UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
* * *
NONPRESCRIPTION DRUGS ADVISORY COMMITTEE (NDAC)
IN JOINT SESSION WITH THE
ADVISORY COMMITTEE FOR REPRODUCTIVE HEALTH DRUGS (ACRHD)
* * *
MEETING
* * *
TUESDAY,
DECEMBER 16, 2003
The
joint Advisory Committees met at 8:00 a.m in the Grand Ballroom of the
Gaithersburg Hilton, 620 Perry Parkway, Gaithersburg, Maryland, Dr. Louis
Cantilena, Jr., NDAC Chairman, presiding.
PRESENT:
LOUIS R. CANTILENA, Jr., M.D., Ph.D., NDAC
Chairman
LINDA C. GIUDICE, M..D., Ph.D., ACRHD Chair
MICHAEL C. ALFANO, D.M.D., Ph.D., Acting Industry
Representative
PRESENT (Continued):
NEAL L. BENOWITZ, M.D., NDAC
ABBEY B. BERENSON, M.D., Consultant (Voting)
TERRENCE F. BLASCHKE, M.D., NDAC
LESLIE CLAPP, M.D., NDAC
SUSAN A CROCKETT, M.D, ACRHD
FRANK F. DAVIDOFF, M.D., NDAC
SCOTT S. EMERSON, M.D., Ph.D., ACRHD
MICHAEL F.
GREENE, M.D., Consultant (Voting)
W. DAVID HAGER, M.D., ACRHD
GERI D. HEWITT, M.D., Consultant (Voting)
JULIE A. JOHNSON, Pharm.D., NDAC
Y.W. FRANCIS LAM, Pharm.D., NDAC
VIVIAN LEWIS, M.D., ACRHD
LARRY LIPSHULTZ, M.D., ACRHD
CHARLES J. LOCKWOOD, M.D., ACRHD
GEORGE A. MACONES, M.D., ACRHD
SONIA PATTEN, Ph.D., NDAC Consumer Representative
VALERIE MONTGOMERY RICE, M.D., ACRHD
WAYNE R. SNODGRASS, M.D., Ph.D., NDAC
JOSEPH STANFORD, M.D., ACRHD
MARY E. TINETTI, M.D., NDAC
PRESENT (Continued):
JAMES TRUSSELL, Ph.D., Consultant (Voting)
LORRAINE TULMAN, RN, M.S., ACRHD Consumer
Representative
DONALD L. UDEN, Pharm.D., NDAC
HENRY W. WILLIAMS, Jr., M.D., NDAC
ALASTAIR WOOD, M.D., NDAC
KAREN M. TEMPLETON-SOMERS, Ph.D., NDAC Executive
Secretary
SPONSOR REPRESENTATIVES AND CONSULTANTS:
CAROLE BEN-MAIMON, M.D.
VIVIAN DICKERSON, M.D.
DAVID GRIMES, M.D.
FDA REPRESENTATIVES:
STEVEN K. GALSON, M.D., M.P.H., Acting Director,
CDER
SANDRA KWEDER, M.D., Deputy Director, OND
JONCA BULL, M.D., Director, ODE V
JULIE BEITZ, M.D., Deputy Director, ODE III
DONNA GRIEBEL, M.D., Deputy Director, DRUDP
CURTIS J. ROSEBRAUGH, M.D., M.P.H., Deputy
Director, DOTCDP
ANDREA LEONARD SEGAL, Team Leader,
JIN CHEN, M.D., Ph.D., Medical Officer, DOTCDP
DANIEL DAVIS, M.D., M.P.H., Medical Officer,
DRUDP
KAREN LECHTER, J.D., Ph.D., Social Science
Analyst, DSRCS
C O N T E N
T S
Introductions .................................... 6
Conflict of Interest Statement .................. 12
Opening Remarks, Dr. Sandra Kweder .............. 13
Introduction to the Issues, Dr. Curtis
Rosebraugh
................................ 20
Sponsor Presentation:
Dr.
Carole Ben-Maimon ............. 26,
40, 64
Dr.
Vivian Dickerson ...................... 33
Dr.
David Grimes .......................... 59
FDA Presentation:
Dr.
Daniel Davis .......................... 98
Dr.
Karen Lechter ........................ 114
Dr.
Jin Chen ............................. 124
Open Public Hearing:
Dr.
Melanie Gold ......................... 155
Dr.
Vanessa Cullins ...................... 157
Dr.
Gretchen Stuart ...................... 160
Delegate
Bob Marshall .................... 162
Rachel
Laser ............................. 165
Dr.
Felicia Stewart ...................... 167
Wendy
Wright ............................. 169
Linda
Freeman ............................ 171
Carole
Denner ............................ 176
Erin
Mahoney ............................. 179
Teresa
Harrison .......................... 180
Dr.
Hanna Klaus .......................... 182
Kirsten
Moore ............................ 185
Dr.
Beth Jordan .......................... 185
Dr.
Robert Carroll ....................... 188
Dr.
Janet Engle .......................... 189
Hillary
Flowers .......................... 192
Kelly
Mangan ............................. 194
Dr.
John Bruchalski ...................... 195
Dr.
Chris Kahlenborn ..................... 197
Dr.
Daniel Hussar ........................ 199
Heather
Boonstra ......................... 202
C O N T E N T S
(Continued)
PAGE
Open Public Hearing (Continued):
Dr.
William Colliton ..................... 204
Karen
Coleman ............................ 206
Alexandra
Leader ......................... 208
Amy
Allina ............................... 210
Judie
Brown .............................. 212
Stephanie
Seguin ......................... 214
Jane
Boggess ............................. 216
Silvia
Henriquez ......................... 218
Vera
Brown ............................... 220
Carol
Petraitis .......................... 222
Erika
Gubrium ............................ 224
Jill
Stanek .............................. 226
Kim
Gandy ................................ 228
Deven
McGraw ............................. 230
Andre
Ulmann ............................. 232
Dr.
Erin Gainer .......................... 233
Candi
Churchill .......................... 235
Jennifer
Taylor .......................... 238
Rev.
Robert Tiller ....................... 240
Dr.
Albert George Thomas ................. 242
Clarifying Questions from Committee ............ 246
Question for the Committee ..................... 301
P R O C E E D I
N G S
(8:05
a.m.)
CHAIRMAN
CANTILENA: Good morning, everyone. We'd like to get started.
I'd
like to welcome you to the December 16th, 2003, meeting of the Nonprescription Drugs Advisory Committee and
jointly with the Reproductive Health Drugs Advisory Committee.
We're
here today to discuss the proposition of switching Plan B from Rx to
over-the-counter, and before we get started, Dr. Somers has a statement that
she needs to read for all of us.
DR.
TEMPLETON-SOMERS: Good morning, and
welcome to this joint session of the Nonprescription Drugs Advisory Committee
and the Advisory Committee for Reproductive Health Drugs.
All
committee members have been provided with copies of background materials from
both the sponsor and the FDA and with copies of the letters from the public
that were received by the December 5th deadline. The background materials were posted on the
FDA Web site yesterday morning.
Copies
of all of these materials are available for viewing only at the FDA desk
outside this room.
Today
we have a very large table, a full house, and an exciting topic. So we'd like to start with a few rules of
order.
FDA
relies on its advisory committees to provide the best possible scientific
advice available to assist us in making complex decisions. We understand that issues raised during the
meeting may well lead to conversations over breaks or during lunch.
However,
one of the benefits of an Advisory Committee meeting is that the discussions
take place in an open and public forum.
To that end, we request sincerely that members of the committee not
engage in private, off-record conversations or interviews on today's topic
during the breaks or during lunch.
Whenever
there is an important topic to be discussed, there are a variety of
opinions. One of our goals today is for
this meeting to be conducted in a fair and open way where every participant is
listened to carefully, treated with dignity, courtesy, and respect. Anybody whose behavior is disruptive to the
meeting will be asked to leave.
We
are confident that everyone here is sensitive to these issues and can
appreciate that these comments are intended as a gentle reminder. We look forward to a productive and
interesting meeting.
Thank
you.
CHAIRMAN
CANTILENA: Okay, and as I said earlier,
my name is Dr. Lou Cantilena, head of clinical pharmacology at the Uniformed
Services University. I'll be chairing
this meeting.
And
we'd like to go around so that everyone can introduce themselves, and we'll
start on this side.
DR.
ALFANO: Michael Alfano, Dean of the
Dental School at New York University.
DR.
