the
134
1
consent, so you might want to say did you or your
2
guardian or parent do X, Y, or Z.
3
There are times when we do talk to parents
4
confidentially if they have something to say or
5
give the prescription, so the young person filling
6 out
a survey may not know that there is a sticker
7
involved.
8
So, there may be a few little
9
modifications that could be done on the survey, as
10
well.
11
DR. GROSS: I have a question of
Dr. Epps.
12
Would you like to make some suggestions?
You
13
brought up the issue of selecting the patients who
14 you
think would be appropriate rather than just
15
accepting whether they say yes, I will comply.
16
This might be helpful in designing a plan to
17
particularly say maybe this person is not
18
appropriate assuming they have cystic acne.
19
DR. EPPS: Well, as has been
alluded to
20
earlier, the doctor-patient relationship is
21
extremely important. I mean it is
pretty unusual
22 to
give, unless it's a male, to give Accutane on
135
1 the
first visit. I mean it is not usually
done.
2 You
need blood tests, you need follow-up, you need
3 consents.
4
As a subspecialist, I have sometimes
5
referred patients who already had treatments. They
6
come with a reference from their physician. I
7
usually talk to them or I might have medical
8
records from the referring physician indicating
9
what medicines they have had and how long they have
10 had
them, but still you are still going through
11
consent, you are still giving out the bound spiral
12
notebook folder, and proceeding in that way.
13
A lot of times--I guess part of my
14
pediatric background--you talk to the young people
15 and
ask them, well how is school, well, you know, I
16
skip and I don't go all the time or I am not in
17
school right now. I mean it is
probably not a good
18
person.
19
Multiple visits are helpful because you
20
will know whether they come back or whether they
21 are
compliant. If they come back with half a
vial
22 of
pills, then, that is probably not a good
136
1
Accutane patient.
2
I know some of us have been talking about
3
pills and people who have them left over and people
4 who
share, and that is always a concern, too, and
5
some of that is timing of appointments.
6
You tell them take all of your pills, you
7
know, and sometimes it requires a follow-up after
8 the
end of course, not only whether you are
9
monitoring blood tests, but to find out how they
10 are
doing.
11
You can't repeat the Accutane course for
12 two
weeks anyway--not two weeks, two months--if you
13
need to repeat a course. Most of
them don't need
14 it,
but they sometimes do like to follow-up with
15
questions or concerns.
16
I think most people are trying to do the
17
right thing. That is what I would
like to
18
emphasize, and I think most patients are trying to
19 do
the right thing, I really do.
20
DR. GROSS: Dr. Schmidt.
21
DR. SCHMIDT: I pass. Dr. Epps said
22
everything that I wanted to say.
137
1
DR. GROSS: Wonderful.
2
Dr. Sawada.
3
DR. SAWADA: I just wanted to get
back to
4 Dr.
Venitz's and Dr. Strom's comments. I
would
5
certainly agree with them that from the outset
6
yesterday, getting the information and the numbers
7 and
the wonderful slides, et cetera, it became
8
inherently confusing as to how valid the basic
9
numbers were.
10
Certainly, I think that things
11
contributing to this confusion with the validity of
12 the
numbers obtained has to do with the voluntary
13
nature of the survey. I certainly
think that is
14
something that we have to discuss.
15
The other thing is the recall nature of
16 the
survey, as well. I know that if I don't
17
dictate in the first 24 hours of seeing a patient,
18 if
I have to wait 24 hours, that information is
19
lost. It may just because I
am--no offense to
20
seniors--but it may just be that I am advancing
21
myself in age, but I certainly would suggest that
22
something other than recalling nature of the survey
138
1 is
something to consider.
2
The other thing is contacting the
3
physician. I have never been contacted
or informed
4
that a patient has filled out any of my surveys. I
5
certainly think something has to be done to protect
6 the
privacy of the patient when we review those
7
records, but that would at least be able to give
8 you
a corollary between what is in my record and
9
what the patient says.
10
DR. GROSS: Dr. Wilkerson.
11
DR. WILKERSON: A couple of
comments. We
12
have a saying in Texas you can lead the horse to
13
water, but you can't make him drink.
That
14
certainly applies to trying to legislate or trying
15 to
force people into compliant behavior, so whether
16 we
make these requirements mandatory or not, there
17 is
nothing that prevents that person from putting
18
untruthful answers on a document that they send
19
back to an anonymous third party, no more than it
20
prevents them from making false statements to their
21
physicians. Patients tend to
respond to your
22
expectations and I think they feel very bad when
139
1
they do fail.
2
Sixty percent, I was surprised that that
3 was
the goal that was set. If anyone has
ever done
4
measurement in population satisfaction surveys,
5
whatever, 60 percent is a lofty goal.
Generally,
6 if
you can get 10 percent back on a voluntary
7
survey of any type, I am told by industry is very
8
good, and sometimes even 1 percent.
9 So, to see that we are getting over
20
10
percent return is certainly quite amazing,
11
particularly when we are looking at the intimate
12
details that patients are revealing about
13
themselves. We are thinking about
these details in
14 a
clinical sense, but to the patients revealing
15
this, this is like taking their clothes off in
16
public almost.
17
My other question about this is from the
18
data, which I didn't see, is do we have particular
19
physicians who are non-compliant and result in an
20
overly large number of represented pregnancies.
21
This is an issue that we don't like to deal with.
22
We know that there are good drivers and
140
1 bad
drivers, and certain people seem to have
2
accidents more than others do, but certainly every
3 one
is, because the risk of probabilities expose
4 the
potential of having an Accutane-exposed
5
pregnancy no matter now good a job they do, but
6
certainly we need to look at practitioners also in
7
terms of are some people over-represented and why
8 are
they over-represented.
9
The other comment I had was I thought that
10 the
survey forms that I saw was the first time I
11 had
had an opportunity to see those documents that
12 I
could recall, I thought they were incredibly
13
complex and written well above what I would expect
14 for
the average patient.
15
I had to sit there and read through the
16
questions a couple times sometimes to try to grasp.
17 I
think we need a simpler, shorter document.
18
DR. GROSS: Well spoken. I think the data
19
presented to us at least really showed a paucity of
20
risk factors that would help us deal with failed
21
implementation, and hopefully, future surveys will
22
include more obvious, not so obvious risk factors.
141
1
The next questioner is Dr. Honein.
2
DR. HONEIN: I think one
implementation
3
factor that may have decreased the effectiveness of
4 the
current risk management plan is the existence
5 of
multiple names of this program and multiple
6
brochures and multiple surveys, which I think is
7
very confusing to patients and likely decreased
8
participation in the survey, or conversely, we
9
don't know how many patients enrolled in both
10
surveys, because there is no information going to
11 the
patients to even tell them that they shouldn't
12
enroll in the second survey.
13
I assume the vast majority of prescribers
14 got
the S.M.A.R.T. materials from Roche because
15
that came out first, and unless they got a very
16
small supply, they probably didn't have to request
17 the
other materials, but we saw yesterday that now
18
over half the prescriptions are for the generics,
19 so when they are getting their medication,
they are
20
getting a different information, a different
21
enrollment form.
22
I think unifying this into one approach
142
1
would help the situation a lot.
2
DR. GROSS: Good point.
3
The next question comes from Dr. Bigby.
4
DR. BIGBY: I think that the major
problem
5
with this medication is that it is uniquely and
6
highly effective for treating nodular acne, and I
7
think for most dermatologists, it is a drug that is
8
very important for us to be able to take care of
9
patients, but it also is teratogenic and therefore
10 I
think that the fact that we are talking about
11
making decisions about rates on the basis of
12
spontaneous reports and utilization really is
13
something that--I think we are remiss in having to
14
rely on such a paucity of data in trying to make
15
decisions.
16
I think one of the things that has to be
17
accomplished is that we make a mechanism where we
18
will actually detract female patients who are
19
taking the drug and make a really good effort to
20
make sure that we learn the outcome of those
21
patients while they are on the drug and for
22
sometime after.
143
1
I think only that way can we start to have
2
accurate measurements about basically what the rate
3 is
and what effects interventions have.
4
In terms of implementation factors, one of
5 the
things that struck me is that, you know, I see
6
patients at a university health service twice a
7
week, and the sort of demand for Accutane is
8
extremely high. Obviously that
age group patient
9 is
one that is at high risk for becoming pregnant.
10
One of the things that I try to make sure
11 is
that patients are at least on one effective form
12 of
contraception, and I think it is very well known
13 and
published in a book "Contraceptive Technology,"
14
what are the effective forms of birth control in
15
actual use. I mean they are
basically
16 sterilization
and hormonal therapy, and that the
17
failure rate of just about everything else is
18
unacceptably high for this drug.
19
So, one thing that we can do is to make
20
sure that people are at least on one effective form
21 of
contraception, and then I would just like to
22
make a sort of comment about the abstinence
144
1
loophole, I like to call it.
2
Someone said, well, if a patient insists
3
that they are abstinent, you can't make them take
4 the
pill. Well, yes, you can. You can give them
5 the
choice of either use an effective form of
6
contraception or not give them Accutane.
7
It always puzzled me about, you know,
8
abstinence as a loophole because if abstinence is
9
your primary form of contraception, what is the
10
secondary form.
11
So, if are abstinent on the pill, that
12
works for me. But if you are abstinent
and your
13
secondary form of contraception is a condom, then,
14 it
makes no sense whatsoever, because once you have
15 to
use a condom, you are not abstinent anymore, and
16 a
condom by itself is not an effective form of
17 contraception.
18
You know, the sort of published efficacy
19 of
condom alone is extremely low. Condom
and foam
20
gets to be I think around failure rates of 1
21
percent, but condoms alone, I think the pregnancy
22
rate is as high as 10 percent in use.
145
1
So, I think that we should eliminate the
2
abstinence loophole and make sure that all patients
3 are
at least on one effective form of
4
contraception, and then we can talk to them all we
5
want about using two simultaneous forms of
6
contraception, but I think we can at least start
7
with them being on at least one effective form of
8
contraception.
9 DR. GROSS: Thank you for your comments on
10 the
twists and turns and human logic.
11
Would anyone like to comment on whether or
12 not
the survey in the future program should be
13
mandatory? Dr. Cohen.
14
DR. COHEN: I think it should be
15
mandatory. Yesterday and today, I
think especially
16
with the patient survey, I guess, several of us
17
remarked about how little we know about the actual
18
causes. I know I did yesterday,
and I think you
19
did, Peter, as well, and others.
20
To me, not only should it be mandatory,
21 but
I think particularly with any follow-up that is
22
done with patients that became pregnant, where the
146
1
failures were, we really have to spend time asking
2
questions about what actually went wrong.
3
To me, that is absolutely critical, and
4
sooner or later, you would be able to put together
5
some data that would be of tremendous help in the
6
future in reducing these failures.
So, to me, that
7
would be critical, a different design, at least
8
with the follow-up that is done, and then tracking
9
what those reasons are.
10
DR. GROSS: Dr. Crawford.
11
DR. CRAWFORD: Thank you. I wish to
12
expand upon what both our Chair and Dr. Cohen just
13
said, and it is also follow-up to the first
14
question I asked yesterday. One,
I do think
15
surveys should be a mandatory part of the risk
16
management program, but I think they must be
17
coupled with some type of failure mode effects
18
analysis.
19
In response to different ways of saying
20 how
it was handled, to my recollection, yesterday,
21 Dr.
Huber stated that Roche had some follow-up
22
steps based on the S.T.E.P.S. and the S.M.A.R.T.
147
1
program.
2
Dr. Mitchell described some follow-up with
3
their survey processes this morning that included,
4
with permission of the patient, talking with the
5
physicians and comparing some of that data.
6
Dr. Miller gave two case reports.
One of
7 the
speakers from the open hearing, of course, that
8 is
another case report, but that was a different
9
risk factor that was brought up that hadn't been
10 put
on the table before.
11
So, I think part of the risk management
12
program, in addition to the survey, that we really
13
should strongly suggest the need for more
14
formalized follow-up of the failure cases including
15
qualitative data, not simply asking what went
16
wrong, but truly doing histories in cases, because
17 the
patients may not know what went wrong.
We have
18 to
ask questions beyond what could just be checked
19
off, really hear their descriptions of everything
20
that happens.
21
DR. GROSS: Thank you.
22
Dr. Ringel.
148
1
DR. RINGEL: I was going to
address
2
specific parts of the program that were implemented
3
that could have contributed to the number of
4
pregnancies, and I think one of those was the
5
stickers. The stickers are a
surrogate, and I
6
think that the FDA has shown very clearly that they
7
correlated very poorly with the pregnancy testing,
8 but
that is not all they did poorly.
9
Supposedly, those stickers, there was a
10 lot
in those small stickers. Supposedly,
those
11
stickers meant that your patient had the pregnancy
12
test, it meant that they had the pregnancy test
13
during menses, which, of course, you have no way of
14
knowing.
15
It means that you had made sure they were
16
going to be on two forms of birth control, that you
17 had
educated them, that you have done the consents,
18 and
that they had been on birth control for a full
19
month. That is a lot for a little
yellow sticker
20 to
do, and I don't think it did it very well.
It
21
didn't even do the one thing it was really supposed
22 to
do, which was to correlate with pregnancy
149
1
testing.
2
So, I would suggest that we do one of two
3
things, either just get rid of
the stickers and
4 get
the pregnancy tests faxed to the pharmacy, so
5
they will know that they are really there and they
6
have really been done, or make those stickers mean
7
something.
8
In other words, make them into a
9
checklist, so the doctor actually has to say yes,
10
they have been on birth control for a month,
11
because I know it has been a month since I last saw
12
them and I got in touch with the gynecologist, yes,
13 I
did the consents, you know, yes, I did the
14
pregnancy testing, and at least let them check off
15
that they have done the things that they have done,
16 so
it has some meaning. At least it will be
a
17
reminder, if nothing else, or just get rid of them.
18
DR. CRAWFORD: Dr. Gross temporarily
has
19
stepped out, so again, I get to say I have got the
20
power.
21
Dr. Day.
22
DR. DAY: A lot has been said so
far and
150
1
will continue to be said about human behavior, and
2 I
think the problems with human behavior should be
3
pointed in all directions. To be
human is to err,
4 and
there are errors that happen along the way from
5 the
physician's office, the pharmacist, the
6
patient, and so on.
7
Very often, for example, in the
8
physician's office, the affixing of the sticker is
9 an
interesting question. What happens if
the
10
patient comes in and needs to get the refill, and
11 the
physician is with another patient or out of
12
town, does anyone else in the office have authority
13 to
apply the sticker, such as the office nurse or
14
administrator, and what they might do is go and
15
look in the chart and say, oh, yes, this patient
16 has
been qualified by the doctor.
17
That was sometime ago, and if that person
18
then doesn't know that there has to be a
19
requalification procedure every single time, that
20
person might say, on, here is your sticker, go to
21 the
pharmacy.
22
So, we could generate many, many
151
1
opportunities for human error to happen along the
2
way. But to focus on the
patients, I think we have
3
confounded human behavior with some other things,
4 and
one of the most important things is
5
comprehension.
6
To my knowledge, there has not been
7
comprehension testing provided in the survey
8
materials. There is questions did
you do this, and
9 so
on, and so forth, and do you understand that,
10 and
then it tells you what you are supposed to
11
understand. Of course, you say
yes.
12
So, I think that there is a confound when
13
someone doesn't do something, is it because they
14
don't know that they are supposed to do it, or is
15 it
because they know but either they choose or
16
forget or circumstances get in the way of them
17
doing the thing.
18
A colleague here reminded me yesterday
19
about the speed limit. We all
know that the speed
20
limit might by 65 miles an hour in a certain area,
21 but
not everyone goes 65 miles an hour, some people
22 go
faster.
152
1
So, we have this confound of comprehension
2 and
behavior, but it is not insoluble.
Currently,
3 at
Duke University, we have a government-funded
4
project on studying comprehension of the
5
information to patients in the Medication Guide for
6
Accutane.
7
So, it may well be when the results are in
8
that the comprehension level is high and therefore
9 it
is a behavioral problem, and interventions need
10 to
be addressed there, or if the comprehension
11
level is low in some aspects, but not others, then,
12
additional materials or education or something
13
needs to be addressed to those points.
14 So, I don't think we should throw up our
15
hands about human behavior, and so forth. It can
16
always be, if you will pardon the expression, more
17
better, but we have to understand why there are
18
failures, not only of the failure effects approach,
19 and
so on, but is it comprehension or is it
20
behavior, and a relative blend of those, and how do
21
those interact.
22
So, I am sorry our Chair is absent while I
153
1 put
forward this plea to de-confound the many
2
important aspects that go into behavior that is not
3
fully appropriate.
4
DR. CRAWFORD: Thank you.
5
Dr. Schmidt.
6
DR. SCHMIDT: I think we need to
magnify
7 our
certainties, and one of the certainties is that
8
people, when they just listen to one person or they
9
look at one page, are not going to pick up the
10
information.
11
At least I and my colleagues in Houston
12
usually have people go to the gynecologist and get
13 a
consultation for their birth control if they are
14 in
a risk population, and then the other thing I
15
want to address is I don't want to put all my
16
patients on birth control pills.
17
I really have young girls who are
18
genuinely abstinent, and I do not want to put them
19 at
risk for retinal hemorrhage, and I truly believe
20
when they come in with their mother that they are
21
abstinent.
22
Now, human nature being what it is, there
154
1 is
a wonderful word in a prescription called
2
Prevent, and I always tell my patients that if they
3
have unprotected sex, and I have had them call, I
4
will give them a prescription for Prevent to take,
5 the
morning after pill. I think this is
something
6
that needs to be mentioned.
7
DR. GROSS: Robyn Shapiro, did you
have a
8
comment?
9
MS. SHAPIRO: I am going to
respond to
10
what I think you wanted us to talk about, and that
11 was
the surveys. This plays on Ruth's point a bit.
12
I think that when we look at some of the
13
proposals in the packages about the interaction
14
with the program, and I am not so sure what that
15
means, but I have an idea about maybe what it could
16
mean, and that is, before the first prescription is
17
written, that there be a check of understanding
18
about what is supposed to happen in that informed
19
consent process.
20
If there is a failure and/or depending on
21
what the survey says, there is an indication of
22
intent to engage in risky behavior even with
155
1
understanding, that that be looped back to the
2
prescriber, who then who would have to readdress
3
whatever the problem in understanding or intention
4 is
with the potential patient, and that then the
5
prescriber loop back to the program to confirm that
6
yes, in fact, we cleared this up and therefore, as
7 a
substitute for a sticker, rather direct
8
communication from the prescriber to the program,
9
which would go to I guess the pharmacy, that there
10 be
a check on assurance of understanding and intent
11 to
comply, and that maybe that happens, that kind
12 of
interaction with the program and, if need be,
13
then, back to the doctor and to the program, every
14
prescription, period.
15
DR. GROSS: How do you suggest
this be
16
done again?
17
MS. SHAPIRO: Computer.
18
DR. GROSS: Dr. Epps.
19
DR. EPPS: In regards to the
stickers and
20 I
guess the scenario that was introduced, the
21
sticker has your name and your DEA number on it.
22 It
is not something that a staff or a nurse or
156
1
someone else can substitute.
2
Also, in regards to birth control, birth
3
control pills and hormonal contraception is
4
contraindicated in certain populations.
There are
5
some people who should not take oral contraceptives
6 or
Depo or whatever, I mean there is now I guess a
7
monthly injection. There are
complications. There
8 is
a whole list of not only contraindications, but
9
potential side effects, and everyone should not
10
take them.
11
Of course, some of my patients come, they
12
have talked about it with the pediatrician, they
13
come with the blood tests in hand, they come with I
14
have already been to my doctor, I am on my birth
15
control pills. A lot of patients
are really,
16
really prepared, and I don't think a lot of
17
patients or their parents, if they are a minor, are
18
that ignorant about it.
19
I mean these people read, they go on line,
20
they talk to their friends. The
visit before, I
21
usually give them some literature to look at
22
regarding the side effects and the risks and the
157
1
benefits.
2
So, I agree education is important, I
3
think that it should be ongoing at every entry
4
point possible. If they are
seeing me, they are
5
seeing the pediatrician, everybody is reinforcing
6
this stuff, and sometimes the information can
7
change, too, just as before, as someone alluded to,
8
that they used to recommend on the third day of the
9
period, then, it was the fifth day, and changes in
10 the
protocols, but I don't think people are just
11 winging it.
12
DR. GROSS: The last couple of
comments
13
have been on the stickers, which is really Question
14 No.
2, so we could move to Question 2. Any
other
15
comments on what aspects of the program made the
16
stickers not meet the role they were intended to
17
meet? Dr. Raimer.
18
DR. RAIMER: Before we go to
stickers, I
19
just wanted to comment again. I
do think that
20
every patient should have to sign up to be part of
21 the
patient registry, and I think that should be
22
done in the physician's office before the patient
158
1 is
ever given Accutane, that they should sign up,
2
register for the survey before they are ever given
3
Accutane, that that should be part of what has to
4 be
done to get the Accutane.
5
I think it ought to be looked at, an
6
on-line sort of process--might should be looked at,
7 I
don't know all the ins and outs about doing
8
that--but at least you could get to the patient a
9
little more quickly with the survey, and I think
10
there should just be one vendor.
It is much too
11
confusing having more than one vendor.
12
DR. GROSS: Thank you.
That comment
13
actually is very relevant to Question No 4, which
14
talks about registers, so that is important to
15
note.
16
Dr. Katz.
17
DR. KATZ: Part of Question 1 says
discuss
18
measurement factors that have contributed to a lack
19 of
having accurate numbers, and we keep talking
20
about the response rate of 28 percent to the
21
survey, and that is easily taken care of with
22
mandatory--as other people have alluded
159
1
to--mandatory enrollment, and it is not that
2
burdensome.
3
You are having people sign the consent for
4 two
consent forms before they leave the office,
5
before they get Accutane, having bloodwork done or
6
having it done at the lab, and this enrollment form
7 is
very simple.
8
Instead of what we have been doing now, we
9
strongly urge you to fill that, because there could
10 be
more restrictions if you don't, instead of that,
11 you
also have to fill that out, and you send it
12
from the office, postage paid, and you send it from
13 the
office, and if they don't respond to the
14
questionnaire, you get feedback in a couple weeks
15
that they didn't do that, and case closed. It is
16 not
even added burden.
17
So, a mandatory enrollment would eliminate
18 our
whole discussion of do we have accurate
19
numbers, what can be done at follow-up, and we can
20
take that 28 percent and push it close to 100
21
percent very easily.
22
DR. GROSS: So, really Questions
1, 2, and
160
1 4 are
all kind of interconnected, which is fine.
2
Dr. Vega.
3
DR. VEGA: This is a comment
regarding why
4 are
we going back and forth on these questions, and
5 why
is to assess the pregnancy, stickers, testing,
6 all that.