HAGER: David Hager, Reproductive Health
Drugs, from the University of Kentucky.
DR.
LAM: Francis Lam from University of
Texas Health Science Center in San Antonio, a member of NDAC.
DR.
LIPSHULTZ: Larry Lipshultz, Professor of
Urology, Baylor College of Medicine.
DR.
JOHNSON: Julie Johnson from University
of Florida Colleges of Pharmacy and Medicine, from the Nonprescription Drug
Committee.
DR.
MACONES: George Macones. I'm Associate Professor of OB-GYN and
Epidemiology at the University of Pennsylvania on Reproductive Drugs.
DR.
PATTEN: Sonia Patten. I'm a consumer representative. I'm an anthropologist on faculty at
Macalester College in St. Paul, Minnesota, and I'm part of the Nonprescription
Drug Committee.
DR.
CROCKETT; I'm Susan Crockett. I'm a general OB-GYN Director of Maternity
Services for the CHRISTUS Santa Rosa Family Practice Residency Program, and I'm
a member of the Reproductive Health Drugs Committee.
DR.
UDEN: I'm Don Uden, a professor at the
University of Minnesota College of Pharmacy and member of NDAC.
DR.
STANFORD: Joseph Stanford, University of
Utah, Department of Family and Preventive Medicine on the Reproductive Health
Drugs Committee.
DR.
BENOWITZ: Neal Benowitz. I'm an internist and clinical pharmacologist
from U.C., San Francisco, on the Nonprescription Drug Committee.
DR.
LOCKWOOD: Charles Lockwood, Chair of
OB-GYN at Yale and Reproductive Drugs.
MS.
TULMAN: Lorraine Tulman, Associate
Professor, University of Pennsylvania School of Nursing, Reproductive Health
Advisory Group, and I'm the consumer representative for that group.
DR.
TRUSSELL: James Trussell from the Office
of Population Research at Princeton University.
DR.
GIUDICE: Linda Giudice, reproductive
endocrinologist and Professor of OB-GYN at
Stanford University, and Chair of
the Reproductive Health Drugs Committee.
DR.
TINETTI: Mary Tinetti, Department of
Medicine, Yale, Nonprescription Drug Committee.
DR.
HEWITT: I'm Geri Hewitt, Assistant
Professor of the Department of OB-GYN and Department of Pediatrics at Ohio
State College of Medicine.
DR.
GREENE: I'm Michael Greene, Professor
of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School.
DR.
CLAPP: Leslie Clapp, pediatrician,
Buffalo, New York, and Clinical Associate Professor of Pediatrics, University
of Buffalo.
DR.
SNODGRASS: Wayne Snodgrass, Department
of Pediatrics, University of Texas in Galveston, and clinical pharmacology on
the Nonprescription Drug Committee.
DR.
LEWIS: Vivian Lewis, Professor of OB-GYN
at University of Rochester, and I'm on the Reproductive Health Drugs Committee.
DR.
BLASCHKE: Terry Blaschke,
internist/clinical pharmacologist, Stanford.
DR.
WOOD: I'm Alastair Wood from Department
of Medicine, Department of Pharmacology at Vanderbilt, and I'm on NDAC.
DR.
EMERSON: Scott Emerson, Professor of
Biostatistics at the University of Washington on Reproductive Drugs.
DR.
BERENSON: Abbey Berenson, Professor of
OB-GYN and Pediatrics at University of Texas Medical Branch at Galveston.
DR.
DAVIDOFF: I am Frank Davidoff. I'm the editor emeritus of the Annals of
Internal Medicine; also now the executive editor at the Institute for
Health Care Improvement, and I'm on the NDAC.
DR.
MONTGOMERY: Valerie Montgomery Rice,
Professor and Chair of Obstetrics and Gynecology, Meharry Medical College, and
I'm on the Reproductive Health Drugs.
DR.
GRIEBEL: Donna Griebel, Deputy, Division
of Repro. and Urologic Drug Products, FDA.
DR.
ROSEBRAUGH: Curt Rosebraugh, Deputy of
Over-the-Counter Drug Products.
DR.
BEITZ: Julie Beitz, Deputy Director,
Office of Drug Evaluation III, CDER, FDA.
DR.
BULL: Good morning. Jonca Bull, the Director of the Office of
Drug Evaluation IV in CDER, FDA.
DR.
GALSON: Steve Galson. I'm the Acting Director of the Center for
Drug Evaluation and Research.
DR.
KWEDER: I'm Sandra Kweder. I'm the Deputy Director of the Office of New
Drugs in CDER.
DR.
TEMPLETON-SOMERS: Thank you. I'm Karen Templeton-Somers, Executive
Secretary to the Committee, FDA.
And
the following announcement addresses conflict of interest issues with respect
to this meeting and is made a part of the record to preclude even the
appearance of impropriety at the meeting.
The
conflict of interest statutes prohibit special government employees from
participating in matters that could affect their own or their employer's
financial interests. All participants
have been screened for interests related to the product, competing products and
companies that could be affected by today's discussions The agency has reviewed the interests
reported by the committee participants and has determined that there is no
potential for a conflict of interest at this meeting.
We
would like to disclose that Dr. Michael Alfano is participating as the acting
industry representative, acting on behalf of Regulated Industry.
In
the event the discussions involve any other products or firms not already on
the agenda for which FDA participants have a financial interest, the
participants are aware of the need to exclude themselves from such involvement,
and their exclusion will be noted for the record.
With
respect to all other participants, we ask in the interest of fairness that they
address any current or previous financial involvement with any firm whose
products they may wish to comment upon.
Thank
you.
CHAIRMAN
CANTILENA: Thank you, Dr. Somers.
We'll
now hear from Dr. Sandy Kweder, who will open the meeting for the FDA.
DR.
KWEDER: Well, good morning, everyone,
and welcome. I'd first like to start off
the meeting by acknowledging the large size of the panel today and thanking all
of you on the panel for coming here.
Sometimes a large panel makes interchange more difficult, but I think
Dr. Cantilena is probably up to the challenge.
Your
discussion is extremely important to us, but before you begin that, I'd like to
provide some background perspective as to how we got here.
Following
my remarks, Dr. Curt Rosebraugh will introduce the subject in more detail and
get on with some of the scientific presentations.
First,
let me be clear that we're here today to discuss the scientific data available
to address Barr Lab's application to remove the prescription requirement for
their product Plan B. Plan B is an
emergency contraceptive that is indicated for use in the unexpected
circumstance when another standard contraceptive method fails or fails to be
used.
While
previously established safety and efficacy data for this medication will be
referenced, you'll be asked to consider these data only as they relate to Plan
B's suitability for nonprescription status.
You'll hear a lot more about FDA's general approach to making decisions
about switches from prescription to nonprescription status. So I'm not going to address that further.
But,
secondly, I would like to assure you that we at FDA recognize the broad array
of issues related to emergency contraception, in general, that may arise in
your discussion. None of these are new.
In
June of 2000, FDA, CDER particularly, held a Part 15 hearing. The purpose of that two-day hearing was
solely to solicit public testimony on the future of prescription to
nonprescription product shifts. We
requested that experts and any concerned member of the public come and share
their perspectives in several areas.
What
products should and should not be considered for nonprescription status?
What
are the perceived incentives and perceived barriers to such shifts?
And
outstanding issues, what are they that might be addressed to modify incentives
and barriers?
I
was part of the FDA panel listening to that testimony. In addition to other product groups
discussed, like cholesterol lowering agents, non-sedating antihistamines and
antihypertensives, we heard several hours of testimony regarding oral
contraceptives as potential candidates for being available without a
prescription, but in particular, many speakers favored or did not favor making
emergency contraception nonprescription.
Those
in the favoring group pointed out that the clinical safety of the product and
the importance of access to emergency contraception are the keys to maximizing
its effectiveness. For example, if the
product is to be used as directed, the woman must be able to take it within 72
hours of intercourse. This is often not
achievable given our current system of pharmacy practice.
They
also cited studies in the literature which showed that women do not appear to
substitute emergency contraception for other more traditional forms of
contraception.
Those
who did not favor nonprescription status raised public health concerns about
potential effects of wider availability of the product on adolescent health and
behavior. For example, these speakers
did not find the published literature convincing with regard to the impact of
more readily available emergency contraceptives on adolescent behavior. Of particular concern to them were whether
nonprescription access would increase sexually transmitted infections and
decrease the use of other more effective contraceptives or even affect choices
about sexual behavior in adolescent groups.