If we think about it in the normal way
7
when the drug is coming to the market, if we had
8
isotretinoin coming down the pipeline as a new
9
drug, and knowing what we know right now, I am sure
10
that we will have no hesitation, no fear, in fact,
11 we
will not dare to let this drug go into the
12
marketplace without the shackles of a good, strong
13
mandatory pregnancy prevention program, risk
14
management program, that will help us to control
15 the
use and prevent or minimize the pregnancy
16
exposure.
17
However, we are going backwards, it is
18
already out, and there is a lot of use, and now we
19 are
trying to contain, and that is why it is so
20
hard to go backwards, but we need to maintain the
21
forward perspective and try to apply it in a
22
backwards way.
161
1
This sounds kind of confusing, but the
2
principles are the same, and we should apply them
3
even when we are trying to read backwards into this
4
issue.
5
DR. GROSS: Dr. Gardner.
6
DR. GARDNER: With respect to
stickers, I
7
think that we simply cannot examine--I mean we
8 can't recommend any program going forward
that does
9 not
take into account the opportunity to gather or
10 to
communicate through computerized order entry,
11 PDA
entry, that is going to be the way that
12
prescriptions are delivered, communicated, and it
13
already is in many places.
14
It certainly is in institutions, many
15
institutions that have dermatology clinics. We are
16
going to have to address that.
Yellow stickers do
17 not
address that, so whatever system we have,
18
whether it incorporates yellow stickers for
19
hand-carrying to reach all pharmacies or not, it
20
also has to address these other things.
21
I would also like to have us look over the
22
next hour or so about what are we going to do about
162
1
mail order sales.
2
DR. GROSS: On the sticker issue,
I think
3 the
question has been answered as to why there is a
4
disconnect between the stickers and inadequate
5
birth control measures, because that may be
6
impossible to ever assure.
7
But how about the issue of the
8
inconsistent link between monthly pregnancy testing
9 and
the stickers? Why do you think that
failed?
10
Yes, Sarah.
11
DR. SELLERS: I would like to,
first of
12
all, agree with the comments that Dr. Ringel made
13
earlier concerning the amount of information that
14 is intended
to be conveyed by the yellow sticker,
15 and
again why problems with the sticker may have
16
contributed to the findings.
17
I would like to go back to my comment
18
yesterday on what exactly the qualification date,
19 what information that conveys, because again,
in
20 the
S.M.A.R.T. package, briefing package, it states
21
that the date is actually the date a sample is
22
taken, not the date that there is a confirmed
163
1
negative pregnancy test.
2
That seems to be in conflict with the
3
labeling of the drug, which requires two negative
4
pregnancy tests prior to prescribing of the drug.
5
DR. GROSS: Dr. Kibbe.
6
DR. KIBBE: I think we are all
trying to
7 get
our handle around the entire program, and while
8 we
address each question, we end up addressing all
9 the
questions and all the issues, and there are
10 some
human behavior issues, and then there is lack
11 of
data issues.
12
Then, there is an issue that I think some
13 of
us are struggling with, and that is how
14
draconian does the risk allow us to become in terms
15 of
preventing the risk. I know Dr. Venitz
said
16
that he didn't trust the abstinence, it wasn't one
17 of
those really great dependable methods.
18
There is, of course, the medieval
19
admonition that when you are going to be an
20 abstainer,
you should get to a nunnery. The real
21
issue is how draconian are we going to be, how
22
forceful can we be in our society, and upon whom
164
1
should we exercise the additional level of control
2 in
terms of behavior.
3
I think that if we took a quick
4
run-through, we would all agree that a mandatory
5
survey gets us a lot more information, a lot more
6
data. Whether or not a mandatory
survey gets us
7 any
improvement in pregnancy rates is completely
8
disconnected from me in my mind.
I can't see how
9
mandatorily surveying people gets them to change
10
their behavior.
11
I also understand that education is a
12
variable and active education versus passive
13
education makes a difference, but 100 percent
14
recall of educated material is absolutely
15
impossible.
16
I have done it at universities for many
17
decades, and you can't get students who are trying
18 to
even get into medical school to remember all the
19
stuff they learned in any one lecture of
20
physiology, and we are dealing with a cross-section
21 of
American people.
22
We just can't expect education to be all
165
1 the
answer. I have a tremendous faith in the
2
dermatologists. I think they are
truly devoted to
3
getting the right result, and they see the results
4 all
the time, and it is right in front of them.
5
They are really motivated.
6
I don't think we need to worry about the
7
physicians wanting the outcomes.
I think we have
8 to
empower them to get those outcomes. If
we have
9 a
mandatory survey system and a mandatory
10
registration for our patients and our pharmacists
11 and
our physicians, we will have a way of
12
collecting data, and we will still have
13
pregnancies.
14 The answer really is can we
differentiate
15
between the 99 percent or more of women who, when
16
given the option and explained the situation, will
17 be
very careful and not get pregnant, from the 1
18
percent or less of women who no matter what we do
19 on
an educational basis, will find a way to have a
20
failure rate, and that is what we are looking at.
21
If we can get data from the 99 and compare
22 it
to the 1, and find some trends or some ways to
166
1 get
our physicians well informed about what are
2
risk factors, then, are we willing to ask them
3
that, since you are in a high risk and we are not
4
willing to take the chance with you, that you will
5
have to be on one or more forms of birth control
6
that we control as a clinician rather than that
7
they control as a patient, and how draconian do you
8
want to be.
9
You could very well look at them and say
10 all
right, we will start you on this therapy two
11
months from now, but today you are going to the
12
gynecologist and you are going to get an IUD, and
13 we
are going to do pregnancy tests, and two months
14
later we are going to start you on this therapy,
15 and
two months after the therapy is over, then, we
16
will let you go back to the gynecologist and take
17 the
IUD out or something comparable to that.
18
Now, that is as close as you can get to
19
putting them into 100 percent assuredness, but I am
20 not
prepared to say we do that to all of our
21
patients. I am saying let's find
a way to figure
22 out
which patients are at high risk and offer
167
1
them--and I don't know whether that is the exact
2
method--but there has to be something more than
3
what we are getting to.
4
So, sure, we can recommend to the FDA to
5 go
ahead and accept a mandatory survey system and a
6
mandatory education system, and what have you, but
7 it
is not going to end pregnancies for women of
8
childbearing age on this drug unless we have with
9 it
a more draconian second step.
10
DR. GROSS: I guess another
question is it
11
won't end it, but will it decrease it, and also
12
dermatologists aren't the only one that prescribe
13 the
medication as we have heard.
14
Dr. Whitmore.
15
DR. WHITMORE: I am not quite sure
what
16
question we are on, but as far as--
17
DR. GROSS: All of them.
18
DR. WHITMORE: Okay. As far as the survey
19 and
registration, I think mandatory survey and
20
registration is essential. I
wonder if there is a
21 way
we can also have a simultaneous anonymous
22
survey be sent in just so we can be comparing our
168
1
data that we are receiving. So,
that is one
2
question.
3
The next is about the yellow stickers and
4
pregnancy tests going to the pharmacy, and things
5
like that. I think we have to remember that the
6
pregnancy test is only going to be helpful in
7
preventing persons who are starting Accutane from
8
starting Accutane while pregnant.
9
The follow-up pregnancy test is going to
10
tell us to stop the drug earlier than we would
11
otherwise, but we will still be needing to tell the
12
patient that their baby may have a retinoid
13
embryopathy.
14
So, think remembering that, that our
15
pregnancy test is only going to be effective in
16
preventing persons who are pregnant from starting
17
Accutane, and is going to do nothing else, nothing
18 for
the other individuals who become pregnant
19
during Accutane therapy.
20
DR. GROSS: Sarah Sellers?
21
DR. SELLERS: No.
22
DR. GROSS: Dr. Epps.
169
1
DR. EPPS: Just a couple of
comments.
2
Medicaid requires that prescriptions be written, so
3 if
we are of opinion that Accutane should have
4
written prescriptions, then, that could be, too.
5 It
doesn't have to be electronic, it doesn't have
6 to
be by PDA, it probably shouldn't be.
7
Occasionally, Medicaid, pharmacies may accept a
8
written faxed prescription, but regardless it has
9 to
be written, and that would eliminate the hackers
10 and
the other people who want to get it to sell it
11 or
do whatever they want to do it.
12
Survey is a good idea if that were to be
13
implemented. As far as
registration and pregnancy
14
testing and faxing it to a pharmacy, I don't agree
15
with that. I think there are real
privacy issues
16
especially when you are talking about minors.
17
It is not like a WBC count, you know,
it
18 is
not like a white count. If you have one
19
pharmacy and you are in a small town, and if there
20 are
certain pharmacies that do it, I mean there are
21
real confidentiality issues there.
22
That's enough.
170
1
DR. KWEDER: Excuse me for
interrupting
2 the
order, but I am hearing a lot around the room,
3
there is a back and forth about surveys and
4
registries, and I am not sure that we are all
5
talking about the same thing.
6
I wonder if it would be helpful perhaps
7
after the next break if the staff could present a
8
description of the S.T.E.P.S. program which employs
9
both, and they are very different.
You know, the
10
registration and the survey itself are different,
11 and
they have raised for us and the company
12
different kinds of issues with regards to privacy
13 and
what is acceptable to OHRP.
14
We have some slides that might
help
15
clarify some of that, to try and put a framework
16
around that before final decision and
17
recommendations are made.
18
DR. GROSS: Do you want to pull
those
19
together, because we may get to them before lunch?
20
MR. LEVIN: Could we also have a
21
description of the other program?
22
DR. KWEDER: That is what I mean.
171
1
MR. LEVIN: I mean both programs.
2
DR. KWEDER: What both programs?
3
MR. LEVIN: Clozapine and the
Thalidomide
4
programs.
5
DR. KWEDER: I think so. I think we can
6
pull that together.
7 DR. GROSS: I am going to take the
8
prerogative of the Chair to say it sounds as though
9 we
are pretty much done with Question No. 1.
There
10 may
be some issues that come up later on, and
11
that's fine, but to move us along.
12
Some of the issues that have come up for
13 the
second part of Question 1 regarding
14
measurement, surveys, mandatory surveys, rewriting
15 the
survey, so that it is at maybe a seventh or
16
eighth grade level, implementation factors.
17
We talked about stickers, which is really
18 the
next question. Use of FMEA, qualitative
19
assessment, that the survey would have to be
20
rewritten to include many more possible factors.
21
So, those are some of the issues that were
22
raised. Also, it was pointed that while zero
172
1
pregnancies is our goal, no matter what we do, we
2 are
probably never going to be able to reach that
3
level.
4
On Question No. 2, we have had a few
5
comments on stickers. Would
anyone like to comment
6 on
what aspects of the program made them
7
ineffective? The use of the
stickers was high, but
8
apparently it didn't prevent pregnancy.
9
Dr. Katz.
10
DR. KATZ: That is not a proven
statement.
11 The
lack of link between the stickers and whether
12
patients really got pregnancy tests because we were
13 told
earlier that when doctors' offices were
14
checked, they did have pregnancy tests on the
15
chart, which was my initial question, because when
16
people are asked on that survey, that onerous
17
survey, whether they had pregnancy tests, they may
18
forget that the pregnancy test was included in the
19
blood tests.
20
I have had people ask me, oh, was that the
21
pregnancy test, too, and they have to be told that.
22 A
lot of times when they get the regular blood
173
1
tests, you don't repeat, now, this time I am
2
getting a CBC, hepatic profile, triglycerides, and
3
pregnancy test. You are repeating
the blood tests,
4 and
reminding them about the pregnancy. They
may
5 not
have that, they may disconnect that.
6
So, we are getting this disconnect data
7
from the questionnaires of 28 percent of people
8
that return that, that said no, I got the stickers,
9 but
I didn't get the pregnancy test. Well,
that is
10 not
necessarily true.
11
DR. GROSS: Anyone else have any
comments
12 on
the stickers per se? Dr. Bergfeld.
13
DR. BERGFELD: I would like to say
I like
14 the
stickers, and I like the stickers because it is
15 an
imprint on the physician that when you have to
16
move to using the stickers, you have to be
17
constantly reminded of your responsibilities. So,
18 it
is a reminder to the physician.
19
I would also like to comment that I would
20
like to see addressed on the next folding out of
21
whether it be a registry, a registry and survey,
22
that you look very carefully at what you really
174
1
want to glean from that, and I will definitely say
2 has
to be simplified and easy to read.
3
Included in that, the physicians need some
4
kind of flowchart that they can attach to their
5
medical record, whether it be paper or computer, so
6
that they can have a flowsheet that these records
7
just don't go in a patch-like way into the
8
patient's record. It would be
very helpful to have
9 a
drug list record.
10
Thank you.
11
DR. GROSS: Dr. Raimer, did you
have a
12
comment on stickers?
13
DR. RAIMER: I did. I just wanted to
14
reiterate something that was brought up yesterday.
15 I
think we should continue to re-educate the
16
physicians also. It has been
almost two years
17
since most of us signed up for the S.M.A.R.T.
18
program. I think you should have
to re-enroll
19
every year.
20
I think it should be an on-line program
21
where you actually take a little test and you have
22 to
say, yes, I realize the second pregnancy test
175
1 has
to be done during the menstrual cycle.
2 I think the doctor should have to get
all
3 the
answers correct before they get the stickers.
4
They can take the test as many times as they need
5 to,
but, you know, just a short exam to be sure
6
they know all the facts and be re-educated every
7
year, and then they should get a sticker that is
8
good for a year, have to redo it every year.
9
DR. GROSS: So, this is a
different kind
10 of
sticker. This is a sticker for the
physician,
11 not
the patient.
12
DR. RAIMER: No, it is the yellow
sticker.
13 You
get a supply of yellow sticks from the company.
14 So,
you get your resupply of yellow stickers each
15
year after you have passed the test, just to be
16
sure you remember all the things you are supposed
17 to
do, but a flowsheet would not do the same thing.
18
DR. GROSS: That is a new
suggestion.
19
Would anyone else like to comment on that?
20
Basically, annual recertification of people who are
21
using Accutane or related drugs, should that be
22
part of a program that we are going to recommend?
176
1
DR. WHITMORE: I second that idea
and
2 would
say that the stickers can just expire one
3
year from the time they are sent out.
4
DR. GROSS: Yes.
5
DR. WILKERSON: A couple of
comments at
6 the
risk of drawing ire from the pharmacy lobby.
I
7
mean the role of the physician is to diagnose and
8 to
prescribe. The role of the pharmacist is
to
9
fill the prescription according to proper labeling.
10 The
pharmacist is not a clinician.
11
I would really hate to draw pharmacists
12
into this any more than they have.
Their job is
13 not
to do the doctor's job, to be sure that the
14
patient has had their pregnancy test.
15
That lands squarely on the shoulders of
16
physicians to be sure that patients are following
17 the
guidelines. It is not the friendly
pharmacist
18
down the street who should be entering into the
19
exam room to make sure that the patient is doing
20
what they should be doing, and the doctors should
21 be
doing.
22
I do like the stickers. I think
it is
177
1
like a badge. It indicates to the
patient that I
2
have taken some additional study, I know what I am
3
prescribing here, and I am the one who can
4
prescribe this for you.
5
I like Dr. Bergfeld's idea about having
6
some type of flowsheets that prompt physicians and
7
nurses to order the right test and to be sure that
8 the
things are done in a timely fashion.
9
These stickers or special prescription
10
pads, however we want to look at this, I think is
11 the
other thing. We could look at a triplicate
12
form, such as used in many states for narcotics, is
13 yet
another way to track physicians and to track
14
enrollment of patients in the data bank.
15
DR. CRAWFORD: Dr. Wilkerson, yes,
you are
16
about to draw some ire. I just
must respond as an
17
associate professor in the college of pharmacy and
18 as
a pharmacist.
19
I agree that the pharmacist's role is not
20 to
diagnose. I disagree that the pharmacist
is not
21 a
clinician; if anything, I think the role of the
22
pharmacist should be increased in the risk
178
1
management program because it has been brought
2
up--I didn't particularly agree with the comment
3
yesterday that the pharmacist should be a
4 policeman,
but the pharmacist is the last step
5
typically in the drug use process before it gets to
6 the
patient, and the dispensing process is much
7
more than simply filling the prescription.
8
It also involves or should involve patient
9
education in case there are comprehension problems,
10
patient counseling in case there is a need for
11
customization. It was not
determined at the
12
prescriber-patient relationship where the
13
pharmacist may get back in touch with that
14
prescriber, but I disagree with the fact that it is
15
just a technical process.
16
DR. GROSS: Any other comments on
Dr.
17
Raimer's suggestion of annual physician
18
recertification by I guess some simple,
19
straightforward tests?
20
Dr. Bigby.
21
DR. BIGBY: I think it's a good
idea.
22
DR. GROSS: Brevity is the soul of
wisdom.
179
1 Any other comments? Ruth.
2
DR. DAY: There would be a way to
combine
3 the
sticker with the flowchart idea and also meet
4
some other concerns about what does a sticker mean
5 in
terms of the qualification date.
6
Each sticker could be at the top of an 8
7 1/2
by 11 piece of paper, and to peel it off to put
8 on
somewhere, there is a checklist, so the
9
physician would check through each thing that has
10 to
be met because at present, if you have looked at
11
that sticker recently, it just says that you are
12
prescribing this based on whatever is in the
13
contraindications and warnings of the package
14
insert.
15
So, if there was a checklist that the
16
physician checked off and then took off the sticker
17 and
put it on the prescription, that would be very
18
good, and that checklist could then be dated and
19 put
in the patient's file at that time.
20
So, this is in the interest of decreasing
21 the
paperwork load and the pieces of paper floating
22
around. It could all be together,
and that would
180
1 be
documentation of what happened on that day.
2
DR. GROSS: Other comments on Dr.
Raimer's
3
suggestion? Mr. Levin.
4
MR. LEVIN: I just want to make a
5
suggestion that we are talking a lot about changes,
6 and
yet we have two programs to draw on that are
7
managing risk, we think, better than this effort
8
has.
9
So, I would like to suggest that rather
10
than spending a lot of time with each of us coming
11 up
with our little or not so little, major ideas,
12 and
I have lots of them about what could improve
13
this program, that we really learn from the
14
experience with the S.T.E.P.S. program and the
15
clozapine program, and then come back together and
16 say
do those solutions begin, using those programs,
17
those approaches begin to offer us an opportunity
18 to
build on experience where, by the way, there is
19
data, because whatever we are proposing here, we
20 are
not going to know its effectiveness for another
21
couple of years.
22
I would be remiss as a consumer advocate
181
1 not
to express my annoyance, to put it mildly, at
2 the
fact that we are here discussing the lack of
3
data because after the Advisory Committee in the
4
year 2000, and I was part of that process, asked
5 for
a lot of what we are talking about asking for
6
today, and which, in fact, Roche today is coming
7
forward and saying we are willing to do.
8
If that had been done when the Advisory
9
Committee had asked it to be done, we would have
10
much better data to have this discussion with. So,
11 I
just want to caution that all of these things we
12 are
suggesting which are new will need time to get
13
evidence that they are successful or not, and in
14
that interim, more people are going to be hurt
15
because we haven't taken an action.
16
We have a responsibility to prevent
17 further injury if we can prevent it, and it
seems
18 to
me that we have an opportunity to learn from two
19
programs, which as far as I know have been
20
apparently more successful in controlling risk and
21
still permitting appropriate access.
22
So, I would suggest that we have lunch and
182
1
then listen to a description and explanation of
2
those programs' successes and failure, and then
3 come
back and draw on that experience where we
4
actually have data that backs up various parts of
5
those programs' successes and failures, and then
6
have a discussion.
7
DR. GROSS: Mr. Levin is hungry,
so why
8
don't we recess because we don't want to have an
9
unhappy committee member. We can
all sate our
10
appetites and we will see you--do you want an hour
11 for
lunch--let's get together at 12:30.
12
[Whereupon, at 11:45 a.m., the proceedings
13
were recessed, to be resumed at 12:30 p.m.
183
1
A F T E R N O O N P R O C E E D I
N G S
2
[12:35 p.m.]
3 DR. GROSS: Dr. Uhl will make the
4
presentation on risk management programs that Dr.
5
Kweder mentioned earlier.
6
Dr. Uhl.
7 FDA Presentation
8
DR. UHL: We have been asked to try
and
9
address the program that is used to monitor and to
10
dispense Thalidomide. Up here
with me is Carl
11
Kraus. Carl is a medical officer
from the Division
12 of
Special Pathogens and Immunologic Drug Products.
13
Carl is the medical officer in CDER for
14
Thalidomide.
15
I am going to go through a couple of
16
slides and then Carl is going to go through more of
17 the
intricacies of the program for Thalidomide.
18 Dr.
Trontell will address clozapine.
19
[Slide.]
20
The program for Thalidomide is called
21
S.T.E.P.S. It is the System for
Thalidomide
22
Education and Prescribing Safety.
The company that
184
1
manufactures and distributes Thalidomide is the
2
Celgene Corporation. I am not
sure if there is
3
anyone in the audience from Celgene, but if they
4
are, it will obviously be the Chair's prerogative
5 if
he would like them to address any questions, as
6
well.
7
[Slide.]
8
In your briefing package, there was
9
information provided about the S.T.E.P.S. program.
10
This is just to reiterate what are the program
11
objectives for S.T.E.P.S.
12
The objectives include to prevent fetal
13
exposures to Thalidomide, to educate regarding the
14
risks of Thalidomide, to provide procedures to
15
reduce the risk of fetal exposure to Thalidomide,
16 to
identify at-risk behaviors by surveying patients
17 and
prescribers, and to provide a mechanism for
18
intervention and remediation when at-risk behaviors
19 are
identified in S.T.E.P.S.
20
The S.T.E.P.S. program is also a mechanism
21 for
restricted distribution.
22
[Slide.]
185
1
I am going to walk through the original
2
S.T.E.P.S. program very briefly.
There is now a
3 new
program that has been implemented.
4
The original S.T.E.P.S. program, very
5
briefly, the patient had the physician visit, the
6
consent is signed. This is a
consent by the
7
patient to participate in the S.T.E.P.S. program.
8 A
prescription is provided, and a pharmacist, who
9 is
registered within the program, is able to
10
dispense the product.
11
A survey is provided to the patient with
12 the
dispensing of the medication. The drug
is
13 dispensed to the patient. This survey subsequently
14 is
completed by the patient and is given to the
15
Boston University Slone Epidemiology Center. They
16
review this survey and take action as to some of
17 the
responses that the patient has provided.
18
[Slide.]
19
Very briefly, there were some problems
20
identified with the old S.T.E.P.S. program, and
21
there were areas of improvement that were
22
specifically targeted. For
example, the Boston
186
1
University survey identified at-risk behaviors
2
basically after the drug was dispensed.