We
at FDA understand the complexity and the multiple perspectives on these
matters. We will consider their full
breadth before arriving at any final regulatory decision following this
meeting.
Finally,
I want to say a few words about seeking answers to difficult questions and
decision making. One of the things that
we at FDA do when we're faced with one is we often look to others' experiences
to see what has happened with those who have gone before us.
For
example, we look to the experience of products as they may be marketed in other
countries. Some of those experiences may
come up today in the presentations and your discussions. You may be reassured by these or frustrated
because there are not detailed data to answer questions you might like to have
addressed.
Please
keep in mind that considering the effects of nonprescription or prescription
medicines in countries other than the United States is fraught with challenges
of interpretation because of differences in pharmacy models.
For
example in some countries having things, what might be called behind the
country, only means that a person has to ask for them. For example, in those countries this status
is applied to hundreds of medicines. The
open shelves in the shop are there only for toiletries and other supplies.
In
these countries, including many in Europe, most of the products that we
routinely consider over-the-counter and readily available even in a grocery
store are distributed in this manner at a pharmacist's counter, as are many
products that we are used to only having available by prescription.
In
other countries, the term "behind the counter" refers to the need to
request the product of a pharmacist and obtain or have the opportunity to be
counseled by a pharmacist.
The
bottom line is that data from these countries can only be looked at from an
arm's length, and they do not necessarily translate into data that give solid
answers to bigger picture questions that we or you may have. We just have to do the best we can.
Again,
thank you for coming and for your willingness to help us with a challenging
decision. Discussions at these meetings
are as important, if not more important, than any vote tally on the formal
questions that we pose, and we're looking forward to your discussion today.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you, Dr. Kweder.
Dr.
Rosebraugh, would you like to continue with the FDA introduction, please?
DR.
ROSEBRAUGH: Good morning. On behalf of the Divisions of Over-the-Counter
Drug Products and Reproductive and Urologic Drug Products, I'd like to welcome
the members of each respective Advisory Committee to today's meeting regarding
the nonprescription status of Plan B.
By
way of introduction, I would like to briefly go over the regulatory history of
Plan B, go over the regulatory requirements for nonprescription marketing of
drug products, and outline today's agenda.
Plan
B was approved for prescription use on July 28th, 1999, for the indication as
an emergency contraception to be used to prevent pregnancy following
unprotected intercourse or a known or suspected contraceptive failure. Prescription directions for use indicate that
to obtain optimal efficacy, the first does needs to be taken as soon as
possible within 72 hours of intercourse, and the second dose needs to be taken
12 hours later.
Women's
Capitol Corporation, the applicant for the original prescription NDA, submitted
an application for Plan B switch from prescription to nonprescription status in
April of 2003. As the efficacy of Plan
B, when used as per directed has already been established and the sponsor is
not seeking a new indication or dosage regimen, this will not be a topic at
today's meeting.
However,
the efficacy based on a use in a nonprescription setting is of interest to
us.
The
purpose of today's Advisory Committee meeting is to determine whether Plan B
meets regulatory requirements for nonprescription marketing.
Regarding
nonprescription requirements or requirements for nonprescription marketing, the
Durham-Humphrey Amendment to the Federal Food, Drug, and Cosmetic Act, which
was enacted in 1951, formally differentiates between prescription and
nonprescription drugs. This is
articulated in the Code of Federal Regulations 21 CFR 310-200(b) and states,
"Any drug limited to prescription use under Section 503(b)(1)(C) of the
Act shall be exempt from prescription dispensing requirements when the
Commissioner finds such requirements are not necessary for the protection of
public health by reason of the drug's toxicity or other potentialities for
harmful effects, the method of its use, or the collateral measures necessary to
its use, and he finds that the drug is safe and effective for use in
self-medication as directed in the proposed labeling."
So
the bottom line is this regulation provides that a drug be sold nonprescription
if it is safe and if adequate directions for use can be written that are
discernable to a lay person.
When
approaching a possible prescription to nonprescription switch candidate, there
are several questions that the agency takes into consideration to assess
whether the product is, indeed, a suitable switch candidate. Regarding the questions that we take into
consideration, we wonder if the product has an acceptable safety margin, as
demonstrated from prior prescription marketing experience; whether it has low
misuse and abuse potential, a reasonable therapeutic index of safety; whether
the condition that it is being used for can be adequately self-recognized and
self-treated with minimal health care provider intervention; whether the
benefits outweigh the risks; and when the product used under nonprescription
conditions, is it safe and effective?
If
the answer to the above questions are yes, then the proposed product may meet
regulatory requirements for nonprescription safety and effectiveness and is a
candidate for consideration of nonprescription marketing.
In
order to address the questions that face switch candidates, the Plan B switch
NDA application components included summaries from previously existing data and
newly conducted studies. To address the
safety profile and misuse and abuse potential of the product, the sponsor has
submitted safety data from their original NDA and a review of post marketing
safety, both foreign and domestic, and a review of the published literature.
To
evaluate consumers' ability to self-recognize the condition they are treating
and whether self-treatment with the product is safe, the sponsor has conducted
label comprehension and actual use studies.
We will be hearing greater detail about these things during this
morning's presentations.
This
type of data and the studies that the sponsor has performed are consistent with
other submissions that have been evaluated in the past where the switch did not
involve a change in dosage or indication.
To
review today's agenda, we will begin with a presentation by the sponsor, and
that will be followed by a question and answer session.
Then
following a break, we will have presentations by the FDA. Dr. Dan Davis will be presenting the FDA's
review of safety. Dr. Karen Lechter will
be presenting the FDA's review of the label comprehension study, and Dr. Jin Chen
will be presenting the FDA's review of actual use studies and the literature
review.
That
will then be followed by a question and answer session of the FDA.
We
will then have an open public hearing, then a much deserved lunch, and finally
we will dedicate the afternoon to the panel discussion.
During
the presentations the joint committee members should consider the information
and use the question and answer session to prepare to answer the questions
posed to the committee regarding the possible prescription-to-nonprescription
switch of Plan B.
With
that as a background, the agency looks forward to today's discussion.
CHAIRMAN
CANTILENA: Thank you, Dr. Rosebraugh.
Okay. At this time we will move to the sponsor presentation, which will
be led by Dr. Ben-Maimon from Barr.
Dr.
Maimon, if you would start and then as you go through you can introduce the
other members of your team.
For
the committee, we'll hold our questions until the end of sponsor presentation.
Thank
you.
DR.
BEN-MAIMON: Good morning,
everybody. I'd like to start by just
thanking the panel, the FDA, for giving us this opportunity to present the data
supporting the prescription to over-counter switch. We're all very interested, as the FDA stated,
in hearing the panel's discussion and comments, and of course, interested in
answering as many of the questions as we possibly can.
I'm
Carole Ben-Maimon, President/COO of Barr research.
You
may have heard that Barr Laboratories has signed a letter of intent to acquire
the assets of Women's Capitol Corporation.
That includes Plan B for emergency contraception. That transaction has not yet closed, and so
today I'm actually representing Women's Capitol Corporation.
A
little bit about what I'm going to cover in the presentation today. First, the background, a little bit of an
overview, and a discussion about how Plan B prevents pregnancy. I'll talk a little bit about the rationale
for the over-the-counter switch, try and not duplicate what was already said,
and then I'm going to turn the podium over to Dr. Vivian Dickerson, who is the
President-elect for the American College of Obstetricians and Gynecologists,
for her to discuss with you the benefit-risk assessment as ACOG sees it.
I'll
return to the podium and give you some background on our clinical trials, the
label comprehension and actual use, and then Dr. David Grimes, Vice President
of Biomedical Affairs at Family Health International and clinical professor at
the Department of Obstetrics and Gynecology at the University of North Carolina
School of Medicine, will give a presentation and discuss the health
consequences of an OTC switch for Plan B.
Finally,
I'll return to the podium and discuss with you our CARE Program, which many of
you saw in the briefing document. That
program is really designed to increase access and awareness, as well as
availability of Plan B, and I'll discuss some of the rationale and the
presentation for that.
What
is emergency contraception? Emergency
contraception is therapy for women who desire prevention of pregnancy, have had
unprotected sexual intercourse, including contraceptive failures and sexual
assault.
It's
really important that we look at this in the context of what's going on in this
country today. Fifty-three percent of
unintended pregnancies occur in women who are using contraceptives. These are method failures or user failures,
condoms that break, slip, women who miss their pills, but clearly, 53 percent
of the unintended pregnancies are in women who have been using contraceptives.
Unplanned
pregnancies are a major health care problem in this country. There are over three million unintended
pregnancies in the United States each year.
With typical use, 15 percent of women who are using condoms will be
become pregnant each year and eight percent of those using oral contraceptives
will become pregnant each year.
Half
of the unintended pregnancies in this country will result in abortion. It is estimated that up to 50 percent of
these pregnancies could be prevented with greater access and use of emergency
contraception.
There
are two approved products today in the United States: Preven, which was approved in 1998, and Plan
B, which you already heard was approved in 1999.
I
hope they're not putting you to sleep.
Preven
is a combination product with an ethinyl estradiol, and Plan B is actually just
a levonorgestrel product, a progestin only product, and that's really of
significance as we get into how these products prevent pregnancy.
But
you can see that the regimens are essentially identical. Both have to be taken within 72 hours of the
active unprotected sexual intercourse, and the second tablet has to be taken 12
hours later.
The
most fertile days of the female cycle, the menstrual cycle, are the five days
leading up to ovulation and then 24 hours after, and within 24 hours of ovulation,
the egg is no longer viable and fertilization cannot occur.
Plan
B works like other progestin only oral contraceptives and prevents
ovulation. Plan B is an oral
contraceptive, not an abortion pill. The
direct evidence is highly in favor of the fact that the primary mechanism of
action, if not the sole mechanism of action, is prevention of ovulation.
There
are two hypothetical mechanisms that have been proposed: interference with fertilization and
interference with implantation, but for levonorgestrel only contraceptives,
levonorgestrel only emergency contraceptives, there is no data to suggest that
either of these are impacted, either of these events are affected by Plan B.
Again,
I would reiterate Plan B works by preventing ovulation. It is an oral contraceptive, not an abortion
pill.
What's
really critical when we consider the over-the-counter switch of Plan B is this
chart, and what this is is the data from the efficacy trial that was included
in the original NDA that supported the approval of the prescription drug
product, and this was the WHO study that was done in the late '90s.
And
what it shows is that if Plan B, if the first tablet is taken within 24 hours
of the active unprotected sex, the pregnancy rate is as low as .4 percent. Many of you may know that with a single act
of mid-cycle sex the pregnancy rate is about eight percent. So clearly, the reduction is significant
within the first 24 hours.
If
a woman waits until 48 to 72 hours, the pregnancy rate rises to 2.7 percent. It is imperative that women have access to
this product quickly so that they can maximize its effect.
What
does the prescription requirement do?
Well, it creates delays. The
woman needs to identify the need, clearly a need that is easily identified by
most women given the fact that they have either had a contraceptive failure,
coercive sex or rape, or unprotected sex.
They
need to then locate a prescriber who is willing to prescribe emergency
contraception for them. Again, we can't
forget that most of these events are not occurring between nine to five Monday
to Friday. They're occurring at night
and on weekends, and so this is not always an easy undertaking.
They
have to call the prescriber. They have
to talk to the prescriber. The
prescriber then has to call them back and decide to prescribe the product.
If
a woman does not have a physician that she sees regularly or somebody that
follows her regularly, the doctor may want for them to come into the office and
be examined because clearly, doctors are reticent sometimes to calling in
prescriptions to patients who they don't know and probably for good reason.
And
so once she gets her prescription, she now has to go to pharmacy, and at the
pharmacy I can tell you and will show you data to support this, not a lot of
pharmacies stock this product, and the reason is the volume and the demand are
quite low to date because awareness is low.
So just finding a pharmacy where she can obtain the product in a timely
fashion can also be a challenge.
And
finally, she can purchase the product.
So the prescription setting actually creates significant barriers and
time delays as we go through the process.
With
that, I'm going to turn the podium over to Dr. Dickerson. Dr. Dickerson is President-elect of the
American College of Obstetricians and Gynecologists. She is the Director of Obstetrics and
Gynecology at the University of California Irvine
Medical Center, and with that, Dr. Dickerson.
DR.
DICKERSON: Good morning. My name is Vivian Dickerson, and I am an
Associate Professor at the University of California-Irvine and Director of the
General OB-GYN Division at UCI Medical Center.
I
have no financial interests or potential conflicts of interest to disclose in
this case.
As
President-elect of the American College of Obstetricians and Gynecologists, I
am representing ACOG in support of over-the-counter status for Plan B. The college rarely presents product specific
testimony. However, we are delighted to
have the opportunity to present today because we strongly believe that Plan B
meets the FDA criteria for over-the-counter status, and because there is a
public health imperative to increase access to emergency contraception.
ACOG's
mission is to improve health care of women.
We pursue that mission through education and advocacy. On behalf of ACOG, a national organization
representing over 45,000 members who provide health care for women, I am
speaking today to encourage the FDA to act favorably and quickly on the Women's
Capitol Corporation/Barr Laboratories application to make Plan B available to
women over the counter.
Plan
B is safe, and it is effective. It is
not teratogenic. It has no potential for
overdose or addiction. It does not
require special medical screening. It is
easy to use, and the labeling instructions are clear and understandable.
We
know that Plan B works. It prevents
pregnancy. By preventing unintended
pregnancy, it also prevents abortion.
We
know that women use it correctly and are very unlikely to substitute it for an
ongoing method of birth control. For
these reasons, ACOG supports the removal of the prescription requirement for
Plan B for all women of reproductive age.
As
an OB-GYN who has seen thousands of patients over the past 20 years and as a
spokesperson for an organization to which 95 percent of all Board certified
OB-GYN's in the United States belong, I would like to take the opportunity to
clarify why a clinician does not need to oversee a woman's use of Plan B and
why women of reproductive age should have access to it.
I
think it's important that everyone understand why timely access to Plan B is
imperative. Now, this may be a review
for most of us, but let me begin by talking about how pregnancy occurs.
First,
there must be normal maturation of sperm and egg. Following release into the vagina, the sperm
are transported through the cervix, uterus, and fallopian tube. Capacitation of the sperm occurs in the tube
in preparation for fertilization of the egg.
After ovulation the egg is transported from the ovary to the fallopian
tube.
Fusion
of the sperm and egg occurs in that tube, and the fertilized egg is transported
to the uterus. During transport, the
fertilized egg begins to divide until it reaches the blastocyst stage, at which
time it implants into the lining of the uterus.
This is the point at which pregnancy begins.
It
can take five to nine days from the time of fertilization for implantation to
actually occur.
Clinical
research data demonstrate that Plan B primarily prevents pregnancy by
inhibiting or preventing ovulation and secondarily perhaps by impairing the
migration and function of sperm. In
other words, it prevents pregnancy prior to fertilization.
Plan
B is, therefore, most effective when used within 24 hours of unprotected
intercourse, although it has been shown to prevent pregnancy for up to three
days, and recent data show that it may even work for up to five days after
unprotected intercourse.
Each
Plan B tablet contains three-quarters of a milligram of levonorgestrel, which
is a synthetic progestin contained in many current oral contraceptives. The safety and efficacy of levonorgestrel as
a daily contraceptive or a postcoital backup are well established. Indeed, the only absolute contraindication to
Plan B is a known or suspected hypersensitivity to the product.
If
a woman takes Plan B while pregnant, it will not cause an abortion, nor is
there evidence that it increases teratogenicity.
Unintended
pregnancy is a substantial problem in the United States. Nearly 50 percent of the 6.3 million annual
pregnancies in the U.S. are unintended due to either method failure or failure
to use a method.
It
is important to recognize that unintended pregnancy does not discriminate. It affects women of all ages, from teenagers
to women in their 40s. It is equally as
important to recognize that not all women, and adolescents, in particular, have
control over the occurrence of intercourse or the use of contraception. Examples of such cases are rape, date rape,
partner pressure, or other socio-cultural pressures to engage in sex without
contraception.
Overall
it is estimated that widespread use of emergency contraceptive pills has the
potential to decrease by at least 50 percent the current incidence of
unintended pregnancies and subsequent abortions.
Nonetheless,
Plan B is no substitute for ongoing methods of contraception, such as the IUD,
the birth control pill, or injectable contraceptives, all of which have a
higher proven efficacy.
One
of the major barriers to the use of emergency contraception is timely
access. By removing the prescription
requirement, women will be more likely to obtain emergency contraception when
it is most effective. Data show that
women who had emergency contraception on hand were more likely to use it than
women who were simply told about the product or even given a prescription.
However,
these data indicate that women do not substitute emergency contraception for an
ongoing form of birth control, and this applied to teens as well.