3
There was a time delay to identify these
4
at-risk behaviors and to intervene, which was felt
5 to
be suboptimal, and the Boston University Slone
6
Epidemiology Center's survey, the primary focus was
7 not
for real-time patient intervention.
8
There were other areas of improvement,
9
such that the program's design could do more to
10
assure the compliance with the program procedures,
11 and
the example of this is the pregnancy tests that
12 are
required with the S.T.E.P.S. program.
13
I erroneously spoke yesterday that the
14
patients have two pregnancy tests prior.
They
15
actually have one pregnancy test within 24
16
hours--that pregnancy test must be done within 24
17
hours of the patient getting a prescription for
18
Thalidomide. Then, the patients
have weekly
19
pregnancy tests for the first month, and then
20
monthly thereafter.
21
The frequency of testing is a little bit
22
different if you are a woman who does not have
187
1
regular menses.
2
The original S.T.E.P.S. program, there
3
were limited risk group classification, basically
4
just based upon male or female.
It did not include
5
strategies that targeted this.
This is adult
6
females of childbearing potential who would
7
obviously be at a different risk for pregnancy to
8
adult females not of childbearing potential.
9
There were other things that were
10
identified such that the program didn't utilize
11
current technologies to target specific risk groups
12 and
interventions for specific risk groups.
There
13
were issues with current technologies about record
14
availability, storage, management, archiving, et
15
cetera, and then also the efficiency, quality of
16
accounting, auditing, reporting of the S.T.E.P.S.
17
activities.
18
[Slide.]
19
So, a new S.T.E.P.S. program was launched
20
July 30th of 2001. These were
basically
21
modifications to the original S.T.E.P.S. program.
22
Many of the elements were the same.
These are some
188
1 of
the similar elements.
2
There is registration of all
prescribers,
3 all
pharmacists, and all patients within the
4
S.T.E.P.S. program, that is, anyone who is involved
5 in
writing for the drug, dispensing the drug, or
6
receiving the drug are registered within the
7
program.
8
There are educational materials, which
9
includes brochures and videotapes.
There are
10
materials for all three elements - prescribers,
11
pharmacists, and patients. There
is the issue of
12
patient counseling and education.
There is a
13
limited supply, such that patients get a 28-day
14
supply, and the Thalomid comes in a blister pack.
15 It
is a unit of use packaging.
16
There is also a mechanism for follow-up of
17 suspected fetal exposures whether the patient
be
18
male or female with a toll-free number for
19
notifying Celgene.
20
It is interesting to bring this up in that
21
there is not a distinction between pregnancy or
22
positive pregnancy test, and what Celgene focuses
189
1 on
in the Thalidomide S.T.E.P.S. program is a
2
positive pregnancy test, hence, getting around your
3
issue of what is the definition of pregnancy when
4 you
are near the Potomac River. The flag for
the
5
S.T.E.P.S. program is a positive pregnancy test.
6
Other of the same elements is that there
7 is
no blood donation, and the issues of
8
contraception for females of childbearing
9
potential, and the use of condoms for males who are
10
taking the drug.
11
The frequency and periodicity of pregnancy
12
testing was not changed with the implementation of
13 the
new S.T.E.P.S. program.
14
[Slide.]
15
What the new S.T.E.P.S. program did was to
16
have more classification along patient risk
17
stratification. Adult females of
childbearing
18
potential, adult females not of childbearing
19
potential, female children of childbearing
20
potential, female children not of childbearing
21
potential, adult males, and male children.
22
If you remember from my slide yesterday
190
1
about the demographics of Thalidomide users, the
2 age
distribution was from 1 to 100.
3
The new S.T.E.P.S. program has consent
4
forms that are computer generated, and they are
5
generated specific to the risk category for the
6
patient who is to receive Thalidomide.
7
There are specific information that get
8
entered, such as the patient's date of birth, the
9
address, and the diagnosis for which the drug is
10
being used to treat.
11
What is mandatory is that the patient and
12 the
physician and the pharmacist must participate
13 in
the registry, and they must use this telephone
14
interactive voice response system, which Celgene,
15 the
company, administers and performs interventions
16
based on this IVR. I have a
subsequent slide to
17
talk about the IVR.
18
There is then a patient follow-up survey,
19
which is performed by the Boston University Slone
20
Epidemiology Center. This survey
is not mandatory,
21 it
is optional, and Dr. Mitchell can certainly
22
address this a little bit more, the issues that
191
1
they have had with doing the survey and some of the
2
targets to get to quality assurance and program
3
evaluation.
4
But the distinction here is that the
5
registry has mandatory elements for all patients,
6
providers, and pharmacists, but the survey is
7
optional, is not mandatory.
8
[Slide.]
9
The IVR is a technology that uses
10
interactive voice response system.
It uses an
11
automated telephone-based survey.
This is
12
administered by the company Celgene.
The survey
13
questions are tailored to the patient's specific
14
risk group.
15
The patient calls in, as well as the
16
pharmacist and the physician.
They call in to this
17
number. They have an identifier
that they enter
18 for
the patient. It is a unique identifier
that is
19
based on their Social Security number.
20
According to what the patient keys in, in
21
this IVR, it asks specific questions to get at
22 at-risk
behavior, and if there is patient at-risk
192
1
behavior identified, it triggers real-time
2
interventions to Celgene, whereby the patient is
3
transferred to an actual person who will talk to
4
them about their at-risk behavior.
5
The IVR system is also used by physicians
6 or
the physician administrator to enter the results
7 of
the patient's pregnancy test. The IVR
system is
8
also used by the pharmacist to get the information
9
that that prescription has been activated and get a
10
dispensing number.
11
Dr. Kraus will walk you through some of
12 the
elements of this complicated--
13
DR. KRAUS: It is not as
complicated as it
14 may
seem, I think.
15
[Slide.]
16
Initially, what occurs with the S.T.E.P.S.
17
program at the initial physician visit is the
18
informed consent process occurs after discussion of
19 the
risks and benefits of Thalidomide therapy, and
20 the
consent is signed.
21
Of note, after this visit, the physician
22 is
required to call into the IVR system and answer
193
1 a
number of questions that are related to the
2
physician side of the IVR system.
3
The prescription is provided only after
4 the
patient has a negative pregnancy test within 24
5
hours, as well as having instituted some type of
6
highly effective therapy for contraception at least
7
three days prior to the prescription being written.
8
So, the consent is signed, and that is
9
called in to the IV, the physician calls in to the
10
IVR, and when I say that, after the consent is
11
signed, the patient also calls in to the IVR. I
12
think I wrote that on the second little arrow
13
there.
14
Then, once the two parties, the physician
15 and
the patient, have called in to the IVR system,
16 a
number is generated that the physician writes on
17 the
prescription, which quote, unquote, "activates"
18 the
prescription, so that when the script is taken
19 to
the pharmacy, the pharmacy recognizes that this
20
indeed is an activated script, will call in to
21
verify that with the IVR, and then Thalomid is
22
given for a 28-day supply.
194
1
Now, at the initial institution of the
2
system for the patient, there is weekly pregnancy
3
testing for the first month.
Assuming they are all
4
negative, then, it goes to monthly thereafter.
5
Any time during the compliance
6 evaluation--and
I consider the IVR system to really
7 be
a compliance issue as opposed to the quality
8
assurance of the survey which would follow--there
9 can
be flagged IVRs, in other words, the most
10
common reason for flagging is an outdated pregnancy
11
test.
12
So, basically, if the pharmacist plugs
13
into the IVR the date of the pregnancy test and it
14
doesn't comply with the seven-day requirement prior
15 to
giving the prescription, then, a flag will go
16
up. The pharmacist will be put in
touch with a
17
Celgene telephonic representative, and the script
18 can
be re-evaluated.
19
Either the patient has to go get another
20
pregnancy test or they call the physician and see
21 if
there is a more recent one. Typically,
that
22
patient will not be given Thalidomide until an
195
1
adequate pregnancy test has been performed.
2
I put two things in yellow here, Celgene
3
mails initial survey with unique identifier. That
4 has
not yet been implemented, and a blinded patient
5 was
sent to Slone has not been implemented yet.
6
Basically, what is going to be occurring,
7 the
identified information on the patient will be
8
provided to the Slone Epidemiology Unit to be
9
mailed out for the follow-up survey, and only
10
Celgene will have and maintain the list as a full
11
registry, but Slone will not as far as who these
12
patients are to be more in accordance with HIPAA
13
compliance, and so forth.
14
That is sort of the gist of this new
15
S.T.E.P.S. program. I am more
than happy to
16
entertain any questions you may have on that.
17
DR. GROSS: Are there any
questions? Yes.
18
DR. BERGFELD: I have a question
of you if
19 you
don't mind. Could you tell me the
numbers of
20
patients involved in this study?
21
DR. KRAUS: Sure.
22
DR. BERGFELD: And the
distribution of
196
1
age, particularly the reproductive female.
2
DR. KRAUS: I was expecting that
question.
3
[Slide.]
4
Approximately 65,000 patients--that is
5
incorrect--it is actually 80,000 now, so the number
6 is
outdated, since July 2001. Just looking
at the
7
third quarter information from last year, there
8 were about 50,000 surveys completed, and
when I
9
said that there can be flagging from the IVR, about
10 5
percent were flagged, and the majority, over 90
11
percent were related to outdated pregnancy tests.
12
Some were related to other pharmacy issues, and
13
some related to other IVR issues.
14
DR. GROSS: Why did you make the
survey
15
optional in the new S.T.E.P.S. program?
16
DR. KRAUS: You mean going from
mandatory
17 to
optional. Much of it has to do with the
fact
18
that in order to have all the appearances of being
19 a
quality program for the FDA to ensure the safe
20 and
effective use of the drug, and not to infringe
21 on
the possibility of being misconstrued as
22
research, it was decided to make this into an
197
1
optional survey since the compliance portion of the
2 IVR
is mandatory.
3
So, there really are two aspects of this.
4 One
is the mandatory IVR portion, which all
5
patients, pharmacists, and physicians are required
6 to
participate in, then, there is the optional
7
follow-up survey, which is a quality issue for the
8
program.
9
I think we had about 40 to 46
compliance
10
with the survey as far as follow-up goes. Not
11
everyone sent in the--
12
DR. KWEDER: It is a little
confusing
13
because even on the slide, it is often call the IVR
14
survey, so it's like there is two surveys, but the
15 one
that is associated with the IVR component is
16 not
optional.
17
It is the follow-up survey that is
18
optional, and the reason that it is optional is
19
because--it used to be mandatory or was stated to
20 be
mandatory--and OHRP raised significant concerns
21
about it because they felt that despite our
22
imploring that this was really a quality assurance
198
1
tool, they felt it was more of a research tool, and
2 if
there was any intention to collect the
3
information and publish it in some way, so that it
4
might be useful for another program, that
5
constituted research, and therefore could not be
6
mandatory.
7
DR. GROSS: Dr. Cohen.
8
DR. COHEN: I would be interested
in
9
knowing, well, first of all, how many patients are
10 on
the S.T.E.P.S. program right now, are involved
11
with the S.T.E.P.S. program, and then, second, what
12 is
your general assessment as far as acceptability
13 to
patients, physicians, and pharmacists, what kind
14 of
feedback are you getting from them?
15
DR. KRAUS: It should be very much
16
recognized that the patients that are enrolled in
17
S.T.E.P.S. are probably very, very different than
18
those that would be enrolled in Accutane risk
19
management program.
20
These patients typically take Thalomid for
21
four months of therapy. The
majority of them are
22
oncologic in nature, and 90 percent or more are
199
1
taking this for some oncologic diagnosis whether it
2 be multiple myeloma, renal cell carcinoma,
what
3
have you, and there is a significant amount of
4
interplay in a hospital setting, as well as an
5
intense oncologic clinic for interaction with the
6
S.T.E.P.S. program.
7
Now, when the physician
enrolls in the
8
S.T.E.P.S. program initially, there is a designee
9 on
the enrollment form that states who will be the
10
S.T.E.P.S. coordinator for that physician, whether
11 it
be the physician himself, someone in the office
12 to
assure compliance with the safety requirements
13 of
Thalomid prescriptions.
14
DR. GROSS: Dr. Day.
15
DR. DAY: In those cases where
there was a
16
flag and an intervention was then required in order
17 to
continue, how long was the interruption of
18
treatment, and is there a window that is allowable,
19 and
then can someone here comment on interruption
20 of
treatment with Accutane and similar products,
21
what consequences that might have for the patient?
22
DR. KRAUS: If a flag occurred
between
200
1
8:00 a.m. and 8:00 p.m., the hours of the manned
2
telephonic survey, there will be direct
3
intervention right then and there, and hopefully,
4 the
problem can get resolved quickly.
5
If it occurs after 8:00 p.m., then the
6
script will no longer be valid until the following
7 day
when intervention can occur.
8
DR. DAY: But the intervention
might then
9
require additional action, such as an additional
10
pregnancy test, it was out of date by a day or
11
something like that. Do you have
evidence about
12
interruption of treatment?
13
DR. KRAUS: I have no data on
interruption
14 of
treatment.
15
DR. GROSS: Robyn Shapiro.
16
MS. SHAPIRO: How is this paid
for?
17
DR. KRAUS: How is this paid for?
18
Celgene. It is all company
sponsored, yes.
19
DR. GROSS: Dr. Schmidt.
20
DR. SCHMIDT: This stuff is used
for a lot
21 of
skin diseases, too, for ENL, erythema nodosum
22
leprosum, prurigo nodularis, and lupus, and it is
201
1
actually quite effective, so we use it in patients
2 who
are not, you know, cancer patients, and it's
3
about $600 a month.
4
So, what I would like to know is how much
5 of
that is the medication, and how much of this is
6 the
program, and then the other thing is I have had
7
some older women on this thing, that one of them
8
called me one time and she said everybody else is
9
having all the fun, and I said what do you mean,
10 and
she said, well, I got this survey that called
11 up
and asked how many times I was having sex every
12
day.
13
So, some of these things, to me, she
14
thought it was real funny. I told
her when they
15
called back again, to tell them with the football
16
team.
17
DR. GROSS: Actually, I have used
the
18
S.T.E.P.S. program myself on one occasion for a
19
patient, and did not find it onerous.
It was also
20
interesting. The patient had a
survey that I did
21 not
observe. The patient filled it out, put
it in
22 a
sealed envelope. I never knew what the
patient
202
1 said,
so I thought that was good.
2
Any other comments? Jackie.
3
DR. GARDNER: Perhaps we heard
yesterday,
4 did
you tell us how many pregnancies have occurred
5 on
the S.T.E.P.S. program among the 80,000 people?
6
DR. KRAUS: There was one, and I
know Dr.
7
Uhl, I think had a slide on that yesterday.
8
DR. KWEDER: There have actually
been a
9
number of false positive tests on the program, and
10 the
database is rich enough that you can actually
11 go
in and determine that those were false
12
positives.
13
DR. GROSS: Mr. Levin, back from a
full
14
lunch.
15
MR. LEVIN: Again, my appreciation
to the
16
Chair.
17
I guess the question would be of FDA, is
18 it
FDA legal counsel opinion that a mandatory
19
survey is going to be thought of as research,
20
because we have been talking about mandating a
21
survey, but if FDA is telling us that it is FDA
22 counsel's opinion that that is inappropriate
203
1
because it becomes research rather than quality
2
improvement, we should know that before we make a
3
recommendation, for example, that there be a
4
mandated survey if that is simply not going to
5
happen.
6
DR. KWEDER: I am not FDA counsel,
I would
7
never pretend to be, but I think the general answer
8 to
that question is if there is a survey, it needs
9 to
be clear what the purpose of the survey is, and
10
that has to be directly related to safe use of the
11
drug.
12
For example, the IVR survey is clearly
13
that. The follow-up survey, which
looks more at
14
some of the qualitative aspects of the program and
15 how
information is communicated or not
16
communicated, really doesn't meet that standard as
17
clearly, despite the fact that we continue to
18
believe it is highly desirable in order to continue
19 to
improve the program, and take away burdens that
20 may
not be necessary.
21
So, that is not a direct answer to your
22
question, but we will work to ensure that the
204
1
elements that are mandatory are things that will be
2 of
use to the safe use of the drug.
3
DR. GROSS: Dr. Whitmore.
4
DR. WHITMORE: I was just going to
answer
5 Dr.
Day's question about discontinuance for a short
6
period of time off Accutane. It
makes no
7
difference. We dose based on
a--for most of us I
8
think--dose based on a cumulative amount of drug
9
getting in over whatever period of time it is, so
10 for
them to be off of it for a week is not going to
11 do
anything.
12
DR. GROSS: Dr. Bergfeld.
13
DR. BERGFELD: I didn't hear the
answer to
14 the
denominator in the study of 80,000 individuals
15 who
have participated actually in the program, and
16 you
had one pregnancy, but how many were women in
17
childbearing age who could possibly get pregnant?
18
DR. UHL: Actually, we did present
that
19
yesterday.
20
DR. BERGFELD: Would you repeat
it?
21
DR. UHL: Yes, ma'am. The females of
22
childbearing potential are 5 percent of the
205
1
patients. It is approximately
4,000, and that has
2
been over the six years that the S.T.E.P.S. program
3 has
been in practice.
4
DR. GROSS: Thank you.
5
Now, I believe the FDA has some
6
information has some information they want to
7
present on the Clozaril program.
8
DR. TRONTELL: The information
that we
9
have on the clozapine program, I will invite Chad
10
Clark, if he is in the audience, to talk about the
11
specifics of how individuals are registered, which
12 is
to clarify the distinction between a registry
13 and
a survey.
14
In the case of clozapine, individuals are
15
tracked by their Social Security number.
There is
16 a
registry solely for those individuals who are not
17 to
be rechallenged with the drug based on their
18
prior experience of a lowered white count with
19
that.
20
There is no survey because, in fact, some
21
component of patient behavior really doesn't apply
22 in
the case of your white count. So, the
206
1
distinction that we wanted to make clear in the
2
discussions earlier, in which Dr. Kweder I think
3 has
already articulated very well, registering a
4
patient for purposes of tracking, to know your
5
denominator is perhaps one process.
6
Collecting ongoing information pertinent
7 to
the safe and effective use of the product, much
8 as
is done through this IVR module with
9
Thalidomide, is yet another component of safety and
10
effective use, that is considered allowable and
11
able to be made mandatory as a condition of safe
12 use
of the drug.
13
But when you talk about important
14 information that is pertinent about risk
factors,
15
failure, mode and effects analysis that are
16
collected through the voluntary patient survey,
17
that is construed by the Office for Human Research
18
Protection, known as OHRP, is not something that we
19 can
mandate for patients.
20
But if you want more particulars, I
21
apologize, we have some individuals with pharmacy
22
practice that can talk about their individual
207
1
experience of how you get registered. Let me also
2
make one clarification to my remarks yesterday.
3
It is pharmacies that are registered, not
4
individual pharmacists for the program.
5 Let me give one additional piece of
6
information that may or may not be pertinent to
7
some of this discussion. All of these programs have
8
less than 100 percent compliance documented with
9
them in terms of what happens at the pharmacy.
10
Occasionally, a product may be released
11
without the pharmacist having had the opportunity
12 to
do the full check. That has occurred
with
13
Thalidomide, it has occurred with clozapine, and we
14 had
evidence to suggest that has happened with
15
Accutane, as well.
16
The system, as you have seen in the case
17 of
Thalidomide, to date has one pregnancy exposure
18
among 4,000 women over a relatively extensive
19
period of time of its use.
20
DR. GROSS: Any questions or
comments on
21
clozapine?
22
Hearing none, I would like to ask Roche if
208
1
they would briefly present four or five slides
2
showing the proposed program. Dr.
Huber will
3
present.
4 Hoffmann- La Roche
Presentation
5
DR. HUBER: Thank you.
6
I would like to point out that in the
7
design of this system, we did incorporate the
8
elements of the S.T.E.P.S. program, as well as the
9
clozapine, and as we walk through, I will try to
10
point out how they are linked in.
11
[Slide.]
12
First of all, I would like to point out
13
that this path across the top here, this registry
14 is
analogous to the IVR registry of the S.T.E.P.S.
15
program. It is a single data
place where the
16
interactions occur.
17
We have not specifically decided on IVR.
18 We
are interested in hearing your input on that,
19
because it is not clear that a telephone is the
20
best interaction. We assume an
IVR is probably the
21
basis, but there may be web-based and other
22
modalities available, but at this point in time, I
209
1
would say work under the assumption we are
2
basically talking about an IVR type system.
3
The initial visit is analogous to the
4
S.T.E.P.S. program in that there is a determination
5 of
childbearing. There is a screening pregnancy
6
test, and this is literally a first pregnancy test
7 to
make sure the patient is not pregnant before
8
they even start. There is no
point in getting them
9
going down the pathway if we already know they are
10
pregnant.
11
Education, informed consent. This
is
12
basically what we do now in the S.M.A.R.T. program,
13 and
the same thing is also occurring in the
14
S.T.E.P.S. program.
15
The patient then gets entered.
This is a
16
registered physician, and this gets entered into
17 the
registry.
18
[Slide.]
19
You will get a patient ID back.
We were
20
intending that the system would generate a patient
21 ID
number to avoid privacy issues such as use of
22
Social Security numbers.
210
1
[Slide.]
2 Once the physician receives that ID
3
number, this interaction with the system is what
4
they are describing in the S.T.E.P.S. program as
5
this IVR survey that the patient does.
6
We have not designed the detailed
7
questions that go here yet, the methodology used.
8 The
intent is that these questions would measure
9
some form of compliance with the program. In other
10
words, they would be questions about did the
11
patient understand, are they on contraceptives, are
12
they using them appropriately, et cetera.
13
There is a lot that has been developed
14
over the past five years, and how you can do this
15
maybe a little better. Randomness
of the
16
questions, so patients don't memorize patterns,
17
variation on scripts.
18
The intent would be that this data would
19 be
asked the patient, they would answer.
Their
20
responses are captured in the registry, so in
21
parallel, this is doing two things.
There is an
22
intervention here in which you are potentially
211
1
identifying an at-risk patient, but at the same
2
time you are building the data set that you can use
3 for
assessing overall what patients are the highest
4
risk, for example.
5
This occurs once again into the same
6
registry, very analogous to S.T.E.P.S.
7
[Slide.]
8
The patient then goes and sees the
9
physician. At this point, they do
a
10
laboratory-confirmed pregnancy test. This is the
11
same concept as clozapine. In
S.T.E.P.S., the
12
physician basically does an attestation that there
13 is
a negative pregnancy test and enters I believe
14 the
date.
15
We are asking actually that the pregnancy
16
test result go into the system.
As was mentioned
17
yesterday, there are some concerns about how the
18
mechanism of this is done. We
don't want to have
19
delays, so it may be an interaction with the system
20 to
call and say there is one, and then a
follow-up
21
with the fax.
22
Ideally, you would love to have, if you
212
1
have electronic laboratory databases, electronic
2
transfer, there are some fundamental issues with
3
that, but the intent will be, in this registry up
4
here, will be a laboratory-confirmed negative
5
pregnancy test, as well as the script will get
6
dispensed with the qualification sticker is what we
7
propose now and the patient ID.
8
[Slide.]
9
So, the registered pharmacy, as analogous
10 to
S.T.E.P.S., verifies this, essentially, checks
11 it
is authorized, and what the system will tell him
12
when he calls in, is was there a patient ID
13
registered, did the patient get through this test,
14 and
was the laboratory test negative.
15 We are proposing that that be a yes/no
16
question in the system. One of
the concerns from a
17
privacy point of view, as was stated several times,
18 it
is one thing to walk to a pharmacist with a
19
white blood cell count, we are very concerned with
20
walking into a pharmacist and handing him a
21
pregnancy test.
22
The other thing is we don't want the
213
1
pharmacist necessarily to get the pregnancy result
2
here, because we think it would be somewhat
3
embarrassing if the pharmacist was the first one to
4
inform the patient at the counter that they are
5
pregnant.
6
We think it would be more appropriate that
7
that result be channeled back to the physician, and
8 if
the patient does get to a pharmacist, it is
9
simply no, you need to call your doctor.
10
We do not have an additional survey
11
intended into this system. Our
intent is that the
12
data that needs to be collected regarding
13
compliance with various patterns, with behaviors,
14 et
cetera, we believe that should be captured as
15
part of the overall process.
16
Once again, its intent is dual.
It is an
17
intervention, but then we can also collect data for
18
assessment.
19
Thank you.
20
DR. GROSS: Thank you, Dr. Huber.
21
What you just described is summarized on
22
your presentation from yesterday, for the
214
1
committee, on page 82 and 85, if anyone wants to
2
look at that.
3
Questions? Dr. Bergfeld.
4
DR. BERGFELD: Thank you.
5
This presentation of the possible registry
6 and
the initial visit through the follow-up, et
7
cetera, this is a combined program of all of the
8
isotretinoin producers?
9
DR. HUBER: Yes, we would envision
a
10
single process.
11
DR. BERGFELD: And that would
include also
12
redoing the patient information, physician
13
information sheets, which would also be a combined,
14 or
would you still have separate everything?
15
DR. HUBER: I think we would have
the
16
patient educational materials being combined.
17
There may be some discussion on details of that.
18
DR. KWEDER: What we would like to
hear is
19
what you think about that.
20
DR. BERGFELD: I think that is
what should
21
happen.
22
DR. KWEDER: What should happen?
215
1
DR. BERGFELD: That it should be a
2 combined
effort, that it is too confusing to us to
3
have all these different groups with different
4
things that we have to do.
5
One combined package for the whole drug
6
isotretinoin is the way we would like to go.
7
DR. GROSS: Any other questions? Dr.
8
Bigby.
9
DR. BIGBY: Two questions. One thing that
10 I
missed, in this system, how is it ascertained
11
when a woman gets pregnant?
12
DR. HUBER: None of the current
risk
13
management programs ascertain when a woman gets
14
pregnant. The only thing we can
do is detect
15
pregnancy prior to dispensing of the product for
16 the
next treatment.
17
So, what you do--it's a 30-day cycle, we
18 may
end up modifying it to 28, we can discuss
19
that--but at the end of the day, basically, on a
20
monthly average is when the patient will get seen
21 by
a physician, have a pregnancy test, and receive
22 one
month of treatment.
216
1
That is very analogous to Thalidomide for
2 the
second treatment on.
3
DR. BIGBY: The other question I
had is in
4 the
booklet, on page 55, there is a description
5
about the education in the first 30-day period, and
6 it
says, "This includes patient viewing of the
7
isotretinoin video, review of comprehensive written
8
materials, and isotretinoin pregnancy prevention
9 and
risk management for women," et cetera.
10
Where do you envision that people view the
11
video?
12
DR. HUBER: Generally, that is
done in--my
13
understanding is that is offered in the physician's
14
offices. I would defer to the dermatologists how
15
they handle that.
16
DR. GROSS: Dr. Day.
17
DR. DAY: Evidently, the
percentage of
18
people who view that video is very low.
I don't
19
have the accurate data, but I understand it is in
20
single digits percent. So, if you
can comment on
21
that, and also if we were to go forward with this
22
program as you have envisioned it, how long would
217
1 it take to implement? So, thinking about the
2
patients who would still be continuing under the
3
present plan while the implementation is taking
4
place.
5
DR. HUBER: Your first question,
with
6
regards to the video is low, but now that we are
7
actually spending more time with the behaviorist as
8
opposed to some of the other people we are
9
traditionally talking with, drug safety, that is
10 too
surprising we are finding. Videos are
actually
11 fairly ineffective. As an educational tool, a lot
12 of
people just don't watch videos.
13
One of the reasons, when we developed
14
this, it was a supplement, it was never intended as
15 the
primary tool. So, one of the things we
are
16
looking at is we do have multiple modes of
17
teaching. I mean there already is
the booklet,
18
there is the other educational materials, and there
19 is
the video. Exactly how that will be
handled
20
going forward, I do not know.
21
With regards to implementation, it
22
somewhat depends upon the level of the complexity
218
1 of
the program that is agreed upon. I would
have a
2 hard
time giving you--it is not something that gets
3
done overnight, let's put it that way.
4
DR. DAY: Well, we can appreciate
that,
5 but
just in the basics of what you have told us, is
6 it
on the order of six months, a year, two?
7
DR. HUBER: You are usually
talking 6 to 9
8
months is our understanding. If
you know what your
9
design specifications are, you can get it done in
10
that time frame. The concern is if you start
11
changing details of the design and things, then, it
12
gets substantially longer.
13
DR. DAY: Well, more fleshing out
of the
14
provision of how the patient is going to get the
15
materials would be a helpful component here. Short
16 of
at the physician's office, having to go into a
17
separate room to watch a video, I mean just what
18 are
the mechanisms? It would need to be
specified.
19 I
am not asking for right now.
20
DR. HUBER: We would envision that
that
21
would continue as we pretty much do it today. We
22
provide the materials to the physicians, and then
219
1
they manage that to the patient for the upfront
2
materials.
3
DR. GROSS: Dr. Honein.
4
DR. HONEIN: Yes. Using the unique ID
5
numbers as you have proposed, how would you
6
identify duplicates within your system either
7
because of multiple courses of treatment or
8
prescriptions from different physicians, or even
9
potentially longer term subsequent treatments by
10
women who have previously had an exposed pregnancy
11
during it, which maybe you would want to identify
12 for
separate intervention?
13
DR. HUBER: If I understand the
question,
14 it
would be how do we identify a patient, for
15
follow-up, we would see them in the system because
16 we
assume they would go back to the same physician.
17
DR. HONEIN: But they might not.
18
DR. HUBER: If they come back from
a
19
different physician, that is an issue.
If they
20
would go through multiple physicians, how we would
21
identify that it was the same patient in the
22
system, that gets very difficult unless you start
220
1
having true identifiers of the patients in the
2
system.
3
DR. HONEIN: How about a second
course of
4
treatment a year later? You would
expect the
5
physician to maintain the link to that ID numbers
6 and
be able to locate that a year later?
7
DR. HUBER: Well, we hadn't
actually
8
thought through that, but on the other hand, we
9
didn't see that as an issue, because from our point
10 of
view, the important thing was the pregnancy risk
11
management through each course of treatment was the
12
focus of the design.
13
DR. GROSS: I have a question for
you.
14
Have you considered using the six risk groups that
15 are
in the S.T.E.P.S. program including adults and
16
children, men, and women?
17
DR. HUBER: No, at this time
not. We will
18
probably focus on females of childbearing potential
19 as
a single risk group. One of the
advantages of
20
this proposal is given the volume of data we will
21
have, which will be substantially larger than the
22
experience S.T.E.P.S. has, we would hope that we
221
1
would be able to identify more quickly patterns
2
that point out specific high risk groups, and then
3 we
may need to adapt to that.
4
MR. LEVIN: Just a point of clarification
5 on
the issue of duplication. The registry
is not
6
anonymous, am I right, there would be patient
7
information within the registry, it is only the
8
unique number that goes out?
9
DR. HUBER: Yes.
10
MR. LEVIN: So, theoretically, if I am
11
correct, you would still have a way of spotting or
12
flagging a duplicate. I mean you
have enough
13
information that you would recognize that that is
14 the
same patient coming back into the database.
15
DR. HUBER: The problem is
accessing that
16
information, can a physician go in and search and
17 see
if that patient already exists, and I just
18
can't answer that question.
19
MR. LEVIN: Couldn't the registry
do that?
20
That is what I am getting at. In
other words, the
21
information goes forward to the registry, the
22
registry has other demographic information that
222
1
identifies a patient specifically, it seems to me
2 it
is taken care of.
3
The registry can do the search and say
4
whoops, you have been in here before with this
5
number.
6
DR. HUBER: My technical people
are saying
7
yes, we could do that.
8
DR. GROSS: Brian.
9
DR. STROM: Two questions. In the system
10 you
are proposing, who are you proposing as the
11
enforcer? In other words, who is
the primary
12 ultimate
body who is responsible for making sure
13
that the patient gets the pregnancy test before the
14
drug gets dispensed?
15
DR. HUBER: At the end of the day,
in this
16
system, if the pregnancy test is--I mean the
17
pharmacist has to go into the system prior to
18
dispensing, so I guess in answer to your question,
19 if
the pharmacist doesn't see the system say it's
20
okay to dispense, they won't dispense the product.
21
So, from that point of view, the final
22
check is the pharmacist to ensure that the registry
223
1 has
okayed the patient.
2
DR. STROM: Let me respond to it
in two
3
ways, and then I have a second question.
One is
4 the
fact that you had to pause to think about it.
5 The
second, which relates, is in the current
6
system, in the S.M.A.R.T. system, the pharmacy is
7
also the enforcer via the sticker system, and it is
8 not
working.
9
So, I guess my concern is in whatever
10
system--and obviously, there are lots of details to
11 be
worked out--I think where the current system has
12
failed is having a clear enforcer who has a vested
13
interest in making sure it happens, and I am
14
concerned about making the pharmacist the enforcer.
15 I
am concerned, it is not fair to them, they are
16 not
being paid for it, and it is also not
17
necessarily feasible. That is
what happened in the
18
sticker system, and it sounds like that is what you
19 are
proposing again.
20
DR. HUBER: Maybe I am misusing
the word
21
"enforcer." What we are relying on is the system
22
will identify is there a negative pregnancy test
224
1
done that meets the time window criteria. The
2
pharmacist's role in this will be to make sure that
3 the
patient has indeed qualified within the system.
4
The difference is in the sticker system,
5 the
sticker represents a physician attestation that
6 a
pregnancy test was done. So, you have
two
7
potential sources of error. One was upfront, the
8
physician on the sticker, the second was the
9
pharmacist in looking at the sticker.
10
We are not eliminating all potential
11
sources of errors this way. What
we are trying to
12 do
is, one, at least eliminate the upfront one
13
because there has to be a laboratory test result,
14
which overrides, shall we say, the physician
15
attestation on a pregnancy test, and on the back
16
end, we are trying to make it as simple as possible
17 for
the pharmacist, so he doesn't have to interpret
18
data, he gets a yes/no answer.
19
DR. STROM: Again, how does the
data, the
20
hard link that you talked about of the pregnancy
21
test, get into the system?
22
DR. HUBER: What we are
envisioning is
225
1
that there probably has to be a two-step process to
2
that, because, one, we had talked about having it
3 go
directly from the lab to the system. One
of our
4
concerns was if there was a pregnancy test, we
5
really think the physician needs to know about it.
6
So, we think the pregnancy test needs to
7 go
via the physician, but there probably, in order
8 to
close this loop of the hard certification, there
9
needs to be some way to enter either the
10
information directly into the system from the lab,
11 or
that there is a fax copy or something to follow
12 up.
13
DR. STROM: I guess my own
preference
14
would be to reverse it.
Certainly, you want to
15
make sure the physician knows, but I wouldn't have
16 the
system dependent on the physician. I
think the
17
hard data should go directly to the registry, and
18
while you are at it, notify the physician, so the
19
physician knows about it, so that there is a
20
positive, so there really is a hard link.
21
My second question is when I read through
22 the
description, and we heard you present it
226
1
yesterday, I was a lot less reassured.
Now,
2
hearing it in the context of the S.T.E.P.S.
3
program, it sounds much closer.
4
Can you nail down for me what the
5
differences are between this and the S.T.E.P.S.
6
program, and in what way is it not the same as the
7
S.T.E.P.S. program?
8
DR. HUBER: S.T.E.P.S. does not
require a
9
certified laboratory test. It is
a physician
10
attestation into the system.
11
Secondly, S.T.E.P.S. requires weekly blood
12
tests the first treatment. We are
not proposing
13
that. The third difference--that
is the two
14
differences. The third element
that will come up,
15 the
difference is in the distribution of the
16
product, because we are in a multi-source
17
environment versus a single source environment.
18
That is one of the issues we are going to have to
19
kind of sort out, because that is novel for this
20 approach.
21
DR. KWEDER: I would add the other
22
differences are S.T.E.P.S. enrolls everyone. This
227
1
would only enroll female patients.
2
DR. HUBER: No, our current
proposal
3
includes males and females.
4
DR. KWEDER: You didn't say that
before.
5
DR. HUBER: I am sorry, I
apologize.
6
DR. KWEDER: And you also don't
have the
7
follow-up survey, correct?
8
DR. HUBER: Our focus on this was
on the
9
interventional elements while the patient is
10
getting treated. With regards to
the follow-up
11
survey, the other point I would like to bring up on
12 the
mandatoriness of that, it kind of comes back to
13 the
question that was raised yesterday about the
14
30-day follow-up.
15
The problem with any follow-up survey is
16 we
can say it is mandatory, but the ability to
17
enforce it is almost nil, because if the patient
18
doesn't have to come back to receive a product,
19
they don't have to do anything.
20
So, we can make them sign and say it's
21
mandatory, but at the end of the day, the reason
22 the
patient is going to show up for their blood
228
1
test and answer the questions on the IVR is because
2 if
they don't do that, they don't get isotretinoin.
3
So, one of our concerns was is any of
4
those follow-up surveys, you are going to get back
5
into significant issues of will patients
6
participate. We see this as
focusing much more on
7 the
intervention, the pregnancy prevention aspects.
8 We think we should be able, with this
9
approach, to get data, the data you are looking for
10 as
part of the ongoing intervention during the
11
treatment.
12
DR. GROSS: You just said that
males will
13 be
included. Are you going to recommend
male
14
contraception, too?
15
DR. HUBER: With regards to male
16
contraception, we do not recommend male
17
contraception. You received the
copy of our
18
report. That report has been
submitted to the FDA
19 in
I believe 2001. We have done multiple
20
investigations, both clinically and preclinically,
21 and
we do not see evidence of a risk from a
22
paternal exposure to a female.
229
1
I would like to remind you the drug is not
2 a
genotoxin, so it doesn't have an effect on sperm,
3 so
the only risk would be transmission via seminal
4
fluid. When we have investigated,
the exposure
5 from seminal fluid is one million times
lower than
6 a
single 40 milligram dose, so based on that data,
7 we
don't see a risk.
8
When we reviewed the case data, we have
9 not
seen--we have seen isolated malformations, but
10
please remember malformations do occur in the
11
population, but in the 20 years out there, we have
12 yet
to see a paternal-exposed pregnancy in which
13 the
triad, the classic triad of a retinoid
14
embryopathy, as described by Lammer [ph], has
15
occurred.
16
DR. GROSS: Are there any comments
from
17 the
generic companies?
18
MR. POLLOCK: Thank you.
19
A couple of things I just want to point
20
out, so everybody is just aware of it, is the
21
generics and the brand name companies first got
22
together to start talking about this on December
230
1
10th, when we were called in to the FDA.
2
From an operational
standpoint, people had
3
mentioned the fact that we might not have the
4
details worked out. Well, we
don't. I mean it has
5
been amazing to get to this point, I think, with
6
five different companies, six different companies
7 in
this period of time.
8
So, we are thankful for all the
9
cooperation, but some of the questions you pose, we
10
might not have answers for because we haven't been
11
able to fully consider them ourselves, and we have
12
learned a lot, I think, from the Advisory Committee
13
comments and things of that nature.
14
To harken on Dr. Kibbe's comments, this is
15 a
fairly complex program. We have to again
I think
16
just recognize the impact on the physician, the
17
patient, and the health care system that is going
18 to
be providing these things, because we don't want
19 to
force people outside of the area.
20
So, I would just like you to always kind
21 of
keep that in the back of your mind.
22
The other issue is--and I raised this
231
1
yesterday--Marty described a system where the
2
educational component and the responses were going
3 to
be tied into this yes/no determination.
This
4 was
one of the things we asked for your input on.
5
If there is a patient that has an
6
inappropriate response during the educational
7
component, but has a negative pregnancy test, we
8
would like your advice on what to do with that
9
patient.
10
Should the patient receive the drug and
11
perhaps automatically a letter be fired off by the
12
registry system itself back to the physician
13
indicating this is a high risk patient, here is the
14
questions they answered wrong, you need to counsel
15
this patient?
16
If the patient fails the second time,
17
maybe that would be the no drug contingency. But
18 we
would like you to also consider that, as well.
19
Those are the issues that we think are
20
very important to keep in the back of your minds
21
when we are evaluating where we are going to go and
22 how
we are going to get there, and whether or not
232
1 it
would be appropriate even to move in a stepwise
2
program--that was kind of a pun, I guess, I didn't
3
mean stepwise--a uniform program over the course of
4
time.
5
Thank you very much.
6
DR. GROSS: Thank you.
7
Dr. Whitmore.
8
DR. WHITMORE: I would remind Dr.
Huber
9
that 32 percent of the pregnancies that occurred,
10
occurred during that last month after treatment
11
with Accutane. I think somebody
had mentioned that
12
after one month, it is okay to get pregnant, so
13
those issues are not important.
14
But coming back to this, 32 percent of the
15
pregnancies did occur in that 30 days after
16
Accutane therapy, which is a critical period, and
17 we
still have no mechanism by which to address that
18 as
far as these women coming back.
19
I would suggest maybe some type of
20
monetary gift to patients when they come back at
21 one
month or something and have their pregnancy
22
tests done, but I think that really does need to be
233
1
addressed considering it's a third of the patients
2 who
do get pregnant.
3
One other thing, too, about the
4
computerized system and everything, in terms of the
5
logistics of the pregnancy test, getting to the
6
pharmacy and everything else, this is going to be
7
very expensive. Robyn Shapiro
asked who was paying
8 for
the Celgene program, and the answer was
9
Celgene, but that's not true.
That's patients and
10
insurance companies or whoever.
So, patients are
11
going to be paying for this program whatever it is.
12
I would suggest that every patient who
13
does receive a prescription with a sticker has to
14
come back to the office to pick that up after the
15
pregnancy test has been done.
Thus, we can give
16
them a copy of the pregnancy test, they can take
17
that to the pharmacist with them.
18
That will eliminate any embarrassment
19
about a positive pregnancy test, going to the
20
pharmacy without the physician knowing about it,
21 the
patient knowing about it, and it can all
be
22
hand-carried to them.
234
1
The pharmacy is well aware of the Accutane
2
Pregnancy Prevention Program, the stickers, and the
3
whole bit. All you have to do is
add in a
4
pregnancy test required to fill the prescription
5 for
it, and then you don't have to have this
6
expensive program.
7
DR. GROSS: Robyn Shapiro has a
question,
8 and
I have a question for her. As the
ethicist on
9 our
committee, do you have any comments you would
10
like to make in that regard as far as the child or
11 the
mother?
12
MS. SHAPIRO: I do, and I was
going to ask
13 you
to ask me that, but, first, can I ask my
14
question, my other question?
15
Getting back to the expensive interaction
16
program, which is along the lines of what I had
17
suggested just a little while ago, to ensure, I
18
hope--I mean it is still pretty vague, so whoever,
19
Roche or generics, whoever wants to answer this
20
question--what would you be looking for?
21
Would you be looking for both
22
comprehension, as well as suggest compliance or
235
1
noncompliance, and then, two, if there is a problem
2
with respect to one or another, my own response to
3 the
request for input from us about what to do,
4
would be to circle that back to the dermatologists,
5
both to enhance, enrich, and inform that
6
relationship, and because I think it would be
7
inappropriate for a computer or a program, or
8
whatever it is, to countermand an order that had
9
been submitted from a doctor on account of the
10
interaction with the program.
11
DR. HUBER: With regards to your
question,
12 the
first draft of questions will be modeled
13
somewhat analogous to the S.T.E.P.S. program
14
current questions. Once again, we
are trying to
15
build on a program that is already in place, and
16
they already have an IVR interaction for questions.
17 Clearly, this is a relatively new
science
18 in
doing this on testing for compliance for
19
pharmaceuticals through IVR.
Anything that is
20
learned from that, we would appreciate, and
21
anything that this committee has to say as
22
recommendations on how to do those questions
236
1
better, we would be interested in knowing.
2
With regards to the latter part of your
3
comment, that is something that has always bothered
4 us
is at the end of the day, the physician is
5
ultimately responsible for the education and
6
information for the patient.
7
We are now adding in, shall we say, a
8
little test along the way to see if the patient
9
really got it, and also reinforcement.
That is
10
difficult for us, and we are struggling with that
11
whole concept. When we look at
the S.T.E.P.S. as
12 the
model, that is what they are doing, and we are
13
basing that on that approach.
14
There is not a lot of other choices of
15
things that have been modeled previously, and kind
16 of
using the basic thoughts of we don't want to get
17 too
experimental here. That is the one approach
18
that has been tried in a population.
19
MS. SHAPIRO: Again, personally, I
think
20
it's okay to do a little test as long as the
21
remedial response is put in the lap of the doctor,
22 and
not you.
237
1
DR. HUBER: Yes, agreed.
2
MS. SHAPIRO: Your request, and
you know,
3 as
a disclaimer, like any good lawyer would do, I
4
guess, this may confuse more than help, but we are
5
struggling with how can we accept that we are not
6
going to have zero pregnancies, and if we do accept
7
that, what number is good enough.
8
In order to do that, we need to weigh and
9
balance, of course, the benefits of the Accutane to
10 the
patient, and I think we are probably all pretty
11
convinced that there are significant benefits, to
12 the
harms.
13
When we get to the harms, we have really
14
potentially two individuals, as well as society, to
15
take a look at. We have the
potential harm of the
16
woman who has to raise an impaired--this is if we
17
fail to prevent pregnancy 100 percent--has to raise
18 an
impaired child, and the life of the impaired
19
child, and the burden or the harm to that child of
20
that life, and the burden to society.