Requiring
a prescription for emergency contraception is, in fact, an unnecessary barrier
to obtaining and using the product in a timely fashion. Women know when they may be at risk for
pregnancy, and the actual use and label comprehension studies indicate that
women understand how to use emergency contraception, and that they use it
correctly.
A
switch to over-the-counter availability of emergency contraception will have a
tremendous impact on access to this vital and easy to use therapy.
The
label comprehension data also demonstrate that women clearly understand that
emergency contraception does not protect against sexually transmitted
infections or HIV. There are no data
suggesting that women who use emergency contraception are less likely to obtain
necessary health services.
In
conclusion, on behalf of our 45,000 members who care for women every day, ACOG
strongly supports making Plan B available over the counter to all women of
reproductive age. If we are truly
dedicated to lowering the number of unintended pregnancies and abortions in
this country, let's prove it by making Plan B an emergency contraceptive
available over the country.
Thank
you very much.
DR.
BEN-MAIMON: Thank you, Dr. Dickerson.
I'm
going to go through very quickly what you've already heard. There are the requirements for the approval
of a product to make a prescription to over-the-counter switch.
The
produce has to have an acceptable safety profile based on the prescription use
and the prescription experience. It has
to have a low potential for abuse and misuse.
It has to have an appropriate safety index, therapeutic index, as well
as a positive benefit-risk assessment.
And
finally, it has to be for a condition that is self-recognizable, self-limiting,
and requires minimal health care practitioner intervention.
With
that, Plan B clearly meets the requirements for OTC use. The post marketing and clinical safety trial
data demonstrate an acceptable safety profile in a large number of women who
have been exposed to the product. There
is a low potential for abuse or misuse.
There is no question that the benefits of over-the-counter availability
strongly outweigh the risks, and finally, based on the label comprehension
studies and the actual use studies, the product has been demonstrated to be or
women have demonstrated that they can properly self-select, determine when they
need it, how to use it, and they can use it correctly.
There
is really no medical reason why Plan B should not be sold over the
counter. Over 7,000 women have been
exposed to Plan B in clinical trials, and you can see that the vast majority of
these trials have used the .75 times two.
There were two additional doses in some of the trials, but the vast
majority of those 7,000 women have been exposed to the identical regimen that
we're talking about here today.
Plan
B in these trials has been shown to be 89 percent effective in preventing
pregnancy if taken within the first 72 hours of unprotected sex. It reduces the pregnancy rate from eight percent
to just over one percent.
The
safety profile is also demonstrated. It
is well described. The most common side
effects are nausea, abdominal pain, fatigue, and all of these are self-limited. Most of them are mild to moderate, and very
few, if any, require intervention from a health care practitioner.
There
have been no deaths associated with Plan B.
And
finally, there is no increase in the incidence of ectopic pregnancy. Professional screening cannot impact the
adverse events or the efficacy of the product.
As you heard from Dr. Dickerson, the intervention of a health care
practitioner before or immediately after does not in any way change the
outcome. Most of the events, as I said
before, the adverse events are self-limited.
They resolve on their own, and the efficacy cannot be impacted by
anything except taking it more quickly.
And
the critical issue here is that to maximize the effect, women need to have
access to it.
With
regard to ectopic pregnancy, there has been some discussion as to whether or
not there's an increased rate of ectopic pregnancy with Plan B, and this comes
from the fact that Plan B is a progestin only emergency contraceptive, and oral
contraceptives that when taken continuously, progestin only oral
contraceptives, have been questionably associated with an increased incidence
of ectopic pregnancy.
There
are six trials in over 7,000 women where they systematically followed women and
followed the pregnancies and their outcomes.
There were 133 pregnancies with only two ectopics. That gives us a rate of about one and a half
percent. The background rate in the
general population is about two percent.
So in a large number of women there is clearly no increased incidence of
ectopic pregnancy that has been demonstrated.
In
post marketing studies, as well, there are over six million women worldwide who
have been exposed to Plan B, and if you look at the exposures and calculate the
number of pregnancies anticipated, there is no increased incidence of ectopic
pregnancy.
Again,
there is no medical reason why Plan B should not be sold over the counter.
Our
two trials that you've heard us allude to are a label comprehension study and
an actual use study, and I'm going to go through that data now and show you
that women can self-select and take the product correctly.
The
first study is a label comprehension study that was done in order to determine
whether women could read and understand the label in an over-the-counter
setting. Women 12 to 50 years of age
were included in those trials, and it was performed primarily at malls. There was a sampling of minority women, as
well as young women and women with lower educational levels, as well as lower
literacy levels, and it was a questionnaire type study.
You
can see from this slide the demographics.
Here you see the age distribution.
We had a large sample of young women 12 to 16. Over half of the population was 17 to 25, the
most likely age group to use Plan B.
There was a large sample of diverse ethnic groups represented in the
United States, and we applied the rapid estimate of adult literacy in medicine
test to women. Women took that test who
were over 18 but had not completed college.
So there was a subset of 395 women who were evaluated for literacy. About 35 percent of those scored in the less
than eighth grade literacy category, and this is a way of looking at whether or
not women with low literacy can understand the product label.
There
were 11 objectives in this trial. There
were communication objectives that we were trying to determine whether women
understood, and I'm not going to go through them. You actually have in front of you a handout
that has all of the 11 objectives, and I'll be referencing that handout as I go
through the presentation.
But
you can see that the first couple dealt with what the product is intended to do
and to be used for. There was a question
about sexually transmitted infections and AIDS, how the product is used, and
then the side effect profile.
Here
this chart shows you the 11 objectives along the bottom. This is the percent of women that were able
to answer correctly, and clearly the vast majority, the overwhelming majority
of women were able to answer all of the objectives correctly.
The
one that had a slightly lower rate of understanding percent of women was
objective number two, and I'll talk about that objective in a couple of
minutes.
This
chart looks at the same 11 objectives along the bottom, and the yellow
represents the 12 to 16 year olds, the pink the 17 to 25 year olds, and the
blue the 25 to 50 year olds, and then the dot is the actual average, which you
saw in the previous slide.
If
you look across the overwhelming majority of women were able to understand all
of these objectives, and really the only one that showed a trend with a lower
understanding, a lower comprehension level in the younger group was objective
number two.
This
looks at the distribution by literacy level, and the yellow represents the
lower literacy women, with the pink representing the women with literacy levels
greater than eighth grade, and you can see, again, objective number two has a
difference between the two groups, and you might suggest that objective number
four also, and I'll be talking about those.
I'm
sorry. I also forgot to mention
objective number eight, which was also slightly lower on the overall than the
others and also shows a distribution.
This,
if you refer to your sheet, this objective was the objective that discussed
unexplained vaginal bleeding, and at this point in the prescription label
unexplained vaginal bleeding is a contraindication. Through discussions with the FDA with regard
to this contraindication, it has been decided that this will no longer be a
contraindication. It will be a
warning. Women should follow up with
their health care practitioners if they continue to have unexplained vaginal
bleeding, but it will not be and it is not a contraindication to the use of
Plan B. So this really goes away, which
is why I've sort of ignored it.
Objectives,
and I know this is a busy slide. So let
me just walk you through it a little bit.
Plan B is intended as a backup method and not for regular contraception. That was the objective that was meant here.
Women
had to get at least three of these questions correct in order to be counted as
having understood the objective. You can
see the distribution by age here, and then question number nine, 21, 22, and 25
were the questions that were relevant.
Question
number nine and number 22 are direct questions.
According to the label, should Plan B be used as a regular form of birth
control? And you can see that most women
were able to answer both these questions correctly.
The
two situational questions here, where we were talking about situations where
the partner doesn't want to use condoms and is it for routine birth control or
not; these questions women scored lower.
And
we have a couple of hypotheses why that may have been. Clearly, the situational questions were more
difficult for women to answer. Was it a
result of the fact that we used the terminology "husband," where
husband implies a monogamous, long-term relationship and pregnancy may not be
such a big deterrent?
There
could be any number of reasons why women didn't answer these two questions
correctly, but clearly, those were the two questions that made it difficult,
whereas the direct question suggests that they do understand that it is not a
routine form of birth control.
With
regard to the lower literacy group, you see the same trend. Question nine and question 22 they do quite
well on, but, again, in the lower literacy group there is a trend towards less
understanding of the two situational questions.
What
we tried to do to deal with that was bold the label, and I know it's hard to
see here because of the quality of the PDF, but it's on the board, and I'll be
handing out a package to you in a little bit and you'll be able to look at it
in your hands.