21
If we are successful 100 percent in
22
preventing pregnancy, no one has those burdens. If
238
1 we
are not, the woman has a choice. We
could, but
2 I
hope we don't, get into a conversation about
3
abortion at the moment, but she does under the
4
current state of the law in the country have a
5 choice
about whether to continue with that
6
pregnancy or not.
7
If she chooses to terminate, then, she has
8 the
burden of going through that, which clearly is
9
significant, as well. The child
is spared, there
10 is
no child, so that harm goes away, as I suppose
11
does the harm to society to a certain respect.
12
If she chooses not to, can't, won't have
13 an
abortion, then, she bears the burden of going
14
through the pregnancy and raising an impaired
15
child. In response to that, if we
are good at what
16 we
are trying to do, which is to fully inform and
17
provide a way for her to avoid that, in part, that
18 is
her responsibility and then her choice.
19
But she has been forewarned, the child, on
20 the
other hand, hasn't. So, in some ways,
one
21
might see the harm to the impaired child as being
22
more significant than the harm to the woman who is
239
1 in
the position of having to raise the child.
2
How do we place a value on or get our arms
3
around the burden to the child?
What does that
4
mean? What is the
importance? What is the gravity
5 of
that? That is where we really have a
problem.
6
If we analogize to what courts have done
7 in
wrongful life lawsuits, and typically, these
8
lawsuits are brought when there is a failure to
9
inform about a potential genetic test or something
10
like that, and the woman is deprived of that
11
information, so doesn't have information about
12
which she can base an abortion decision on.
13
An impaired child is born, and the child
14
will then sue and say, doctor, had you only told my
15
mother about these options, I wouldn't have been
16
born, but I am, and therefore I want bunches of
17
money because this is a terrible burden to me.
18
Many more jurisdictions than not will not
19 act
on the lawsuit, will not provide that child any
20
recovery because the judge will say you are putting
21 me
in the position of having to say that any life,
22
while impaired, is worse than no life at all,
240
1
because the option, the alternative in your
2
situation, you plaintiff child, is that you would
3 not
have been born. I will not say that not
having
4
been born is more valuable than life while
5
impaired.
6
This, to me, just shows the difficulty in
7
getting our arms around the nature of the harm that
8 we
are trying to prevent here, which makes it all
9 the
more important that we do a really good job in
10
preventing the situation in the first place, so
11
that we are not left weighing and balancing this
12
abortion decision, and what if, and what if not,
13 and
what is the value of the harm to the child that
14 is
born.
15
DR. WHITMORE: May I ask a question?
16
DR. GROSS: Yes.
17
DR. WHITMORE: I am sorry, of
Robyn
18
Shapiro. What do you think of
having that
19
information, just the gravity of that information
20
with regard to having an impaired child and raising
21
that child if indeed you got pregnant when on
22
Accutane or otherwise having to have an abortion
241
1
because of the pregnancy occurring during Accutane
2
therapy, what do you think of having that on the
3
consent form just to give the patient the gravity
4 of
what we have been discussing here today?
5
MS. SHAPIRO: If that were doable,
I think
6 it
would be great. I mean I am all for more
7
information again mostly, so that we can ensure a
8
real reasoned decision upfront, and therefore
9
compliance with what we are urging them to do, and
10 not
have to grapple with these horrible sensitive,
11
unanswerable question later.
12
DR. CRAWFORD: Thank you. I have just a
13 few
comments about the patient registry and a
14
question about the patient process.
15
With respect to the registry, I think one
16 of
our responsibilities is to recommend advice with
17
respect to what entity should be responsible for
18
registration and maintenance of a registry if it
19
existed.
20
My opinion is that I would agree with what
21 others have said, it must be a consolidated
system,
22 one
program meaning there will be the need for
242
1
negotiation and agreement as to the components of
2 it,
ideally administered by qualified, third-party
3
vendor or contractor.
4
In addition to helping to achieve program
5
goals, that would help allay any concerns that
6
anyone might have about potential promotional use,
7
which I am sure is not the goal of any of the
8
sponsors, but sometimes there are questions about
9
that, not on the ethics part, but that process
10
would also include what information should be
11
collected, such as things Dr. Shapiro and others
12
were saying, and how the information of the
13
registry would be used to prevent embryonic
14
exposure.
15
My question, living in Chicago, I know
16
that many languages are spoken by patients and
17
their practitioners. My question
is if the patient
18
cannot comprehend English or Spanish, would they be
19
excluded under the described program from receiving
20 the
drug or would the physician be able to work
21
with those patients on a case-by-case basis.
22
DR. HUBER: We have discussed
English and
243
1
Spanish, we have not discussed any languages beyond
2
that at this point in time.
3
DR. CRAWFORD: I am sorry. To make my
4
question clear, I am not expecting the program to
5
necessarily be able to adapt to any language as
6
opposed to would there be a different mechanism,
7
more one-on-one with the practitioners if it was
8
believed the patient needed the drug therapy and
9
couldn't understand English or Spanish.
10
DR. HUBER: I don't know the
mechanism.
11 We
would be happy to hear if the committee has any
12
recommendations on that.
13
Committee Discussion
(Continued)
14
DR. GROSS: I am trying to move
along
15
here, and I think we can call on the next few
16
people that have some questions, but I am beginning
17 to
get a sense that we are in the process of
18
answering Question 3.
19
I was asked to take a vote on the slide on
20 the
bottom of page 3. Let's just do that one
and
21
then we will talk more about the particular
22
program.
244
1
The statement on that slide says, "Should
2 we
continue the current risk management program
3
without additional tools?" I
think I know the
4
answer of the group, but I think
each person is
5 going to have to declare themselves.
6
So, let me read the question again, and
7
then starting with the sated Mr. Levin, should we
8
continue the current risk management program
9
without additional tools?
10
If you vote no, that means we don't want
11 to
continue the current risk management program.
12
Mr. Levin.
13
MR. LEVIN: Arthur Levin. No.
14
DR. SAWADA: Kathy Sawada. No.
15
DR. VENITZ: Jurgen Venitz. No.
16
DR. STROM: Brian Strom. No.
17
DR. BERGFELD: Wilma
Bergfeld. No.
18
DR. RAIMER: Sharon Raimer. No.
19
MS. KNUDSON: Paula Knudson. No.
20
DR. BIGBY: Michael Bigby. No.
21
DR. HONEIN: Peggy Honein. No.
22
DR. COHEN: Mike Cohen. No.
245
1
DR. WHITMORE: Beth Whitmore. No, but not
2
with the proposed plan.
3
DR. GROSS: We are not there yet.
4
MS. SHAPIRO: Robyn Shapiro. No.
5
DR. EPPS: Roselyn Epps. No.
6
DR. SCHMIDT: Jimmy Schmidt. No.
7
DR. CRAWFORD: Stephanie Crawford. No.
8
DR. GROSS: Peter Gross. No.
9
DR. WILKERSON: Michael
Wilkerson. No.
10
DR. RINGEL: Eileen Ringel. No.
11
DR. VEGA: Amarilys Vega. No.
12
DR. DAY: Ruth Day. No.
13
DR. KIBBE: Arthur Kibbe. I am forced to
14 say
no, but I really would rather have had a vote
15
between this plan and another one, so I had
16
something to compare it to, because this is better
17
than nothing.
18
DR. GROSS: We will meet your needs
19
momentarily.
20
DR. GARDNER: Jackie Gardner. No.
21
DR. KATZ: Robert Katz. No.
22
DR. SELLERS: Sarah Sellers. No.
246
1
DR. GROSS: That is about as
unanimous as
2 you
can get. There are some more questions
that we
3
will then apply to the fact that we are going to
4
recommend something different.
5
Michael Cohen.
6
DR. COHEN: I guess touching on
what Dr.
7
Strom mentioned earlier about the enforcer and
8
workloads, et cetera, and where they might lie, do
9 you
have plans if an enhanced program is
10
implemented to interact with the medical and
11
pharmacy community, get feedback?
12
A few times people alluded to failure mode
13 and
effects analysis. Do you have plans to
conduct
14
that and involve practitioners in that process? I
15 am
asking that of industry.
16
DR. HUBER: One of the first steps
would
17 be
the establishment of a scientific advisory
18
board, which we have had for all of the previous
19
risk management programs. We
would intend that
20
that would include stakeholders in the program, as
21
well.
22
There would need to be some interaction
247
1
with the dermatology community, the pharmacy
2
community, et cetera, but we would see that as
3
something done in parallel to the scientific
4
advisory board as part of that activity.
5
DR. COHEN: And the concept of
failure
6
mode and effects analysis? In
other word,
7
developing this process, flow diagram a little bit
8
further and then going back and trying to determine
9
where failures might occur in that process, and
10
then come up with a way to prevent those failures.
11
I think you do need an advisory group to
12 do
something like that.
13
DR. HUBER: Yes.
14
DR. GROSS: I have been advised to
try to
15
keep the discussion among the committee, and not go
16
back to industry for answers unless it is
17 absolutely necessary.
18
The next person, Dr. Honein.
19
DR. HONEIN: I am very concerned
that they
20
don't plan to do a follow-up survey as a component
21 of
this for a couple of reasons. One, I
think
22
during the interactive process to get the
248
1
prescription, the really only alternative is for
2 the
patient to give the best case scenario plan, to
3
things like what do you plan to do for
4
contraception, both socially desirable responses,
5 and
maybe their intentions, they don't get followed
6
through upon, whereas, a survey after the fact can
7 get
at what did you really do, during the course of
8
treatment.
9
While some people may still give socially
10
desirable responses, at least you have the
11
opportunity to let them sort of look back on it and
12
provide the best information.
13
My second concern is since we are already
14
under-ascertaining pregnancies, that this would
15
increase the under-ascertainment.
I think if a
16
woman diagnoses her own pregnancy during the course
17 of
treatment, she is not going to go back to the
18
system for the next refill. She
is going to go to
19 a
separate health care provider that deals with
20
that pregnancy, and where does the system find out
21
about this.
22
The follow-up survey is one more
249
1
opportunity to locate that. With
that regard, I
2 was
wondering if we could refresh our memory on
3
what proportion of the pregnancies we know about
4 now
came from the follow-up surveys, after the
5
fact.
6
DR. GROSS: Does FDA have any
information
7 on
that?
8
DR. KWEDER: Can you state the
question?
9 I
got all the beginning, but the question again.
10
DR. HONEIN: Of the pregnancies
that we
11
know about in total, exposed to isotretinoin, how
12
many of those do we know about because of the
13
follow-up survey rather than another mechanism?
14
DR. TRONTELL: As Dr. Pitts
described
15
yesterday, the majority of reported pregnancies to
16 the
Agency come via the manufacturer. The
17
minority--we can pull up the slide to give you the
18
percentage--but my recollection, it is about 20
19
percent come by the follow-up survey.
20
DR. HONEIN: Right, but I think
that would
21 be
a big loss to lose 20 percent of the pregnancies
22
that we know about now by not doing that follow-up.
250
1
DR. GROSS: I think when we come
up with a
2
final plan, you can put that in as a suggestion to
3 be
part of the plan.
4
Dr. Gardner.
5
DR. GARDNER: In Dr. Huber's
response to
6 Dr.
Strom, there was something of concern to me,
7 and
that was that the pharmacist would be asked to
8
interact with the registry system in order to
9
further document the negative pregnancy test.
10
I think this builds in another potential
11 for
failure in that the pharmacist now has a yellow
12
sticker that we have discussed, that has, in
13
theory, the physician's documentation that there
14 has
been a negative pregnancy test, whether it does
15 or
not.
16
If we now ask the pharmacist to take that
17 and
do an additional step, and that is to
18
double-check that information against the registry,
19
which is what I thought I heard from Dr. Huber,
20
then, I think that we are building in another point
21 of
potential failure there, some 55,000 pharmacies
22 in
the U.S., and many of them are high volume.
251
1
Yesterday, in the FDA presentation, we
2
learned that of the places where there were
3
problems with stickers coming incorrectly, they
4
tended to be to high-volume pharmacies and to rural
5
pharmacies. My guess is that
adding an extra step
6 in
those circumstances where we are already seeing
7
where some problems lie, would ask for trouble.
8
So, I would suggest that whoever mentioned
9
that the pregnancy test result loop should go back
10 to
the physician who then attests on the sticker or
11
something else, so the pharmacist has one thing to
12
look at, and that is it, I think would reduce that
13
potential.
14
DR. GROSS: Mr. Levin. Mr. Levin went out
15 for
a snack.
16
Dr. Kibbe.
17
DR. KIBBE: As soon as Mr. Levin comes
18
back, I will give him a chance to jump in.
19
I have just a couple of observations about
20
what we have been doing for a while.
First, you
21
cannot test quality into any system, and the
22
pregnancy test that we do prior to initiation of
252
1
therapy assures that the patient at least is not
2
pregnant when they start.
3
Pregnancy testing during therapy seems
4
like a QA test to me, and it's a QA test of whether
5 the
patient is behaving appropriately in terms of
6 not
getting pregnant.
7
That is never going to change the
8
patient's behavior and prevent the pregnancy, it is
9
just going to tell us when it happened, and then
10
what do we do about it, and it is my impression
11
that by the time we find out, the damage is done
12 and
we have to do all sort of other things, so that
13 is
not even helping us get to what we want, which
14 is
no pregnancy, it is just testing for it, and
15
testing just to prove that something is going wrong
16 is
just--an awful lot of what we talk about around
17
here is changing behavior, but everything I hear
18
them talking about in the program is changing the
19
behavior of the physician and the pharmacist, and
20
what we really want to do is what?
21
It is change the behavior of the less than
22 1
percent of women who, when they are counseled on
253
1 how
to behave during taking this drug, somehow
2
don't get the job done. So, that,
we need to focus
3 on
a little more.
4
I wanted to get back to my ethicist here,
5
because I know that some of my ideas, I admit
6
freely that they might sound draconian, but if the
7
result is draconian, then maybe the cure is
8
draconian.
9
So, would it not be a lesser harm to
10
society and to the individual if we require anybody
11 of
childbearing age who wants to take this drug to
12
have a permanent IUD put in before and removed two
13
months after, so that we close down the loop.
14
If we can identify people at risk,
15
wouldn't that be a better way of maintaining the
16
zero pregnancy option or at least getting close to
17
zero pregnancy than trying to do a lot of things,
18 and
education never works 100 percent of the time.
19
MS. SHAPIRO: From a theoretical point of
20
view, you are probably right, or, you know, give a
21
shot or something like that. The
problems that we
22
encounter are, first, what are the risks or side
254
1
effects of that. I don't know.
2
Second, in this country, in the law and in
3
ethics, we tend to accord reproductive
4
decisionmaking a lot of latitude in terms of
5
freedom of choice and privacy, and so forth. So,
6
that might--I am not saying that you couldn't do
7
it--but I think it would not be an easy sell from a
8 PR
point of view.
9
DR. GROSS: Mr. Levin.
10
MR. LEVIN: Two things. One is a caution
11
about loading up informed consent documents with
12
lots of information and the assumption, which I
13
think is disproved in the literature, that informed
14
consent does what it is intended to do.
I mean I
15
think there is a lot of stuff that has been written
16 and
a lot of taking a look again at how the
17
informed consent process works, as well as how IRB
18
processes work.
19
The other thing I would like to reiterate
20
what I said before the lunch break, which is it
21
seems to me that we may all have our personal ways
22 of
sort of trying to tweak this system, but they
255
1 are
not based on any evidence.
2
I would once again emphasize that we sort
3 of
have a responsibility to patients taking this
4
drug to make decisions based on the best possible
5
evidence that they are actually working to prevent
6 the
outcomes that we are committed to preventing.
7
So, I think we really ought to look at the
8
existing programs and only nibble at them with
9
changes if we believe there is something about them
10
inappropriate to this particular population and
11
drug.
12
But I think it is a good place to begin
13 and
I think Roche has constructed a program that
14
comes pretty close to sort of borrowing a lot from
15
S.T.E.P.S. and a little bit perhaps from the other
16
program.
17
I just want to emphasize that it's
18
evidence based and that we have data that tells us
19
that that approach may be an effective approach,
20 not
that it can't be improved, and to suggest again
21 a
hypothesis of what we would like this to look at,
22
that have no evidence is simply going to delay this
256
1
process even more and mean that more patients will
2 be
hurt in the intervening years until we get data
3 to
prove whether our suggestions were workable or
4
not.
5
DR. GROSS: Art, since you are
moving us
6 in
that direction, the other part of Question 3 is
7
what would we propose. So, why
don't we consider,
8
let's say, accepting the Roche Risk Management
9
Program and decide whether there any additions that
10
need to be made to it, such as making sure that
11
males are included and what you want to do about
12
making a survey mandatory, et cetera, if we could
13
perhaps direct our comments to those issues.
14
There are a couple other people that
15
wanted to comment. Dr. Bergfeld.
16
DR. BERGFELD: I was only going to
address
17 the
foreign-speaking individuals who might need
18
Accutane. I think they need to be
handled on a
19
case-by-case basis. I think most
of those
20
individuals, depending on their geographic
21
location, might be referred into tertiary care
22
centers where there are interpreters, and
257
1
frequently, in some of the rural areas, there are
2
foreign-speaking nurses, so we are taking care of
3
these people at the present time.
4
DR. GROSS: Sarah Sellers.
5
DR. SELLERS: I am sorry, are we
on the
6
actual Question 3?
7
DR. GROSS: We are on page 4, the
top
8
slide.
9
DR. SELLERS: My comment was given
the
10
goals of the pregnancy risk management program, to
11
ensure continued access to a drug that has been
12
proven to be effective in patients who suffer from
13
severe nodular acne, is there a model or is there a
14
mechanism, or indeed does the FDA have the
15
statutory authority to restrict the use of the drug
16 to
its labeled indication, and then provide a
17
mechanism for treatment IND to off-label use.
18
DR. GROSS: Does anyone from FDA
want to
19 answer that?
20
DR. KWEDER: Yes, I can answer
that. We
21 do
not regulate the practice of medicine, and
22
off-label uses generally have historically been
258
1 considered practice of medicine issues.
2
What we usually do when we are trying to
3
influence the practice of medicine is we restrict
4 the
labeling or we impose other kinds of programs,
5
such as the ones that have been discussed today, to
6 try
and minimize a use that is not consistent with
7
labeling.
8
So, in terms of ensuring, for example, if
9 you
look at one of the examples presented today was
10
Thalidomide. Thalidomide is not
approved for the
11
treatment of any oncologic condition, but the vast
12
majority of uses are for treatment of different
13
kinds of cancers, particularly multiple myeloma.
14
We have not found that we are in a
15
position to be able to restrict those uses.
16
DR. GROSS: Dr. Ringel.
17
DR. RINGEL: It is sort of hard to
get
18
anybody's attention deep in the recesses of the
19
table, so I have actually collected quite a few. I
20
will try to go through them quickly.
21
One is that people need to remember that
22
there are practitioners who are in rural areas and
259
1
their patients may live very far away, and I would
2
ask, when you make the rules, please don't make the
3
rules so that patients need to come back the next
4 day
to pick up X or Y, you know, the pregnancy test
5
results, the prescription. Don't
make them make
6
trips just for silly things like that.
7
I would think fax could be an option for
8
some of those things, faxing a prescription with
9 the
sticker on it to the pharmacy, something or
10
other. I think that is an
unreasonable burden.
11
The other thing is that I think the first
12
pregnancy test is problematic because the value of
13 a
negative first pregnancy test is basically
14
worthless if the patient has conceived within the
15
week before that test.
16
The two ways the FDA has decided that that
17
won't happen is, number one, to make sure the test
18 is
taken during the menstrual period, and, number
19
two, to make sure that they have been on two forms
20 of
contraception for a month before that test.
21
We have done nothing to address that those
22
have happened, so I have these proposals, and I
260
1
think actually that happens a lot.
I think that
2
people who, for example, have been on birth control
3
pills, why make them wait a month to use a second
4
form of contraception, how silly, except it is not
5
silly. I think that actually
people go on Accutane
6 in
less than a month after that first visit quite
7
often.
8
So, what I would suggest is two things.
9
First of all, the pharmacist, when he or she checks
10 the
prescription to make sure that a pregnancy test
11 is
there, can also make sure that it has been a
12
month since the patient registered, because it
13
needs to be at least a month between that
14
registration date and the date they have picked up
15
those pills to know that they have had a month to
16 be
on two forms of contraception.
17
The other--and I am not sure if this would
18
work, but it is just an idea--people want to get on
19
this stuff, they don't want to wait until they have
20
their menstrual period. Would it
be possible to do
21
urine pregnancy tests and then do a dipstick for
22
blood assuming that that specimen was done without
261
1 a
tampon? You would know the patient is
2
menstruating, at least you could verify that.
3
There was another issue brought up about
4
nobody is addressing how to keep people from
5
getting pregnant while they are on the drug, and it
6
seems to be an issue of education.
How do you
7
educate the patient to both understand the issues
8 and
to believe that they really can get pregnant
9
just on one form of contraception or none?
10
What I would suggest there is that the FDA
11
fund some educational studies.
There are various
12
ways that I can imagine to try to convince people
13
that it might be a good idea to be on two forms of
14
contraception, but I can't tell you which one would
15
work, and I would think that funding small studies
16 to
find out what educational methods are really
17
most effective might be a quick and cost effective
18 way
of doing it.
19
Last but not least, given the last
20
discussion, I am not sure this would work, but
21
seeing the three people from the community who
22
testified today, the man who had birth defects, and
262
1
those two poor women, it is very difficult for me
2 to
justify giving this drug to any acne patient who
3
does not have severe scarring, either nodular or at
4
least papular, pustular acne.
5
I know, and you know, that many of the
6
prescriptions for women who are using this
7
medication, are used for those other purposes. If
8
that weren't true, the number of males being
9
treated would vastly outweigh the number of females
10
being treated, but that is not the case. Almost by
11
definition, the females are being treated for less
12
severe acne with Accutane.
13
I think that Dr. Wolfe's suggestion about
14
faxing photos may not be the worst thing in the
15
world. Almost everybody has a
digital camera, it
16
would be easy to do. Frankly, I don't think that
17 you
would even need to make a decision, oh, well,
18
this guy has severe enough acne or that guy
19
doesn't.
20
I think if people just had the
21
responsibility of knowing that someone else was
22
going to look at those photos, sort of knowing that
263
1 big
brother is watching, I think that the rate of
2
Accutane use in females would go down dramatically.
3 DR. GROSS: Dr. Ringel, you have brought
4 up
a number of excellent points that we will have
5 to
consider when we come up with our final plan.
6
I am going to take two more comments and
7
then I am going to ask you to consider voting on
8
Roche's plan as an initial ingredient of the plan,
9 and
then come up with other areas that you think
10
should be added to the plan, if that is your
11
pleasure.
12
The next two comments will be Dr. Strom
13 and
Dr. Day.