But
we have bolded Plan B should not be used in place of regular
contraception. In addition, this is a
message that we will be trying to drive home with our ancillary materials
through our CARE Program to insure that women do understand that they need to
use routine forms of birth control.
This
was objective number four, and if you remember, there was some difference
between the lower literacy group and the higher literacy group. This question they had to get this number ten
correct in order to be able to be counted as correct, and you can see that all
of the other answers were correct.
The
objective here is that the first pill should be taken within 72 hours, and you
can see that the correct answer to ten was as soon as possible and within three
days, if they answer that, or within three days. But as soon as possible was not counted as a
correct answer because we wanted to see the 72-hour time point.
And
clearly that weighs in, and some women -- this was an open-ended question. They had to fill it in. It was not multiple choice -- and so some
women put as soon as possible and didn't put within 72 hours, and that clearly
is what happened here, and the results of the as soon as possible are down
below. So really women do understand
that they need to take it within 72 hours, and that is clearly demonstrated in
the actual use study, and I'll show that to you in a minute.
So
with regard to the results of this study, the intent to treat analysis shows
that we had satisfactory responses to all objectives, 80 percent or greater
correct responses to nine of the 11 objectives, and the two objectives that
were not answered correctly, one of them was the unexplained vaginal bleeding,
which is no longer a contraindication and, therefore, no longer relevant.
Finally,
in conclusion, the study demonstrates adequate label comprehension, and based
on the results and in an effort to insure we had the best label we possibly
could, we did make some minor changes before the actual use study and,
therefore, enhanced we hoped the understanding and the ability to use the
product correctly.
And
these just included bolding emergency contraception to make sure that women
understood it was for an emergency; bolding a serious medical problem. This section relates to severe abdominal
pain, and we wanted to make sure that women understood that if they were
experiencing severe abdominal pain, they needed to follow up with a physician
because it might be the sign of an ectopic pregnancy.
We
bolded the 12 hours to make sure they understood they had to take the second
tablet within 12 hours, and we changed the term "birth contraception"
to "birth control."
That
was the label then that was employed in the actual use study and was used in
the actual use study. The actual use
study was intended to demonstrate whether or not, to find out whether women
could self-select. Could they determine
that they had a need and then identify that they needed the product, go get it,
and then use it correctly?
We
did this study at five Planned Parenthood affiliates and five pharmacies. The pharmacies were all in Washington State. That's because Washington State has a
pharmacy access program. So it was
feasible to do it there. Other states
were not feasible.
The
way it worked was women came in, and they said, "I need emergency
contraception," and they were then told that there was a study going on
and did they want to participate. If
they said they did, they were handed the package closed and sealed with the
drug facts panel on the back. They were
then asked to review that and decide whether or not Plan B was right for them.
If
they decided that it was, they then signed an informed consent, and they
received the product and a data card and were followed up in one and four
weeks.
You
can see here the demographics. This is
the actual use study. This is the label
comprehension study. This is all U.S.
women 14 to 44, and what you see here is that we have a large sampling of women
17 to 25, which is the population we would expect being most likely to use Plan
B, and clearly a nice number of young women, and then a distribution
throughout. And obviously all of the
ethnic groups in the United States are presented, well, not all, but most.
The
way it worked, there were 665 patients screened; 585 were enrolled and 80 were
not. They decided not to
participate. Forty-two were completely
lost to follow-up. We have no data. Five hundred and forty-three provided
data. Three of these women did not take
the Plan B. So their information is not
included because obviously if they didn't take it, we don't have times of pill
taking and stuff.
There
were 540, therefore, that supplied us data.
Of those, 506 supplied us all three times, the time of sex, the time of
the first pill, and the time of the second pill. Five hundred and twenty-three gave us the
first and the second pill, and 509 gave us the time between the sex act and the
first pill.
So
we looked at contraindications. The
three contraindications for use are: are
you already pregnant? Again, as Dr.
Dickerson said, there's no data to suggest that Plan B has any teratogenicity
or will have any kind of a negative impact on the pregnancy, but clearly once
you're pregnant, you're pregnant. We
can't prevent the pregnancy, and so there's no reason to take it.
The
contraindication clearly of allergy to any of the ingredients, and finally the
unusual vaginal bleeding which will no longer be a contraindication.
Ninety-nine
percent of the women who took the product took it without any
contraindications. There were only seven
women out of the 540 who had a contraindication. One woman was pregnant, and there were six
who had unexplained vaginal bleeding, again, no longer a contraindication.
So
the vast, vast majority, almost all of the women were able to take it without a
contraindication and understood the contraindications.
Could
they take it correctly? If you look
here, the first pill less than 72 hours after the sex act, 98 percent of the
women took the first pill within the 72 hours after the act of unprotected sex. The second pill, the criteria for correct was
exactly 12 hours. There was really no
latitude, and so 74 percent of the women were able to take the second pill at
exactly 12 hours.
To
take both pills correctly were 72 percent.
So almost all of the women were able to take the product correctly, and
one of the things I think is important to note is that this is the same dose
and the same regimen as the prescription drug product. And so you can presume that if the
distribution in timing that the women take the doses of these pills is similar
or the same as the WHO study which supported the safety and efficacy of the
product, you can anticipate that the efficacy and the safety will be the same
or be similar.
And
so we looked at the data in the actual use study for each pill and compared it
to the WHO study, the distribution, and you can see less than 24 hours, 25 to
48 hours, 49 to 72 hours, and greater than 72 hours. The distribution, percent of women taking it
in each of those time frames -- and this is the first pill -- is very, very
similar to the WHO study.
The
same holds for the time between the first and second pill, less than 12 hours,
12 hours, 12 to 16, and greater than 16.
Again, the distribution is very similar between the two trials.
So
we can anticipate that the efficacy and the safety profile should be the same
as that that was described and ultimately approved in the pivotal trials that
supported the NDA.
With
regard to pregnancy, there were ten pregnancies in the trial. That gave us a pregnancy rate of about 1.9
percent. If you remember, the WHO study
had a pregnancy rate of just over one percent, very similar. Of the ten pregnancies, four ended in
abortion and six were lost to follow-up.
So,
in conclusion, the study design simulates the OTC environment. Women were able to come in on their own and
identify the need. Subjects were
representative of the OTC setting. We
had a distribution both in age and various ethnic groups. Subjects were able to self-select. They knew they needed the product. They came and they got it. They took it home, and they were able to use
it correctly.
The
results are similar to the WHO pivotal study, and thus, Plan B should be as
safe and as effective in the OTC setting as it is in the prescription setting.
With
that I'm going to turn the podium over to Dr. Grimes to discuss with you the
health consequences of over-the-counter levonorgestrel. Dr. Grimes is Vice President of Biomedical
Affairs at Family Health International.
He is clinical professor at the Department of Obstetrics and Gynecology
at the University of North Carolina School of Medicine, and he is one of the
few OB-GYNs in the country who are double Boarded in preventive medicine and in
OB-GYN.
So
with that I'll turn the podium over to him.
DR.
GRIMES: Thank you, and good morning.
I
begin with a most important message first, and that is that easy access to
emergency contraception improves the health and lives of women. It does this through preventing unintended
pregnancy with its serious consequences.
For
many women the news of a pregnancy is a wonderful gift. Such women readily and happily accept the
discomforts, inconvenience, expense, and risks involved with childbearing. Not so for women with an unplanned and
unwanted pregnancy. What are the medical
consequences for them?
The
traditional way in which we assess the safety of childbearing around the world
is the maternal mortality rate. Despite
impressive progress in recent decades, childbearing remains risky business in
the United States of America.
These
are the most recent data from the Centers for Disease Control and Prevention in
Atlanta. As of 1999, the reported
maternal mortality rate was 13 maternal deaths per 100,000 live births. If one corrects this for under reporting of
such deaths, the true figure is closer to 20 deaths per 100,000 live births.
What
this means is that during the past decade over 4,000 American women have died
from pregnancy and child bearing.
But
the real human suffering is not in deaths but in morbidity, complications of
pregnancy, and childbearing today remains a very complex process. Again, the most recent data from the CDC in
Atlanta are on the screen. Forty-three
percent of all U.S. women have one or more complications during the
hospitalization at which they deliver, such as hemorrhage, infection,
obstetrical tears. Indeed, one in four
American women are hospitalized at least once during the pregnancy but before
delivery for complications of the pregnancy, such as threatened labor,
preeclampsia, urinary tract infection.