14
DR. STROM: Thank you. In follow-up of
15
that, I very much agree with the idea of Roche's
16
plan as a core, but share Jackie's concern, and
17
want to follow up on Jackie's concern and the
18
comments I made before, that the plan is still
19
counting on the pharmacy essentially to be the
20
enforcer.
21
It is the pharmacy that has to do the
22
work, that has to check whether they are pregnant
264
1 or
not, that has to sign into the registry if that
2 is
the case, and get that information. You
are
3
talking about tens of thousands, 50,000 pharmacies
4 you
said?
5
DR. TRONTELL: 55,200.
6
DR. STROM: 55,200 pharmacies with
many
7
more pharmacists. It is a system
which is bound to
8
break down. It is also a system where people are
9 not
being paid for their time, and the pharmacists
10 are
now doing it out of good will, but, in fact,
11 are
very busy and very stressed out, and you are
12
adding more to some very busy people.
13
So, I would argue that that plan should be
14
augmented by a system of a more selective system of
15
pharmacy dispensing. It can be
multiple options,
16 and
I would recommend multiple options, a
17
centralized system whereby you could use mail
18
order, for example, and/or a specialty pharmacy.
19
There is increasing use of specialty
20
pharmacies where pharmacists are paid more to
21
provide a particular kind of care, and I would have
22 the
registration system basically be a
265
1 certification
of specialty pharmacies, that these
2
pharmacies would get paid extra for doing this, but
3
would have the obligation and expectation of doing
4 it
accordingly.
5
So, for the patient in a rural area, there
6 would
be a centralized system that they could get
7 it
from a mail order system. Many people
might use
8 the
mail order system indeed, but I wouldn't
9
necessarily think we need to restrict it to just a
10
mail order access.
11
I think the use of what is
increasingly
12
common in terms of specialty pharmacy makes sense.
13 So,
let's make sure that the person who is the
14
enforcer has a vested interest in doing the
15
enforcing and is paid for that interest, because
16
right now that is not happening.
17
DR. GROSS: Dr. Day.
18
DR. DAY: In the component that
tests
19
patients' knowledge, I think more work needs to be
20
done. Everything that I have seen
presented is
21
about being able to give back information that is
22
already provided, so that factual knowledge or
266
1
repetition even.
2
I think we need to have more complete
3
comprehension, which would involve making
4
inferences and perhaps giving scenarios, say, if
5 you
did this, and then that, would it still be all
6
right to take the medication, and so forth. So, I
7
think a more careful look at the comprehension
8
component.
9
I guess I will save the last part of my
10
intended comment for when we add additional tools.
11
DR. GROSS: Let's take the Roche
handout
12 on
pages 82 and 85 that I referred to before.
13
Let's take a vote on whether or not we would agree
14 to
propose that as a core program that would apply
15 to
all people who are candidates for Accutane or
16 the
generic equivalent, so this will an addition to
17
that program. The same program
applies to those
18
taking generic isotretinoin, as well as the Roche
19
product.
20
Stephanie.
21
DR. CRAWFORD: Thank you. I just need a
22
clarification with respect to I was looking at the
267
1
components because there are certainly some areas
2
that are very good and some that I don't think are
3
sufficient, need to be added to that, so we said,
4 you
know, we wanted modifications initially, such
5 as
I just don't want to be misunderstood if I voted
6 yes
in terms of the components of the system.
7
There are certainly things I would want
8
changed, such as where it said "centralized
9
system," I want that specified as one consolidated
10
system for all the isotretinoin sponsor
11
manufacturers.
12
Also, we will need to address the issue of
13 a
male patient registry. Is that part of
it, or is
14
right now we are just looking at females, et
15
cetera?
16
DR. GROSS: The program is
certainly going
17 to
be added to from the initial. I don't
want to
18
make things too confusing and vote on too many
19
things at once.
20
DR. STROM: Peter, as a point of
order,
21
maybe it makes sense just to have people go around,
22 one
by one, vote on this as a core, and for each of
268
1 us
to describe what we would add to the system in
2 the
process.
3
DR. GROSS: As they are voting.
4
DR. STROM: As they are voting.
5
DR. GROSS: Yes, that's fine.
6
Mr. Levin.
7
MR. LEVIN: My understanding from Roche's
8
presentation is that this is male and female, am I
9
correct? Okay. I would certainly
vote yes in favor
10 of
this as a core, and I think the most critical
11
addendum is what Brian just described as some sort
12 of
centralized and specialized dispensing program
13
added to this core.
14
DR. GROSS: I am going to make a
list of
15 the
ideas that you are proposing be supplemented,
16 and
then we will talk about them. So, it's
the
17
Roche program, it applies to males and females, and
18 the
Roche program will be used by Roche and by the
19
generic manufacturers.
20
DR. HONEIN: Is it mandatory?
21
MR. LEVIN: Absolutely.
22
DR. GROSS: Is what mandatory?
269
1
MR. LEVIN: Yes, I mean Roche's
proposal
2 is
a mandatory program.
3
DR. GROSS: Right, men and women
and any
4
other sex.
5
DR. SAWADA: Kathy Sawada. I would agree
6
with this Roche program as a core program,
7
mandatory, applying to both male and female. I
8
still think that we need to work out a few things
9
with regard to pregnancy testing and dissemination
10 of
that information. I will leave it at
that.
11
DR. GROSS: Good, fine.
12
DR. VENITZ: Jurgen Venitz. I am in favor
13 of
the core program, as well, again with the
14
stipulation that what is listed here is mandatory.
15
That includes registration of physician, patient,
16 and
pharmacy.
17
I do think more effort needs to be
18
dedicated to the educational component to make sure
19
that it is not just an exercise in futility, but
20
there actually is learning occurring, and that the
21
learning outcomes are assessed, not the factual
22
repetition of knowledge.
270
1
I am also concerned, as was discussed
2
before, about patients past their treatment course
3
beyond the 30 days, that there should be at least
4
attempt to systematically follow up on those
5
patients.
6
DR. GROSS: It is understood that in this
7
program, registries are mandatory for physician,
8
patient, and pharmacist.
Pharmacy? All right. We
9 may
have to discuss that.
10
DR. STROM: Brian Strom. I am in favor of
11 the
Roche program as a core program, again, both
12
genders. I think the two
particular things I would
13 add
is a mandatory follow-up survey and the limited
14
dispensing by a centralized dispensing system plus
15
specialty pharmacies.
16
DR. BERGFELD: Wilma
Bergfeld. I am also
17 in
agreement to the Roche program. I would
like to
18 beg
for the physicians that have to evaluate the
19
patients, that the packaging of the educational
20
materials, the consent forms, the pregnancy
21
recording forms, the flowsheets, the stickers, be
22
simplified for easy use and interpretation.
271
1
DR. RAIMER: Sharon Raimer. I have some
2
real qualms about the program as it is outlined. I
3
think it is going to be a very expensive way to be
4
sure that patients have negative pregnancy tests,
5 and
I think you could get at the same thing by
6
having the pregnancy tests sent to the pharmacy or
7
having yellow stickers, have a box where you
8
actually have to put the date of the last negative
9
pregnancy test on it.
10
I would be more for it if there were more
11 of
an educational component. I just don't
see that
12
this gives the patient that much of an education
13
because they will learn the right answers in order
14 to
be able to get the drug to answer the
15
questionnaire.
16
So, I think the number of phone calls it
17 is
going to require, and the expense that it is
18
going to entail, is not justified in its present
19
form.
20
DR. GROSS: So that is no vote?
21
DR. RAIMER: That is a no vote.
22 MS. KNUDSON: I will vote yes for the core
272
1
program. I would like to also
understand the
2
privacy and confidentiality that goes along with
3 the
registry and urge that indeed we build in
4
sufficient safeguards for that.
5
I would like to also add would it be
6
possible to send out a newsletter, to draft a
7
newsletter centrally, send it out periodically to
8 the
patients who are on the drug, reaffirming a lot
9 of
the issues that are necessary for their
10
appropriate education.
11
Thirdly, I would like to be absolutely
12
certain that we have very tight inclusion criteria
13
before dispensing the drug.
14
DR. GROSS: Thank you.
15
DR. BIGBY: Michael Bigby. I actually
16
share Dr. Raimer's reservations about the program,
17 and
I think a program needs to include a mechanism
18 for
tracking and evaluating women who get pregnant.
19
I think it needs to capture and insist, as
20 Dr.
Ringel said, that patients are, in fact, using
21 two
effective forms of contraception while they are
22
taking Accutane, and I also think it is essential
273
1
that a plan be added to collect data on that last
2
month after Accutane has been discontinued.
3
DR. GROSS: So, I understand the
things
4 you
think should be added, but is your vote a yes
5 or
a no as this being a core?
6
DR. BIGBY: No.
7
DR. GROSS: Dr. Honein.
8
DR. HONEIN: Peggy Honein. I would vote
9 yes
to this as the core for the program, but I
10
think it is critical to have a follow-up survey
11
both to get better quality assurance data about
12
what is working in the program and what is not,
13
because I think there will be needs for
14
modifications down the road, and we need to have
15 the
best data possible to make those decisions on,
16 and
also as a tool to better ascertain pregnancies.
17
I would also like to see an additional
18
plan for what other mechanisms can be used to get
19
closer to the number of pregnancies that are
20
actually happening and do more complete
21
ascertainment of that.
22
DR. COHEN: Mike Cohen. I am for the core
274
1 program. I am against severe restrictions in
2
pharmacy access. I think, you
know, all in all, we
3
have seen pharmacists have been doing a pretty good
4 job
with it. I think there could be a
voluntary
5
registration of pharmacies or willingness to
6
participate in it.
7
I also wish there was some way to indicate
8 in
the registry whether or not the patient has
9
severe cystic acne. I realize that you can't
10
restrict the prescribing, but perhaps that still
11
could be included in some way.
12
DR. GROSS: So, your last comment
goes to
13 the
entry requirements, which we should address
14
after we are finished voting.
Okay.
15
Dr. Whitmore.
16
DR. WHITMORE: Beth Whitmore. I vote no.
17 I
don't think this will prevent pregnancies any
18
more so than a sticker and a pregnancy test
19
presented to the pharmacist. I
think that it
20
should be mandatory that a physician reports
21 pregnancy
to the FDA and also to the drug company
22
when it does occur, and I think that needs to be
275
1
said, that that is mandatory and prosecutable if it
2 is
not done.
3
I think that should be in the patient
4
consent form that the physician will inform the FDA
5 and
the company if the patient does become pregnant
6
during therapy, and there is something else that I
7 am
forgetting--oh, the video.
8
The video has been lost in terms of I have
9
never seen it in our office. I
was part of an
10
Accutane educational program, it's a one-day
11
seminar, and saw that video. It
is my fault that I
12
haven't obtained the video and given it to every
13
single patient, but it is an excellent video, and
14
patients are more visually oriented than they are
15
reading all these documents.
16
I think that video should be given to
17
every woman. They can view it at home, and if not,
18
they can view it somewhere where they can get a
19
VCR.
20
DR. GROSS: Robyn Shapiro.
21
MS. SHAPIRO: I guess I vote yes
with the
22
proviso, some which have been mentioned, that we
276
1
assure that there is something that is done with
2
respect to the last 30 days, that my own concerns
3
about the interaction in terms of identifying lack
4 of
understanding and lack of agreement or
5
likelihood of complying have some appropriate
6
resolution, that that loop be tied.
7
Also, that we have some assurance that we
8 are
going to be collecting data. I think
that we
9
have suffered here in the last two days from lack
10 of
data, and hopefully, this will help us get that
11 and
maybe we should even think about a sunset date
12 for
this particular plan to be re-evaluated in
13
light of data that is collected to see if it is
14
really doing anything although that may be
15
implicit, I don't know.
16
DR. EPPS: I vote no.
17
DR. SCHMIDT: I vote no with a oak
leaf
18
cluster because I think that this is going to be
19
unbelievably expensive and I think some of these
20
registries, like this other program for
21
Thalidomide, is a nightmare.
22
I think that what Boni talked
277
1
about--excuse me, Dr. Elewski--I agree with that,
2
that we should have a survey, the survey should be
3
mandatory, and then one of the things is I really
4
wonder whether we ought to simplify this thing.
5
To me, I think one of the scariest things
6
with males is sharing their medication, but as far
7 as
registering males other than that, I don't know
8
that we ought to really have them in the system.
9
DR. CRAWFORD: I vote yes, a qualified
yes
10
with respect to the core components.
The
11
additional thing I would like to ensure, that it is
12 a
consolidated, single system. The
evaluation
13
methods proposed I believe are insufficient, and
14
there needs to be improvements in evaluation
15
methods and the results used for program
16
modification as necessary.
17
Also, I believe there should be some
18
consideration of a case-by-case basis where some
19
patients simply may not be able to do this, such as
20 we
talked about, perhaps with language
21
difficulties.
22
I am sorry, sitting between two physicians
278
1 for
two days has made my own handwriting really
2
bad. I think I wrote the need for
possible
3
recertification of the practitioners or
4
representative from the pharmacy either annual
5
biannual, or some mechanism, because one time may
6 not
be enough to just reinforce the need for all
7 the
steps.
8
DR. GROSS: Peter Gross. I vote yes.
9
DR. WILKERSON: Michael
Wilkerson. Having
10 sat
here for two days, I am astounded at the lack
11 of
information and forethought put into after this
12
drug having been on the market for 22-plus years,
13
that we don't have any better way of dealing with
14
this problem.
15
I don't see that this is an improvement
16
over the current system. I think
there is
17
something better out there, but to experiment by
18
using an entire country at once is folly. What
19
should have been going on, and has not been going
20 on,
are pilot studies to determine what is the best
21 way
to do this.
22 This program does not, in my view,
add
279
1
anything but more layers of complication that may
2
actually lead to less compliance than what the
3
current program is, and I wish the manufacturers
4
would get together and solve this problem on a
5
small-scale basis before we start trying to
6
implement a national program.
7
I would also ask that industry hopefully
8
come up with compounds that we don't have to deal
9
with this particular issue, so that this issue goes
10
away. So, my vote is no.
11
DR. GROSS: Dr. Ringel.
12
DR. RINGEL: My vote is yes, and
the
13
things I would like to have included, first of all,
14 I
think there needs to be a loop for the
15
gynecologic consult, and I didn't see that on here.
16
There should be no return visits solely
17 for
picking up lab slips or prescriptions, that
18
someone should--I am not sure it would work
19
again--but check the urine for red blood cells to
20 see
if they are menstruating.
21
Go through the scenario, whatever we
22
choose, for various real world situations like, you
280
1
know, patient can't get in because it is snowing,
2
physician is on vacation for a week, it's a college
3
student, they start one place, they end up
4
finishing with another dermatologist in another
5
place, is this going to work.
6
I think that the pharmacist should check
7 to
make sure that there is at least a month between
8
picking up the prescription and having registered.
9 I
do think that whatever education we do, there
10
really do need to be pilot studies, and I agree
11
with Dr. Wilkerson, to make sure that when we are
12
educating patients, that we are doing it optimally,
13
otherwise, I don't think it is worth very much.
14
Finally, I think that we should start to,
15
before patients even begin this, we should start to
16
collect their photos, digital photos of those acne
17
patients. Even if we don't
restrict its use, let's
18
find out who it is being used on, and then we can
19
talk about it later.
20
DR. GROSS: Thank you.
21
Dr. Vega.
22
DR. VEGA: I vote yes to the Roche
core
281
1
proposal with the following modifications. The
2
physician's office should be--the physician should
3 be
responsible for entering the pregnancy test into
4 the
system, and at the same time, obtain the
5
confirmation number that will be included in the
6
prescription, so that the pharmacy only needs to
7
confirm that authorization number and add the
8
product information to the prescription before
9
dispensing, and to add the voluntary survey, so
10 that
we can obtain the information in the 30 days
11
after treatment with Accutane.
12
DR. GROSS: You want a voluntary
or a
13
mandatory survey?
14
DR. VEGA: They are proposing that
the
15
survey, their proposal says it is mandatory?
16
DR. GROSS: No, I am asking what
you are
17
favoring.
18
DR. VEGA: What is their
proposal? I
19
don't see any proposal for a survey.
20
DR. GROSS: Right, okay.
21
DR. VEGA: This proposal has no
survey. I
22 am
saying that there should be a survey, and the
282
1
survey to collect patient information should be
2
voluntary.
3
DR. GROSS: Dr. Day.
4
DR. DAY: I vote yes for the core
program
5
with most of the provisions that have been
6
suggested today, and if some of those don't occur,
7 I
would change my vote.
8
I would like to just say in the patient
9
education side, not only true comprehension
10
testing, but I think some reminder tools can be
11
developed that are very usable and for Art Levin's
12
concern about adding in some other neat little
13
thing that hasn't been tried, there is a huge
14
literature about prospective memory.
15
Most of memory we think about as what we
16
remember from the past, but prospective memory is
17
remembering to do something in the future, and
18 there
are specific tools that can be used to
19
enhance that, so a refrigerator magnet with a
20
little tag you have to take off and write down the
21
start of the period, and take that in for testing,
22 and
so on, with reminders continue to use two forms
283
1 of
contraception or whatever it is.
2
So, within patient education, attention to
3
prospective memory, as well as true comprehension.
4 DR. GROSS: Dr. Kibbe.
5
DR. KIBBE: I am going to vote
no. I
6
don't see that this program is going to
7
significantly impact the 1 percent of the women who
8
cannot navigate successfully through this program.
9 Right now we have 99 percent of the
women
10 who
use the drug and don't get pregnant, and hence
11
have obtained the correct education, obtained the
12
right outcome. What we don't
have, and what we
13
need desperately, is an understanding of why those
14 who
made it, made it well, and why those didn't,
15
didn't.
16
Unless you have that, how can you change a
17
program and expect it to increase its impact if you
18
don't even know what you are trying to change it to
19
do. In that case, if we change
this, and we make
20 it
more onerous, and it clearly will be more
21
onerous, what is the likelihood?
22
Well, we have three outcomes.
One, things
284
1
stay the same. Two, things get
better. Three,
2
things get worse. So, if we don't have any data on
3
which we know that this is going to impact the 1
4
percent that we want to impact, then, how can we
5 say
okay, let's change it and see what is going to
6
happen, and lose some of what we are doing well.
7
You can't argue one way or the other
8
without facts, which one of those three outcomes
9 you
are going to get. It is like the forward
pass
10 in
football, right? Three things can
happen, and
11 two
of them are bad and one is good.
12
I think that is what we need. I
think
13
that we need to continue to do the educational
14 processes
we are doing because it seems to be
15
working, and I don't see that this is a great
16
benefit or improvement over it.
17
DR. GROSS: Dr. Gardner.
18
DR. GARDNER: I am concerned about
the
19
implication of a no vote for what will happen next,
20 so
I guess I concur with Dr. Wilkerson and Dr.
21
Kibbe that when we are trying to move the whole
22
system to improve 1 percent or something on that
285
1
order, and don't have the information we need to do
2 it,
I think that my inclination would be to leave
3 the
current system in place and direct the
4
companies, recommend to the companies that instead
5
they devote the next year to the kinds of failure
6
analyses and other suggestions that have been made
7
here, and perhaps cognitive studies, pilot studies,
8 and
come back to us and say here is what we
9
learned, now what changes make sense.
10
So, that is a long no with caveats.
11
DR. GROSS: I would just like to
remind
12
everybody that we voted unanimously to not continue
13 the
current program.
14
DR. GARDNER: Then, yes with
caveats.
15 DR. KIBBE: Can I remind the Chair that I
16
objected to that vote?
17
DR. GROSS: That's okay, you
abstained.
18
DR. KIBBE: But I mean that
reasoning is
19
because if we don't like this one, we have to have
20
something.
21
DR. WHITMORE: I think, at least
for me--
22
DR. GROSS: Wait a minute. Let's continue
286
1 to
go around the table.
2
So, Jackie, what is your vote?
3
DR. GARDNER: Yes, with caveats
relating
4 to
research.
5
DR. GROSS: Sure, agreed.
6
DR. KATZ: I think having to vote
just on
7
this yes or no limits many people.
My vote is no,
8
because I would continue the current program
9
mandating patient enrollment, they are not going to
10 get
the drug unless they enroll.
11
That would satisfy our lack of being able
12 to
keep track afterwards, and perhaps have the
13
pharmacist have to get verification of the dates or
14 the
actual pregnancy tests, or at least the date,
15 as
Dr. Raimer mentioned.
16
Just two comments. It is not 1
percent,
17
it's 0.1 percent of the population, and the
18
suggestion that nodular cystic acne is some sacred
19
separate entity and everything else is okay, for
20 the
folks around the table who are not
21
dermatologists, pustular acne is very severe and
22
very scarring, and what is severe to you may not be
287
1
severe to me, and a lot of it depends upon
2
patient-physician interaction, and somebody
3
someplace else evaluating a photograph is the most
4
draconian aspect that I have heard.
5
They may not think it is severe enough.
I
6 see
patients who have fairly severe acne affecting
7
their life, and they said they didn't get Accutane
8
because the doctor didn't think it was sufficiently
9
severe. Nothing else has worked,
but the doctor
10
didn't say--well, if the doctor's daughter had that
11
problem, maybe they would feel differently.
12
So, my vote is no, but with modifications
13 to
the present program, mandating enrollment and
14
having stricter confirmation of the two pregnancy
15
tests before treatment and pregnancy tests during
16
treatment.
17
DR. GROSS: Sarah Sellers.
18
DR. SELLERS: I vote yes. My comments are
19
that I would request for certain elements that have
20
been undefined, that with respect to patient
21
interactions with the registry, that any data that
22 is
collected is collected in a manner, so that that
288
1
data will be usable for further analysis and
2
potential observational studies.
3
I also would recommend that the informed
4
consent document be modified to a process that can
5 be
evaluated, because as it stands now, it really
6 is
a document that asks questions about whether a
7
patient has received a video, but not if the
8
patient has viewed and understood the video.
9 I would also ask that we explore
10
consequences for noncompliance, and that's it.
11
DR. GROSS: Thank you all. I know it is
12
tough to put our nickels down, but the Agency is
13
asking us for our opinion, and in the absence of
14
enough evidence, we have expert opinion, and that
15 is
why we are all sitting around the table.
16
The vote is 16 to 8 in favor of accepting
17 the
Roche program as a core program for all use of
18
isotretinoin.
19
Let's take a break and reconvene in 15
20
minutes and we will try to put together a list for
21 our
next round.
22
[Break.]
289
1
DR. GROSS: There were a number of
2
excellent suggestions as we went around the room
3 and
took a vote, probably too many suggestions to
4
vote on them individually, so I would like to
5
propose that we lump some of them together.
6 I am going to make a suggestion on
four or
7
five things that might be in our first vote, that I
8 got
a sense there might be unanimity to some
9
extent.
10
The first was that there be a centralized
11
registration system, that all manufacturers use the
12
same registration system. That
would be No. 1.
13
No. 2, that as part of the entry criteria,
14 a
digital photo be sent to the central registration
15
system to document the indication for the drug.
16
The third is that the FDA conduct some
17
research where they try to determine whether or not
18 the
patient understands the consent form that they
19
signed and that the patient understands the
20
educational information given them on the drug.
21
The fourth item is that there be a
22
mandatory survey.
290
1
Would anyone like to comment on these
2
things?
3 MR. LEVIN: I would like to add one other
4
item which I think it has been described in
5
different ways, and that is addressing the lack of
6
data underlying failure, and perhaps that is
7
something that the FDA should be asking the
8
sponsors, and I use the plural, the generics and
9
brand name companies, to be doing, to be conducting
10 a
study to look at failures and to try to bring to
11
light why people fail in this program.
12
DR. GROSS: That goes along with
Dr.
13
Crawford's suggestion that FMEA, failure mode and
14
effects analysis, or something like that be
15
conducted in those particular situations. So, we
16 can
add that in as a fifth item.
17
MR. LEVIN: I just want to add, as
we saw
18 in
S.T.E.P.S., I mean I think one of the things
19
that was somewhat impressive about S.T.E.P.S. is it
20
seems to be recognizing that it should be a
21
work-in-progress. It is learning
from experience
22 and
it is changing.
291
1
One of the changes was that it created six
2
different risk categories that allowed for some
3
interventions and oversight based on those risk
4
categories, and perhaps we should ask for a loop,
5
that as we discover the reasons for failure, that
6 we
sort of go back to the program and see how to
7
apply those lessons to this program.
8
DR. GROSS: Okay. Any other comments?
9
Yes, Sarah Sellers.
10
DR. SELLERS: My comments on
evaluating
11 the
informed consent process were not meant to
12
imply that the FDA do studies. In
fact, it's the
13
sponsors' responsibility, not the FDA's, to make
14
sure that the program is effective.
15
So, I wouldn't support the FDA doing the
16
studies.
17
DR. GROSS: But you would support
that
18
research be done by someone.
19
DR. SELLERS: By the sponsors, yes,
20
generic and Roche. I think the
whole informed
21
consent subject needs to be designed and
22
implemented into the system in a way that allows it
292
1 to
be evaluated and that makes it a process, not
2
just an informed consent sheet.
3
DR. GROSS: Any other comments?
4
Yes, Dr. Epps.
5
DR. EPPS: I am not in favor of
digital
6 photography. Research should be done. I agree
7
that I don't think it's FDA's responsibility to do
8
that although they could certainly advise on it.
9
Surveys, it is okay.
10
Certainly, I agree we need to find out the
11 failures,
the tail is wagging the whole dog, and we
12
need to find out why those people could not
13
accomplish not becoming pregnant from whatever
14
reason, whether it was the doctor, the pharmacy, or
15
their own issue, but I don't think we need to send
16
around digital photos.
17
DR. GROSS: Dr. Ringel.
18
DR. RINGEL: I would suggest
changing the
19
word on the photo item from documentation to data
20
gathering. I don't want to give
the idea that
21
someone is going to be sitting there judging each
22
photo, but I do think that there should be some
293
1
documentation of what is being treated, so that we
2
know if there is a problem or not.
3
DR. EPPS: That is what the
medical record
4 is
for also.
5
DR. GROSS: What was the
implication, Dr.
6
Epps, that you have a digital photo in your medical
7
records?
8
DR. EPPS: No. We
document physical exam.
9 I
don't think we need photographs. I don't
think
10
that needs to be central issue or centralized.
11
DR. GROSS: Dr. Cohen.
12
DR. COHEN: I just wanted to ask
Dr.
13
Ringel where that would be documented.
14
DR. RINGEL: Whatever central
registry.
15
DR. GROSS: Dr. Whitmore.
16
DR. WHITMORE: I agree that
photographs
17 are
not necessary. I would also say that
Accutane
18 is
used off label for things that are not acne,
19
too, so I am not sure where you would be going with
20
that in those cases.
21
DR. RINGEL: We could document the
acne
22
ones.
294
1
DR. GROSS: So, maybe we had
better take
2 the
photo as a separate item rather than bunching
3 it
in.
4
DR. WILKERSON: With all due
respect, I
5
think photographs are the venue of clinical
6
studies, and they are hard enough there with
7
standardized photography, let alone everyone
8
sending in their snapshots, and I think we would
9 end
up with a repository of nothing that was of
10
particular clinical usefulness if they are not
11
standardized and done in clinical format.
12
If the floor is open for motions, which I
13
assume it is, Mr. Chairman?
14
DR. GROSS: A motion on the other
items
15
mentioned?
16
DR. WILKERSON: Well, any of
them. I am
17
assuming we are considering all sorts of items.
18
DR. GROSS: So, something else you
want to
19 add
to this list?
20
DR. WILKERSON: Yes. Being a sore loser,
21 I
would like to put a motion forward that the
22
current concepts be studied for cost of
295
1
implementation and pilot studies prior to being
2
implemented on the entire country.
That is my
3
motion.
4
DR. WHITMORE: Second.
5
DR. GROSS: And that would be done
by the
6
manufacturers?
7
DR. WILKERSON: Yes, and I do
favor one
8
representative of all the manufacturers.
9 DR. GROSS: Let me read the list and let's
10
take a vote.
11
So, the items on the list that we will be
12
voting on. There should be a
centralized system
13 for
all manufacturers, so any patient, no matter
14
which drug they use, will be registered in a common
15
system.
16
The second, that research be done to
17
assess the patient's understanding of the consent
18
form and the educational information.
19
Three, that there be a mandatory survey,
20
and, four, that we do failure mode analysis on
21
women that become pregnant.
22
The last item is that there be an
296
1
assessment of the cost of implementing the program.
2
DR. COHEN: It's root cause
analysis, not
3
failure mode. Failure is
prospective, root cause
4 is
after it has happened.
5
DR. GROSS: FMEA is before it
happens, you
6 are
right, RCA.
7
Mr. Levin, would you like to register your
8
opinion, yea or nay?
9
MR. LEVIN: Is it one yea or nay,
or is it
10 yea
with? It is a very complex package, and
up
11
until the last issue where the person proposing
12
that suggestion tied it to I think a delay in
13
moving ahead pending pilots.
14
DR. GROSS: That was not my
impression.
15
MR. LEVIN: I just want to clarify
it.
16
DR. GROSS: Dr. Wilkerson, is that
what
17 you
wanted?
18
DR. WILKERSON: Yes, this does not
mean
19
that we discontinue the current system.
What it
20
means is that we evaluate going forward before we
21
plunge the entire country into chaos because
22
whenever you change systems, you are going to have
297
1
several months of chaos during which time the
2
current system's effectiveness will probably also
3 be
degraded.
4
So, I think before we do that, we want to
5
make sure that the program that we are moving to
6
actually is accomplishing what we think it is going
7 to
accomplish, because it is going to add many
8
layers of burden and cost to physicians,
9
pharmacists, and patients.
10
DR. GROSS: Let's take that off
the list
11
then and we can deal with it separately.
12
So, we have centralized system,
13
registration system for all manufacturers, research
14 as
outlined, mandatory survey, and root cause
15
analysis.
16
MR. LEVIN: Arthur Levin. Yes.
17
DR. SAWADA: Kathy Sawada. Yes.
18
DR. VENITZ: Jurgen Venitz. Yes on all
19
four.
20 DR. BERGFELD: Wilma Bergfeld. Yes, with
21 the
exception of the mandatory survey. I am
not
22
sure it should be mandatory. I
would suggest it be
298
1
voluntary.
2
DR. RAIMER: Sharon Raimer. Yes.
3
MS. KNUDSON: Paula Knudson. Yes.
4
DR. BIGBY: Michael Bigby. Yes.
5
DR. HONEIN: Peggy Honein. Yes, and I
6
prefer mandatory survey, but if that can't be
7
implemented, I would want a voluntary survey rather
8
than nothing.
9
DR. COHEN: Michael Cohen. Yes.
10
DR. WHITMORE: Beth Whitmore. As far as
11 the
recommendation looking into the cost of doing
12 all
this, I would suggest a one-year period where
13
patients are required to have a pregnancy test
14
along with the yellow sticker and assess pregnancy
15
rates during that time prior to initiation of this
16
central program.
17 DR. GROSS: So, that will have to be a
18
separate consideration.
19
MS. SHAPIRO: Robyn Shapiro. Yes.
20
DR. EPPS: Yes, voluntary survey.
21
DR. GROSS: So, that is yes to
everything,
22 but
the survey should be voluntary?
299
1
DR. EPPS: Yes. I mean I am not in
2
favor--well, I have already said that I am not in
3
favor of registry--but if you are going to have a
4
registry, everybody should use the same thing.
5
DR. SCHMIDT: Yes to all.
6
DR. CRAWFORD: Stephanie
Crawford. Yes.
7
DR. GROSS: Peter Gross. Yes to all.
8
DR. WILKERSON: Michael
Wilkerson. Yes.
9 The
survey should be voluntary, though.
10
DR. RINGEL: Eileen Ringel. Yes to all.
11
DR. VEGA: Amarilys Vega. Yes, but that
12 the
survey should be voluntary.
13
DR. DAY: Ruth Day. Yes to all.
14
DR. KIBBE: Arthur Kibbe. Yes.
15
DR. GARDNER: Jackie Gardner. Yes.
16
DR. KATZ: Robert Katz. Yes.
17
DR. SELLERS: Sarah Sellers. Yes.
18
DR. GROSS: The way I read the
vote is it
19 was
unanimous yes with a caveat that the mandatory
20
survey, there were 5 people who requested it be
21
voluntary, and the rest agreed to mandatory. So,
22
that would be 19 agreed to mandatory.
300
1
I think we are accomplishing a lot here.
2 The
other items we may have to take up
3
individually.
4
Dr. Wilkerson, do you want to vote on
5
delaying the whole thing until a cost analysis is
6
done, or do you want to withdraw that?
I am just
7
trying to be fair.
8
DR. WILKERSON: Samuel Clemens
once said
9
that--I will paraphrase--you don't want to watch
10
sausage or a law being made. I
really think we
11
need some regional studies to see if these programs
12
really work. I really do have
concerns about
13
transition periods going between different
14
methodologies for trying to accomplish what we all
15 want
to accomplish here.
16
I just don't want to complicate this and
17 not
see any--because it is going to be another
18
three years before we see something.
We should
19
have been doing pilot studies the entire time to
20 find
out what really works, and then try to apply
21
those to the populace in general.
22
So, my motion stands to delay pending
301
1
pilot studies and financial impact of these
2
recommendations.
3
DR. GROSS: Is there a second to
the
4
motion?
5
DR. WHITMORE: I would like to
second
6
that.
7
DR. SCHMIDT: I second it.
8
DR. GROSS: That was quick. I would like
9 to
just make a comment. Having done some
cost
10
effectiveness/cost benefit analyses where you come
11 up
against the issue of at least when it comes to
12
mortality, the value of human life used to be
13
50,000, now it is 200,000. That
is accepted in the
14
literature.
15
The value of quality of life, I am not
16
familiar with what those financial numbers are, but
17
anybody here familiar with--I guess it depends on
18
what aspect of quality of life you are talking
19
about.
20
DR. WHITMORE: I am not sure.
21
DR. SELLERS: I am sorry, I was
just going
22 to
say it will become very difficult because again
302
1 we
don't have the data that we need to fully define
2 the
scope of the problem. We have reported
data.
3 We
don't know the entire scope of patients who are
4
affected by this drug to do a cost-benefit
5 analysis.
6
DR. GROSS: Somehow we are going
to need
7
that kind of information to do it, because how are
8 we
going to say that this program is worthwhile
9
doing or not doing.
10
DR. SELLERS: Well, it's worthwhile,
in my
11
mind, because we are going to be collecting data
12
through the registry, and that will allow us to
13
start making better estimates of rates and persons
14 who
are affected.
15
DR. GROSS: We have a motion on
the table
16 to
delay implementation of the study until--
17
DR. WHITMORE: Could I just say
that our
18
goal is to reduce pregnancies, and if during that
19
period before implementation of this, when we are
20
taking a pregnancy test to the pharmacy, that is
21
required with the woman to have the prescription
22
filled, if we can reduce pregnancy rates during
303
1
that time, I think you can assess how much you are
2
reducing rates of pregnancy with that.
3
You are not going to come up with a
4
cost-benefit analysis of this program, because you
5 are
not going to know how much it is going to
6
reduce pregnancy. In the
meantime, you could at
7
least be studying how much just implementation of a
8
pregnancy test going along with the woman reduces
9 the
rate or pregnancy that is occurring right now.
10
DR. GROSS: Dr. Crawford.
11
DR. CRAWFORD: Just to state I will be
12
voting against this because in terms of the FDA's
13
mandate, looking at safety and efficacy, I don't
14
think a cost effectiveness analysis is appropriate
15
beyond perhaps quality of life issues, and I do
16
know for a fact that while I do think sometimes
17
economic analyses are very well done, I am aware of
18 how
without very proper sensitivity analyses and
19
consideration of a variety of variables, those
20
numbers can be biased. So, I will
be voting
21
against this.
22
DR. WHITMORE: I wonder if Dr.
Wilkerson
304
1 was
talking more about just the cost as opposed to
2
cost-benefit, because we are not going to be able
3 to
measure benefit, the question is cost.
4
DR. WILKERSON: Mine was more the
cost of
5
implementation to physicians, their office, to
6
health care plans, not the cost of life or any of
7
those sort of things, so no, it is not a
8
cost-benefit, it is a cost of implementation, the
9
extra 10 or 15 minutes that it takes every doctor
10 or
nurse to punch in all this data, and in the end,
11 you
know, the question at the end of the day, we
12 all
feel better when we have done something, but if
13
that work does not actually produce an end product,
14
then, what is the point of having done that extra
15
work, and that is a critical question here.
16 DR. GROSS: The other critical part of it
17 is
the production of a deformed child, there
18
certainly is a cost associated with society taking
19
care of that child as far as the anguish of the
20
child and the family.
21 DR. WILKERSON: Oh, absolutely, but if the
22 end
result of tightening this up means that we have
305
1 the
paradoxical effect of seeing more deformed
2
children, then, what is the point of that? We
3
don't know the answers.
4
MR. LEVIN: Again, I would like to
5
emphasize this is modeled on programs about which
6 we
have some evidence.
7
DR. WILKERSON: But we only have
4- or
8
5,000 women.
9
MR. LEVIN: I understand that.
10
DR. WILKERSON: It's totally
different
11
populations.
12
MR. LEVIN: I mean it's the best
evidence
13 we
have, and to hypothesize that somehow it is
14
dangerous to proceed based on that evidence, I
15
don't know, I think it's a disservice to the people
16 who
are being hurt and will be hurt, and we saw
17
dramatic testimony today about what the cost of not
18
doing this thing correctly.
19
DR. WILKERSON: Then, why haven't
we been
20
worried about that for the last 22 years?
21
MR. LEVIN: I couldn't agree with
you
22
more.
306
1 DR. WILKERSON: This is not a new problem.
2
DR. GROSS: Hold on a minute. Can we get
3
some clarification from the FDA?
Dr. Kweder?
4
DR. KWEDER: I am not sure what
the
5
question is. What would you like me to clarify?
6
DR. GROSS: I just thought you had
a
7
comment.
8
DR. KWEDER: No.
9
DR. GROSS: Basically, this motion
is to
10
delay implementation of the program that we
11
approved by a two-thirds majority, delay it until a
12
cost analysis is done that would basically undo
13
everything we have done so far.
14
Mr. Levin.
15
MR. LEVIN: Arthur Levin. No.
16
DR. SAWADA: Kathy Sawada. No.
17
DR. VENITZ: Jurgen Venitz. Before I
18
announce my vote, I just want to point out the main
19
reason why I voted in favor of the core proposal,
20 and
the amendments that we just passed, so we can
21
generate data, because there will be another
22
committee meeting in 5, 10 years, and they are
307
1
going to ask the same questions that were asked 4
2
years ago and 10 years ago, and there were no data
3 to
support any contention whether the current
4
system works, it doesn't work, how many people are
5 at
risk, are we talking about 1 percent or 0.1
6
percent.
7
So, the reason why I am voting against the
8 motion,
meaning not to delay, is because I want for
9
something to be in place, that allows us to gather
10 the
data, so the next committee that is going to
11
review this will have an evidence database to base
12
their decision on.
13 DR. BERGFELD: Wilma Bergfeld. I am in a
14
great dilemma because what I would have liked to
15
have heard was that we were going to have it move
16
forward, and we would pilot the program before we
17
launched it, with or without a financial note to
18
that.
19
DR. WILKERSON: That is the
intention, is
20 to
do pilot studies as we move forward.
21
DR. BERGFELD: Not to hold up the
program,
22 but
to move forward, but before launching, to
308
1
pilot--
2
DR. WILKERSON: In a pilot sense,
not as
3 an
entire rollout to the entire country.
4
DR. BERGFELD: If that was the
intent, I
5 would
vote to do this as a pilot. I am not
sure if
6
that is a yes or no.
7
DR. GROSS: Dr. Wilkerson, let me
clarify
8 it
for the group. You are saying that there
be
9
some kind of a pilot study with a cost assessment?
10 DR. WILKERSON: I think that was what I
11
originally said.
12
DR. GROSS: I didn't hear that,
but that
13 is
fine.
14
So, we have 3 nays and 1 yea.
15
Dr. Raimer.
16
DR. RAIMER: Sharon Raimer. I am voting
17 for
a pilot program. I think the S.T.E.P.S.
18
program as it has been used in Thalidomide, I don't
19
think we can cross it over to our population,
20
because those women were mostly in their 40s, and
21 they
were critically ill, most of them, or
22
seriously ill, they had malignancies, so a young,
309
1
healthy population, just because it worked in an
2
older, sick population doesn't mean it is going to
3
necessarily work in ours, so I think we need to see
4
some pilot studies to see if it does work and get
5 the
thing going, how feasible it is.
6
DR. GROSS: Dr. Knudson.
7
MS. KNUDSON: Yes, because it will
be a
8
pilot study to determine if it's feasible and what
9 the
cost might be.
10
DR. BIGBY: Michael Bigby. No.
11
DR. HONEIN: Peggy Honein. No.
12
DR. COHEN: Michael Cohen. No.
13
DR. WHITMORE: Beth Whitmore. Yes.
14
MS. SHAPIRO: I have a
question. I am not
15
quite sure what we are voting on.
We would do a
16
pilot study, not only to look at cost, but also
17
effectiveness, right? Okay.
18
And in the rest of the country, where the
19
pilots were not going on, despite our earlier vote,
20
they would be status quo, is that right?
21
DR. GROSS: The effectiveness,
again, this
22 is
another concept introduced, effectiveness was
310
1 not
mentioned originally, it was just cost.
2
MS. SHAPIRO: I would like to ask
Dr.
3
Wilkerson then, the person who made the motion,
4
whether or not his intent was to also gather data
5
about numbers of pregnancies.
6
DR. WILKERSON: Yes. The purpose of this
7 is
to determine if doing this act actually results
8 in
obtaining the end product that we are looking
9
for, which is namely reduction of pregnancy risk.
10
MS. SHAPIRO: Which makes sense.
11
DR. GROSS: Wait a minute. Wait a minute.
12
If the assessment is effectiveness, then,
13 we
would need to know how many people have to be
14
involved in the study to assess effectiveness.
15
Does anybody know that answer?
16
DR. WILKERSON: It depends on the
power of
17 the
study.
18
DR. VENITZ: The current system,
you have
19 a
voluntary reporting system. That means
you are
20
going to generate the same data, just in a smaller
21
scale with a slightly different system.
22
You still do not know what the pregnancy
311
1
rates are, you still cannot interpret any of the
2
numbers other than how many people actually are
3
enrolled in your program.
4
DR. WILKERSON: But you know what
the
5 optimal effectiveness of the intervention
that you
6 are
trying to do is in a study.
7
DR. VENITZ: What are you
comparing it to?
8
DR. WILKERSON: That is what you
are
9
doing, you are doing a controlled study to know
10
what the optimal effectiveness of your intervention
11 is.
12
DR. VENITZ: The only thing as far
as I
13
understood your motion is, you can assess whether
14 it
is feasible to do what the core proposed plan
15 proposes
to do, but you cannot assess its
16
effectiveness.
17
DR. GROSS: We have got a problem
here
18
because we have a shifting motion.
We started out
19
saying the whole program was going to be delayed
20
until there is a cost assessment.
Then, it was
21
changed that there will be a pilot program. Then,
22 it
was changed that there was going to be an
312
1
assessment of efficacy without any understanding of
2
what the numbers were, what the power requirements
3
were.
4
Basically, the intent is that the overall
5
program will be delayed. I think
that has to be
6
understood.
7
DR. KWEDER: Maybe I can clarify a
little
8 bit
from our standpoint. First, I think from
our
9
perspective, even though we asked it as a question,
10
doing nothing and making no change is really not an
11
acceptable course of action in our opinion.
12 I do think if changes are to be made
to
13 the
system, they need to be made quickly. I
don't
14
think this is the kind of thing where we feel that
15 the
Agency is in a position to pontificate for long
16
periods of time about what changes should be made,
17
could be made.
18
So, from that standpoint, your advice
19
today has been very helpful. As
regards pilot
20
programs, we would like to hear your ideas about,
21 and
you have been offering about, what would
22
constitute a pilot program.
313
1
Often what we do is we work with sponsors
2 to
develop testing and pilot testing of components
3 of
a program rather than an entire program, because
4 we
learn a lot about the individual components one
5 at
a time, or several in combination.
6
But we do get into the question of how
7
much of a pilot test is enough and what is it that
8 we
are measuring. As you will see further on in
9
some of the questions, we do have a question for
10 the
committee about what should be the goal and how
11 do
we establish a goal for success and
12
effectiveness.
13
That is something that we would like to
14
hear from you on whether you are referring to a
15
pilot program or to the entire program.
16
As regards the issue of cost, we do not,
17
under our statute and regulations, have any
18 authority
to regulate medicines or costs of
19
medicines or even particularly costs of programs.
20
Cost plays out in a different way in how
21
drugs are regulated. Sometimes if
things become
22 too
expensive, companies make the decision that
314
1
they can't participate in such a program, so they
2
will no longer manufacture the product.
3
That is not a desirable outcome, but in
4
looking at cost-benefit of how much this program
5
costs, it really all comes down to the
6
effectiveness of the program, what is it that we
7 are
trying to achieve with the program, and is the
8
program helping us to reach those goals.
9 We are open to looking at programs
that
10 are
costly, and we do this all the time, to assess
11 are
all of the components of this program
12
necessary, is the investment in every one of these
13
steps or pieces of it really helping us achieve the
14
goal.
15
That is the kind of question that can be
16
best be addressed by continuous analysis of the
17
program itself, which is something that we have not
18 had
a great deal of information on in the programs
19 we
have reviewed to date.