Now,
if you multiply these percents times the millions of pregnancies every year in
the U.S., you can see how huge is this burden of suffering, and many of these
complications are severe and long lasting.
Now,
in medicine we oftentimes have to make difficult decisions between competing
risks and benefits. Not so here, not
so. Seldom in medicine do we see the
scale so forcibly tipped and permanently tipped in favor of benefit, but let's
consider yet another dimension of the problem of unintended pregnancy in
America, and that is induced abortion.
Induced
abortion is prima facie evidence of unwontedness, and despite impressive gains
in recent years, we still have far too many abortions in America. As you know, our abortion rates are much
higher than in other industrialized nations.
Nearly a million abortions reported to the CDC each year. Two measures commonly indicate how frequent
is abortion in a population, the abortion ratio and the abortion rate.
The
ratio is the number of abortions per 1,000 live births. The rate is number of abortions per 1,000
women of reproductive age, and again, the most recent data from the CDC
indicate that for every four live births in America there is one induced
abortion, and indeed, two percent, one in 50 American women of reproductive age
have an abortion every year.
And
here emergency contraception over the counter has an extraordinary role to play
by reducing the need for induced abortion, and that's a goal around which there
should be broad consensus in America, and this is already happening.
According
to the most recent data from the Alan Guttmacher Institute, in the year 2000,
despite limited use of emergency contraception, it has averted over 50,000
abortions that would have taken place without its use.
Think
what we can do together with easier, wider access to this safe product.
An
old concern about emergency contraception and easy access to it was that this
would in some way sabotage or undermine ongoing traditional contraception. I heard this discussed just an hour ago on
CNN.
There
are studies around the world refuting this.
It doesn't happen. Moreover, a
study done by the World Health Organization looking at frequent repeat use of
the product indicated that it would disrupt normal menstrual cycling, which
itself would deter women from using it in this fashion.
As
you've heard from the prior two speakers, over-the-counter levonorgestrel
easily fulfills the three criteria outlined in the Durham-Humphrey Drug
Amendment Act of 1951. There are no
outstanding medical issues.
Speaking
as a gynecologist, my patients have told me that one of the most important
benefits to them, difficult to measure, is peace of mind. Unprotected intercourse can cause terrible
anguish that may list for weeks to months occasioned by unplanned sex, forced
sex or a contraceptive mishap, such as forgotten pills or a torn condom.
I
would remind all of us here today that this discussion is ultimately not about
a steroid molecule. It is about women,
women at a time of acute and often terrible crisis in their lives. Emergency contraception can help by reducing
unintended pregnancies, induced abortions, and medical suffering.
In
conclusion, today the FDA has an extraordinary opportunity to advance women's
health in America by removing needless gratuitous obstacles that stand between
women and safe medicine. I would ask you
to consider the alternative.
If
we allow these obstacles to stand, if access remains limited, we will be
indirectly causing unintended pregnancies, induced abortions, and needless
human suffering. The public health and
the medical evidence is clear and incontrovertible. The choice before us today should be equally
clear. Over-the-counter emergency
contraception is good medicine. It is
scientific medicine. It is compassionate
medicine, and it is medicine that women deserve.
Thank
you.
DR.
BEN-MAIMON: Thank you, Dr. Grimes.
I'm
going to try and put some background or some sort of meat on the bones and talk
a little bit about what we're seeing happening in the United States with regard
to pregnancy rates, teenage pregnancy, and abortion, and then go into some of
the issues surrounding emergency contraception.
You
can see here the white line is the U.S., women 15 to 44, and the pregnancy rate
since 1990, and you can see that the line is decreasing, but somewhat stable.
What's
really interesting is the pink line, which are women 15 to 19, which is
decreasing disproportionately to the rest of the population. The same thing occurs when you look at abortion
rates since 1990. You see the line here
where abortions that were decreasing now seem to be somewhat stable, but look
at the pink line in women 15 to 19, which is going down. This obviously we would all agree is a very
good thing and a trend we'd like to see continue.
Here
are the percentages of women using various contraceptives in contracepting
women. These are 15 to 19 year
olds. These are 20 to 24 year olds, and
what you see here is that since 1982 the trend in OC use has been going down, but
there has been a corresponding trend increasing in condom use.
Here
in 20 to 24 year olds it tends to be more flat, but again, the increased use of
condoms is demonstrated in these women, and clearly, this is probably a result
of the better understanding and the greater awareness of sexually transmitted
infections and the need to use a barrier method in order to prevent the
transmission of those infections.
What's
interesting here when you look at contracepting women 15 to 19, 20 to 24, 25 to
34, and then 35 to 44 is that young women tend to prefer reversible forms of
birth control, such as oral contraceptives and condoms, whereas older women
tend to prefer sterilization and more permanent forms of birth control, not
something that's terribly unexpected, but clearly an interesting piece of
information.
Again,
unplanned pregnancies are a major health problem in this country as you've
heard from both speakers and the FDA.
Education and awareness programs seem to be working, but clearly, we
need to do more in order to decrease the incidence of unintended pregnancies
and abortion even further.
Despite
these programs, there are over three million unintended pregnancies a year,
half of them ending in abortion. Again,
50 percent of these unintended pregnancies could be prevented by greater use of
emergency contraception.
It's
very important to remember that of women who present for abortion, only 1.3
percent of those women have used emergency contraception, and as Dr. Grimes
said, this is really the ultimate in unwanted pregnancy. They choose to abort the baby, and so
clearly, if only 1.3 percent of them are using emergency contraception, we have
a long way to go in increasing access and availability and awareness, and we
believe awareness of and access to emergency contraception needs to be enhanced
in order to impact this major health care problem that we're facing.
We
believe that Plan B is safe and effective for over-the-counter use, and we
believe the data supports that. Although
pharmacy access programs may increase availability, they create new barriers
that need to be dealt with by women who seek them.
And
so I'd like to spend a couple of minutes talking about pharmacy access and what
is going on with regard to prescriptions in this country for Plan B, and then
I'm going to talk a little bit about our CARE Program, which we hope will help
to increase awareness and availability,
and it's clearly designed to do so.
This
is the prescription data from the United States. It's Plan B, and it's retail pharmacies only,
and what it shows is at this point there are about 20,000 prescriptions a month
for Plan B.
This
is California, which is the pharmacy access state. What's important here is that the legislation
was actually implemented in January 2002, and you can see that with the
implementation of that program, there was an increase in the script writing for
Plan B.
This
is Washington State, which is flatter, still increasing, but flatter, and their
program started in 1997, and so access has been around for quite a bit longer.
There
are five pharmacy access states:
Washington, California, Alaska, New Mexico, and Hawaii. These are newer so I won't be discussing
those, because those states are actually too new to identify what is really
happening, but I'm going to talk a little bit about Washington and California.
It's
important to note that the legislation in Washington actually provided for
pharmacy access, and pharmacy access means access to Plan B without a
prescription through a pharmacist. So
the pharmacist has to write a protocol, file it with the State Board of
Pharmacy, and then they can participate in the pharmacy access programs, and
there are certain educational requirements as well.
What
you see in Washington State -- and this
is the time line -- is that there are about 2,000 scripts a month up from 1,000
over maybe three years ago, but what I think is really important to note is
that in a state where there has been pharmacy access for emergency
contraception since 1997, there are only 26 percent of pharmacies participate,
and only 23 percent of pharmacists. It
takes initiative to participate in these trials. The pharmacists have to be trained. They have to apply. They have to want to participate, and so it's
not just so straightforward that women can walk in and obtain emergency
contraception.
California. One of the things I think that has increased
use of Plan B in California is the fact that they had a huge media
campaign. They had a huge campaign to
try and increase awareness of the product, and they targeted about ten million
consumers and health care professionals.
Over 900,000 women were with print material; a million women and men
through paid advertising; 70,000 health care providers through print material;
and approximately eight million people through free media.
What
did this result in? Again, the
legislation went into effect in 2002, January.
So it is essentially two years.
Only 14 percent pharmacies and pharmacists participate.
So,
again, in a state as large as California, finding emergency contraception
without a prescription is still a significant challenge.
What
does that mean for the United States?
Well, we've got five states.
There's 45 left to go. More than
200,000 pharmacists are throughout the
United States, 53,000 pharmacies. The
pharmacists have to be recruited for pharmacy access, and so this in and of
itself is a huge challenge and really limits the ability of pharmacy access to
act as the mechanism to increase availability.