20
DR. GROSS: Robyn, your opinion or
your
21
vote?
22
MS. SHAPIRO: I still don't know
what the
315
1
motion is.
2
DR. GROSS: The original motion
was that
3 the
program be delayed until an assessment of cost
4 be
made. That was the original motion.
5
MS. SHAPIRO: And has it been
amended or
6
not?
7
DR. WILKERSON: Yes, it has. Basically,
8 it
is do we proceed with pilot programs or do we
9
proceed with the complete implementation of the
10
program not knowing what the ultimate outcome of it
11 is
going to be.
12
DR. GROSS: But a pilot program,
what is a
13
pilot program? How many people
are you talking
14
about?
15
DR. WILKERSON: That's, you know,
I mean
16
McDonald's rolls out sandwiches in one part of the
17
country to see if they sell before they take it all
18
over the place.
19
The same thing here, we are talking about
20
millions and millions of dollars potentially being
21
spent to roll out a program like this, and not
22
knowing if it's going to even produce the end
316
1
result that we are looking for.
2
DR. GROSS: The people who are
spending
3 the
millions are the ones that suggested the
4
program.
5 MR. LEVIN: That's right, the sponsor is
6 the
one who is bearing that cost.
7
DR. WILKERSON: Sponsors,
patients,
8
physicians, health care delivery systems, insurance
9
companies, we all bear the cost of these programs.
10
MS. SHAPIRO: I have a question
for the
11
Agency.
12
DR. GROSS: Robin, yea or nay, and
let's
13
move on.
14
MS. SHAPIRO: Can I just ask one
15
clarifying question of the Agency, and then I guess
16 I
will abstain, because I still don't know what the
17
question is.
18
If the motion were to delay rollout of
19
whatever it is we think should be rolled out,
20
pending a pilot program that could, after input
21
from biostatisticians or whomever tell us what the
22
power has to be, you know, what it has to be to
317
1
both gather effectiveness data in terms of numbers
2 of
pregnancies and gather costs, if we could get
3 all
that, and implement that, and in the meantime
4 put
the current--maintain the status quo, is that
5
something that the Agency would accept?
6
DR. KWEDER: I think we would
certainly
7 take
that counsel under advisement.
8
MS. SHAPIRO: Okay. That is what I want
9 to
vote for.
10
DR. GROSS: Next, Dr. Epps.
11
DR. EPPS: I can be in favor of a
pilot or
12
trial. Of course the endpoint would be no one
13
starting Accutane who is pregnant, and no one
14
becoming pregnant on Accutane.
That would be a
15
more desirable endpoint.
16
I do think that as it has come down the
17
line, the proposal has evolved, so it is kind of
18
hard to know exactly what the--I know what the
19
intent was, it has evolved, and certainly the 3(b),
20
which was modify the current program with
21
additional risk management tools to reduce fetal
22
exposure, was the FDA's question.
318
1
DR. SCHMIDT: I vote for the
Shapiro
2
clarification of the motion.
3
DR. GROSS: What is the Shapiro
4
clarification?
5 DR. SCHMIDT: That if we could get a pilot
6
program on this motion without slowing down the
7
original process of implementing this, and we can
8
figure out--what I am really concerned about is
9
this is going to be really majorly expensive and a
10 lot
of people don't have insurance, and when you
11
start socking people for 600, $2,000, $3,000 a
12
month for medication, even when they pay their
13
co-pays, people who need this stuff are not going
14 to
be able to afford it.
15
That is what I am concerned about.
That
16 is
why I want a pilot program.
17
DR. GROSS: Roche said they would
provide
18
payment for people who can't afford it.
19
MR. LEVIN: Peter, could I just
say--I
20
hate to be saying the same thing over and over
21
again--we have a program which has costs that this
22 is
very similar to, and while it is a different
319
1
population, we certainly can get cost information
2
about that program, so we don't have to reinvent
3 the
wheel here.
4
There is a S.T.E.P.S. program out there,
5
there is another program out there dealing with
6 restricted
access and restricted dispensing, and I
7
think, you know, we can avail ourselves of the
8
experience from those programs to get from those
9
manufacturers and sponsors what the cost is, so we
10
don't have to go out and pilot this as if we don't
11
have any way to get that information.
It makes no
12
sense.
13
DR. SCHMIDT: Hoffmann-La Roche is
out of
14 the
business of giving away free Accutane.
As far
15 as
in Houston, Texas, their rep has been terminated
16 and
is with another company, and with the generic
17
companies, you try to get free medicine for people,
18
they have to have their tax returns for the past
19
three years and have to be eating beans and living
20 on
the street before they will get free medicine.
21
So, I would really like to find out where
22 we
are going to get all this free medicine and who
320
1 is
going to pay for it.
2
DR. GROSS: So, your vote is yes,
right?
3
Okay.
4
Dr. Crawford.
5
DR. CRAWFORD: Stephanie
Crawford. My
6
vote is no delay beyond a reasonable transition
7
period.
8
DR. GROSS: Peter Gross. My vote is an
9
emphatic no.
10
DR. WILKERSON: Michael
Wilkerson. Yes.
11
DR. RINGEL: Eileen Ringel. No.
12
DR. VEGA: Amarilys Vega. No.
13
DR. DAY: Ruth Day. It has been 22 years.
14 No.
15
DR. KIBBE: Just a small
encouraging
16
comment for the members of the committee. The
17
Agency doesn't have to do anything we tell them to
18
do. So, you guys can vote all the
time, any way
19 you
want, and they are going to eventually take the
20 sum
of the discussion and do what they think is the
21
best for the general public, and the fact that 8 of
22 us
are on one side of a vote, and 16 on the other,
321
1
might weigh a little bit on it, but also the
2
quality of the argument.
3
My argument is that we have a system in
4
place today which more than 99 percent of the women
5 who
go through the treatment come away without a
6
problem in pregnancy. We have yet
to actually
7
figure out why the others fail.
8
Then, we are going to go to a more complex
9
system. Whenever you go to a more complex system,
10 people don't adhere to it as well as a simpler
11
system. So, we put a more complex
system in, we
12
might very well lose ground rather than gain
13
ground.
14
Now, my colleague said this is a
15
cost-benefit. For me, it is
really I want to know
16
whether we are going to gain ground on the numbers
17 or
percent of those who aren't pregnant after going
18
through the course of treatment.
19
If there is a way for someone to pilot it
20 in,
to show us that, we are better off than jumping
21 in
with both feet and losing if just for the
22
horrible thought of going from 94 to 150 or 180
322
1
next year because of the confusion of putting the
2
program in.
3
Now, that's my concern and that is why I
4 am
voting. I think I am voting yes, I am
not sure.
5
DR. GROSS: I gathered.
6
Jackie.
7
DR. GARDNER: Jackie Gardner. No.
8
DR. KATZ: Robert Katz. Away from the
9
table, in the hallway, we are all concerned about
10
cost, but I have been told before around this
11
table, cost is not our concern, and getting
12
involved in this and obfuscating renders our two
13
days here ineffectual.
14
So, whatever we decide, we should go
15
ahead. An emphatic no.
16
DR. SELLERS: Sarah Sellers. No.
17
DR. GROSS: Dr. Shapiro, you voted
yes?
18
MS. SHAPIRO: Yes, with my
revisions,
19
right.
20
DR. GROSS: The nays have it 14 to
8.
21
As far as the other suggestions are
22
concerned, I don't know that we are going to be
323
1
able to reach consensus on it, and maybe what we
2
should do, as Dr. Kibbe pointed out, is make other
3
suggestions that might be considered, and
4
Hoffmann-La Roche and the generic manufacturers
5
will hear them, the FDA will hear them, and maybe
6 we
can leave it at that, unless somebody here has a
7
burning issue they want to go through another vote
8 on.
9
The suggestions that we have heard is
10 recertification of physicians. There was a
11
question on the video. Was that
Dr. Bigby, did you
12
comment on that, or who commented on the video?
13
DR. WHITMORE: I did. It's an excellent
14
video, and I would recommend that all patients view
15 it.
16
DR. GROSS: The surveillance that
is done,
17 the
survey that is done should include tracking
18
women who get pregnant.
19
DR. WHITMORE: I have a question
about
20
physician reporting and making that mandatory.
21
DR. GROSS: Physician
reporting. What do
22 you
mean?
324
1
DR. WHITMORE: Of pregnancies.
2
DR. GROSS: Where is that in the
program?
3
DR. WHITMORE: I don't know. I think it
4
should be included.
5
DR. GROSS: Oh, you think it
should be
6
included.
7
DR. WHITMORE: Right.
8
DR. GROSS: Good. All right.
Any other
9
suggestions?
10
Dr. Cohen.
11
DR. COHEN: We had the suggestion
before
12
about the indication being in the registry, an
13
attestation of the indication.
14
DR. GROSS: Attestation of the
entry
15
criteria, indication for the treatment.
Good.
16
If there is nothing else, I think Question
17 4
was taken care of by adopting the program because
18
that includes a registry for patients, physicians,
19 and
pharmacies, not pharmacists. Anybody
want to
20
change that or comment on that?
21
Ruth.
22
DR. DAY: I would like the
pharmacists
325
1
here to convince me it should not be pharmacists.
2 I
know it is a lot more work, et cetera, et cetera,
3 but
why not?
4
DR. GROSS: Sarah Sellers.
5
DR. SELLERS: I agree it should be
6
pharmacists consistent with the type of
7
certification we have for disease management
8
specialists, I think this could be achieved.
9
DR. GROSS: Dr. Cohen.
10
DR. COHEN: I was going to say the
same
11
thing. I think if anything, it
might add to the
12
pharmacists wanting to follow through and comply
13
with the program, et cetera, so
go along with it.
14
DR. KIBBE: There is only one
small
15
drawback. I agree that we ought
to register the
16
pharmacists, the actual health professional who is
17
responsible for doing it.
18
The drawback is that if the patient comes
19 to
the same pharmacy where multiple pharmacists
20
work, if not all of them are registered, they might
21 run
into a problem with the delivery of the
22
prescription or the delivery of the medication
326
1
might be delayed until a registered pharmacist, one
2
that is registered with the program as opposed with
3 the
state might be there to handle that.
4
That is a logistics problem.
5
DR. GROSS: Sarah Sellers.
6
DR. SELLERS: That is where we
have seen
7
noncompliance with the S.T.E.P.S. program. So,
8
that argues for a pharmacist being registered
9
actually.
10
DR. GROSS: That's it. We seem to have
11
fair unanimity on that. Maybe we
had better vote
12 on
it because that modifies the Roche program.
13
Nobody wants to vote?
14
DR. CRAWFORD: No, but may I make
a
15
comment? Certainly, anytime there
is any
16
opportunity for professional development with the
17
pharmacists, I am in favor of it although right
18
now, at this point, I think I would be more in
19
favor of registration of the pharmacies.
20
In the practice of pharmacy in the absence
21 of
state laws and regulations, the state board
22
actually looks at institutional policies and
327
1
procedures, so unless the pharmacy, in this case,
2 for
example, the corporate chains, the independent,
3
whoever owns that community pharmacy, unless they
4 say to do it, it may not be done.
5
I am concerned, I don't know how many
6
practicing community pharmacies, there are
7
approximately 200,000 pharmacists in the United
8
States, my guess would be perhaps about 70 percent
9
practice in community.
10
I think it would be very difficult in
11
terms of access, so saying that the pharmacists
12
have to be registered for this
13
particular--certified, whatever the term is for
14
this particular program--it is okay as long as it
15 is
realized there will be much less access, much
16
less for the patients.
17
DR. GROSS: What happens in the
S.T.E.P.S.
18
program, is it pharmacists or pharmacies?
19
DR. SELLERS: Pharmacies. The S.T.E.P.S.
20
program uses pharmacies. We are
aware that in
21
pharmacy practice, there are people who are working
22
part time or doing shift work and that some of the
328
1
lapses that have been described may, in fact,
2
reflect that the SOPs for the pharmacy aren't
3
perfectly communicated to the individuals who are
4
working there on a part-time basis.
5
DR. GROSS: Brian.
6
DR. STROM: To me, it makes no
more sense
7 to
certify pharmacies than it does to certify
8
physician practices as opposed to physicians. The
9
point is the individual clinician is the one who is
10
going to be doing the care. If
the net impact is
11
there are fewer people able to do it, so be it, but
12
that is the same thing as saying certify
13
dermatologists as opposed to dermatology practices.
14
They are the ones making the decisions.
15 My guess is what will happen would be a
16
move toward what I was looking for before in terms
17 of
specialty pharmacies. There will be some
18
pharmacies that will say we need to have all of our
19
pharmacists certified, and there will be some that
20
will say we are not going to do this.
21
DR. GROSS: Dr. Bergfeld.
22
DR. BERGFELD: I would concur with
that
329
1
wholeheartedly. Why would you
have two different
2
standards for two different professional groups.
3
DR. WHITMORE: This brings up an
issue
4
about nurse practitioners and PAs.
5
DR. BERGFELD: What is that issue?
6
DR. WHITMORE: If they need to be
7
certified or actually if they can be certified and
8 get
stickers, and I don't know if they can get
9
stickers or not.
10
DR. GROSS: Well, certainly the PA
that
11
presented, PAs do it under physician license in
12
many states--
13
DR. WHITMORE: It that under the
14
physicians' certification, though?
I imagine it is
15
under the yellow sticker--
16
DR. GROSS: Not necessarily.
17
DR. WHITMORE: So, they should go
through
18
some kind of training.
19
DR. GROSS: That makes sense and
nurse
20
practitioners can in many states write
21
prescriptions independent of physicians.
22
Stephanie.
330
1
DR. CRAWFORD: Thank you. Real quickly
2
with that one, I do believe anyone with
3
prescriptive authority should be the same rules. I
4 am
not at all opposed to the pharmacists being
5
certified. I welcome it. It is just I am saying
6 if
it is done, we need to realize that it is
7
limiting access and also, Dr. Strom, when it says,
8 I
presume, when it says the pharmacy is certified,
9 that
means the pharmacist in charge, who also he or
10 she
informs all of the pharmacists who work there,
11 be
they part time, full time, registry, whatever
12 the
case may be, what the policies are for that
13
pharmacy.
14
DR. GROSS: Maybe we had better
vote on
15
this. I guess the question would
be that all
16
prescribing health care providers should be
17
registered in the program, so that would include
18
physicians, pharmacists, PAs, and nurse
19 practitioners.
20
MR. LEVIN: Arthur Levin. Yes.
21
DR. GARDNER: Point of order. Not all
22
pharmacists prescribe.
331
1
DR. GROSS: Health care
providers. I am
2
sorry. Pharmacists, as well as
all of those who
3
prescribe, meaning PAs, nurse practitioners, and
4
physicians. I am sorry I didn't
state it clearer.
5
DR. SAWADA: Kathy Sawada. Yes.
6
DR. VENITZ: Jurgen Venitz. Yes.
7
DR. STROM: Brian Strom. Yes.
8
DR. BERGFELD: Wilma
Bergfeld. Yes.
9
DR. RAIMER: Sharon Raimer. Yes.
10
MS. KNUDSON: Paula Knudson. Yes.
11
DR. BIGBY: Michael Bigby. Yes.
12
DR. HONEIN: Peggy Honein. Yes.
13
DR. COHEN: Michael Cohen. Yes.
14
DR. WHITMORE: Beth Whitmore. Yes.
15
MS. SHAPIRO: Robyn Shapiro. Yes.
16
DR. EPPS: Roselyn Epps. Yes.
17
DR. SCHMIDT: Jimmy Schmidt. Yes.
18
DR. CRAWFORD: Stephanie
Crawford. Yes.
19
DR. GROSS: Peter Gross. Yes.
20
DR. WILKERSON: Michael
Wilkerson. Yes.
21 DR. RINGEL: Eileen Ringel. Yes.
22
DR. VEGA: Amarilys Vega. Yes.
332
1
DR. DAY: Ruth Day. Yes.
2
DR. KIBBE: Arthur Kibbe. Yes.
3
DR. GARDNER: Jackie Gardner. Yes.
4
DR. KATZ: Robert Katz. Yes.
5
DR. SELLERS: Sarah Sellers. Yes.
6
DR. GROSS: Well, what a nice way
to end
7 up.
8
The last question, Question 5.
Please
9
identify the critical benchmarks for determining
10 the
success or failure, for example, reducing to
11
zero the number of women who are pregnant at the
12
initiation of isotretinoin treatment.
13
Does anybody have any other suggestions
14 for
the FDA as to benchmarks for assessing success
15 or
failure?
16
Ruth.
17
DR. DAY: Excuse me. We never did vote on
18 the
other things that came up in the other
19
category. They were originally
the
20
recertification, the video, the survey, the
21
indications and the registry, the pharmacists, and
22
then it all went into what we voted, was all health
333
1
care providers. So, what happened to those other
2
items?
3
DR. GROSS: The other items were
4
suggestions to the FDA and the manufacturers to
5
consider. We weren't going to
vote on it.
6
Dr. Ringel.
7
DR. RINGEL: Because achieving an
endpoint
8 of
zero pregnancies is simply not reasonable even
9
though it's what we are all striving for, I suggest
10
that we accept as an endpoint continuous quality
11
improvement, that each time, each year, each time
12
this program is assessed and the change has been
13
made, it should be better than the last time.
14
DR. GROSS: Excellent
suggestion. So,
15
there should be successive iterations of quality
16
improvement as data gets fed into the system.
17
DR. WHITMORE: I would say a good
goal
18
would be to reduce to zero the number of women who
19
have a positive pregnancy test at the initiation of
20
therapy.
21 DR. GROSS: Anything else?
22
DR. STROM: Do you know what the
334
1
benchmarks are for the S.T.E.P.S. program?
2
DR. GROSS: Anybody from the FDA
or
3
elsewhere who want to comment on that?
4
DR. TRONTELL: I will invite
anyone to
5
speak. I don't believe, in fact,
in any of these
6
areas we have set an absolute threshold or ceiling
7 for
performance, that it has been a matter of
8
continued re-evaluation.
9
DR. GROSS: Maybe we could state
it as
10
goals, goals, as well as benchmarks.
11
DR. SELIGMAN: We already have
goals, I
12
think.
13
DR. GROSS: Right. Sorry.
14
MS. SHAPIRO: I just have a
question about
15 the
last suggestion. Doing better, does that
mean
16 in
terms of absolute numbers or rates?
17
DR. WILKERSON: We don't know what
the
18
rates are.
19 MS. SHAPIRO: Right.
That's a problem.
20
DR. GROSS: Dr. Bigby.
21
DR. BIGBY: Actually, I think that
is a
22
very important question, and I think that we should
335
1
actually look at absolute numbers.
I mean if the
2
rate falls and the uses goes up and the number of
3
deformed children goes up, and exposures goes up,
4
nobody is going to be happy with that,
so I think
5 you
have to look at the absolute numbers.
6
DR. RINGEL: As the person who
made the
7
proposal, I definitely agree with that.
8
DR. WHITMORE: Can I remind us
that all we
9 are
doing is targeting the initiation of Accutane
10 in
a pregnant woman, so we are affecting that 12
11
percent, and nothing else, unless education
12
actually works.
13
DR. GROSS: Dr. Vega.
14
DR. VEGA: We need to be aware
that once
15 we
have global registration and we start capturing
16 a
larger population, we might end up seeing a
17
larger number of pregnancies that were slipping
18
down the cracks, and when we capture that
19
population, the numbers will go up, and if set that
20 goal, we will be calling that a failure,
when, in
21
fact, we are starting to see the real picture.
22
DR. GROSS: A good point.
336
1
Dr. Bigby.
2 DR. BIGBY: Can I put that slide up? The
3 one
thing outside of detecting this group of women
4 who
are pregnant when they start the medicine, and
5
eliminating them because we do pregnancy tests, two
6
pregnancy tests before initiating treatment, is
7
that we really need to look at how well sort of
8
contraceptives work and what we are actually doing
9 to
change the number of women who get pregnant.
10
DR. UHL: People want to see this
one as
11 well.
There are two separate slides that we have
12
prepared.
13
[Slide.]
14
This one is the percentage of women
15
experiencing unintended pregnancy during the first
16
year of perfect use of multiple different
17
contraceptive products. These are
data from the
18
Contraceptive Technology Reference in 1998.
19
[Slide.]
20
I am happy to go back and forth between
21
these. This slide are
contraceptive failure rates.
22 As
you can see, both of these are rates calculated
337
1 in
a different way, a different manner.
These are
2
contraceptive failures. These are
rates per 1,000,
3 I
believe there were 1,000 women. Peggy
Honein may
4 be
able to comment even better.
5
I take this back. I thought these
were
6 CDC
data. These are ACOG data. The only one
that
7 is
not per 1,000 is for the IUD data, which are
8 cumulative
5-year failure rates. I think it is
9
1,000 women years.
10
DR. KATZ: Excuse me. The tubal ligation,
11
does that mean 7.5 to 36 per 1,000 failure?
12
DR. UHL: That is total
contraceptive,
13
yes. If you look at the previous slide, that is why
14
there is two separate slides here.
This is
15
unintended pregnancy with within the 12 months
16
following the initiation of that method.
So, here
17 you
have a tubal ligation failure rate of 0.5
18
percent. But these are two
separate sources of
19
data.
20
These also are per one contraceptive
21
method as Dr. Kweder alluded to this morning. We
22
don't have data on failure rates using two sources
338
1 of
contraception.
2
Maybe patients need to be educated with
3
this information.
4
DR. EPPS: Are all intrauterine or
some of
5
them ectopic pregnancies?
6
DR. UHL: I don't have that data.
7
DR. GROSS: I think we are kind of
winding
8
down here. Are there any other
points? Yes, Dr.
9
Ringel.
10
DR. RINGEL: I think there is two
points.
11 The
first is that even though the IUD looks very
12
good, people who are not physicians need to know
13
that it carries a significant risk of sterility and
14
pelvic infections, and most gynecologists would
15
refuse to implant an IUD, for example, in a
16
16-year-old girl, so unfortunately, that is not a
17
possibility.
18
Another thing to look at is, in fact, oral
19
contraceptives that so many women use and really in
20 use
have a fairly high failure rate. I hate to harp
21 on
it again, but anything we can do as an
22
education--I forgot what you called it--something
339
1 to
prospectively remind people to take that pill or
2
remind them if they haven't taken a pill.
3
I don't care if you want to make a box or
4 if
you want to make a magnet or a sticker or
5
anything that you could devise to help that number
6
would probably go a long way.
7
DR. GROSS: If there are no other
8
comments, I would declare the meeting adjourned. I
9
want to thank the Advisory Committee for their
10
incredibly excellent input. I
appreciate the
11
audience's contributions.
12
Once again, thank you all for an excellent
13 two
days.
14
[Whereupon, at 3:45 p.m. the hearing was
15
adjourned.]
16 - - -