Let's
look at barriers again. Clearly, here
there's the barrier of getting the pharmacists and the states to participate,
but let's say we can do that. There's
another barrier, and that is that these programs require protocols. Women have to walk into a pharmacy, talk to
the pharmacist, answer questions, and qualify for pharmacy access and for
emergency contraception.
Many
of you can put yourself in the position of a woman, and I don't know if your
pharmacies are like my pharmacies, but there really aren't any areas where I
could hold a private conversation with my pharmacist and answer these types of
questions in a way that would be comfortable for me.
And
so clearly, the need to consult with the pharmacist, at least be interviewed by
the pharmacist, not and ask questions, but be interviewed and meet certain
criteria, could act as a significant barrier for women to seek emergency
contraception through pharmacy access.
So
again, although Plan B is safe and effective, access and availability are still
too limited to have the kind of effect that we believe it can on the incidence
and rates of unintended pregnancy.
And
with that I'll switch a little bit to the CARE Program. The CARE Program is designed to provide and
encourage awareness and increase awareness of women that emergency
contraception exist; that they can get it; how they should use it; and in what
context it fits in overall reproductive health management.
And
it is also intended to increase availability so that when they do need it, they
can seek it and they can find it and they can get it. I'm going to take a minute and hand out these
packages. You can pass them around.
These
packages are the actual packages that we're proposing and are part of the
supplemental NDA. You can see that
there's an outer package. Feel free to
open them. There's an outer package, and
in it is a smaller package that opens up and actually has the directions for
use. The outer package has the drug
facts section on the back, and that's what the women would see when they went
into the pharmacy.
Included
in the package would be information on routine forms of contraception, as well
as sexually transmitted infections.
There would also be reference to a hotline which I'm going to talk about
in a minute and a Web site, and there's also a data card which I'll talk about
in a couple of minutes as well.
But
feel free to open them, look at them, and pass them around.
The
need for accessible emergency contraception is great, but clearly, awareness is
low and availability is limited. The
program is designed to increase awareness through education. Programs will be comprehensive in nature, and
what we mean by that is we will include information on what we call Plan
A: abstinence, family planning, and
routine forms of birth control.
The
name Plan B was not just a marketing tool.
The name Plan B was chosen in order to communicate to women that this is
Plan B. Plan A is abstinence, family
planning, and routine forms of birth control.
Those are the preferred mechanisms to prevent pregnancy.
But
when Plan A fails, Plan B is available.
The target audience will be consumers, physicians, physicians'
assistants, nurse practitioners and
pharmacists.
The
second part is distribution and availability, and I'm going to talk about that
a little later, but the intent of OTC distribution is to minimize delay so that
we can maximize the earlier use of the product and lower the barriers in order
to maximize appropriate use and, finally, to insure availability.
Again,
the communication objectives. Plan A is
abstinence, family planning and routine forms of birth control, and I can't
reiterate enough how committed we are to helping to support that message.
Plan
B is used when a woman has concerns that Plan A hasn't worked for whatever
reason. Plan B is not a replacement for
routine forms of birth control. Plan B
does not treat or prevent sexually transmitted diseases, and follow-up with a
health care practitioner is strongly recommended.
What
is the problem with regard to awareness and education? Only 43 percent of women know that EC is
available in the United States. Only six
percent have used it, and one of the most important statistics that we have
here today is that only 1.3 percent of women who present for induced abortion
have used emergency contraception.
What
we're intending to do with our program is try and utilize all of the tools that
we have available to us. Barr has a
sales force of about 250 representatives that visit approximately 30,000
physicians throughout the country. We
intend to distribute informational brochures to those physicians through our
sales force so that women while sitting in a waiting room or waiting in an exam
room can read about emergency contraception, understand what's going on, and
talk to their doctors or their nurse practitioner if they have any questions
before this happens.
Again,
these materials will also hopefully stimulate discussions with regard to
routine forms of birth control and family planning issues.
Educational
brochures will also be available at the point of purchase, will be providing
display units that can be put out at pharmacies. There will be no trial offers, coupons or
samples.
We
will have print and radio ads which will include and be mostly designed as
public service announcements and informational materials that talk about
diagnosis, need, and responsible use.
And so the program is really targeted at increasing awareness, making
women understand how and where to get emergency contraception and how and when
to use it.
This
is the label. You have it in front of
you so I'm just going to flip through it in an effort to save some time.
There
is a card in the package, and women will be able to record the time of the
first dose and then calculate the time of the second dose, and of course, it
encourages them to take it as soon as possible.
It
also refers them to our hotline, as well as to the Web site.
The
toll free number will be staffed by a health care professional 24 hours a day
seven days a week. So when women need
and choose to use emergency contraception, they will be able to call if they
need help or if they have questions in order to get additional information.
There
will also be a Web site with links for health care practitioners, and we will
encourage women if they have any further questions to follow up with their
health care practitioner.
From
the standpoint of professional education, and I think this is also important
because clearly OB-GYNs understand about emergency contraception, but there are
many doctors out there who are not as knowledgeable and so we will be
advertising in professional journals. We
will provide continuing education at medical meetings and in relevant settings. We will work with pharmacists through our
national account managers, pharmacy journals, and again provide continuing
education through state boards of pharmacies at their annual meetings, as well
as major pharmacy meetings.
The
problem of distribution. Again, this is
really a two-part issue. It's awareness
and education, but it's also distribution and availability and access. Only 35 percent of pharmacies in Pennsylvania
were able to get Plan B or emergency contraception within 24 hours.
In
Albuquerque, New Mexico, which is a pharmacy access state, 89 percent of
pharmacies did not have Plan B, and 53 percent of them could not access it
within 24 hours. Clearly, the clock is
ticking.
Again,
although the need is great, availability is still very limited. We are proposing to sell to wholesalers, clinics,
or retain chains and stores with valid pharmacy licenses or valid wholesale
licenses.
Again,
we will be supplying display units for pharmacies to put out with informational
materials. We will continue to provide
Plan B at a discount to clinics so that all women can have access to it, and
again, I'm sure you remember from the briefing package we committed to
recommending that Plan B be kept either behind the counter or in view of the
pharmacies.
We
are very comfortable that Plan B is safe and effective for over-the-counter
use. We are very comfortable that it
could be sold completely over the counter, but we recognize that there are
issues surrounding this product and
concerns that need to be addressed, and so we're very anxious to hear what the
committee thinks with regard to the placement of these products in pharmacies,
and of course, if it's recommended that we recommend keeping it behind the
counter, we will take that into consideration and discuss that with the agency.
CARE
is intended to encourage appropriate use of Plan B through professional and
consumer education. It's intended to
insure awareness that Plan B is conveniently available and to teach women when
and how to get it. It's intended to
reinforce that it is safe and effective with appropriate packaging and
labeling, which you see in front of you.
And finally, we will have monitoring programs to see whether or not the
program is working and what modifications need to be made. As we go through time the needs may change,
and clearly, we will be working on that as we go.
Unplanned
pregnancies are a major health care problem in the United States. Over three million unintended pregnancies
occur each year. With typical use, women
using condoms, 15 percent of them will become pregnant each year, and eight
percent of women using oral contraceptives will become pregnant.
There
are approximately 800,000 unintended pregnancies in teenagers. In 2002, 215,000 women in the United States
were the victims of rape or sexual assault.
Half of the unintended pregnancies result in abortion, and again, it's
estimated that up to 50 percent of these unintended pregnancies could be
prevented with the use of emergency contraception.
Plan
B will insure that for those who need EC, there will be convenient availability
and responsible education. Making this
product available over the counter will decrease the barriers and increase
access, hopefully resulting in a reduction of the number of unintended
pregnancies.
Plan
B has a demonstrated safety profile and is suitable for over-the-counter
use. Early use is absolutely critical to
maximizing effect. The prescription
requirement presents barriers that delay the chance for early use of emergency
contraception. Plan B meets an unmet
medical need, and the Plan B CARE Program insures responsible and appropriate
education and distribution.
Plan
B for OTC use, along with the CARE Program, will provide important benefits to
the consumer. It will enhance
availability and minimize delay while maximizing efficacy, and ultimately it
will reduce the number of unintended pregnancies, a major health care problem
in this country.
With
that, thank you very much.
CHAIRMAN
CANTILENA: Okay. Thank you.
We
now have time for questions from the committee to the sponsor, and I would ask
the committee members to signal me so they can be called on. We will not allow cross-talk, and we would
ask also that your questions at this point be focused and specific in terms of
exactly, you know, the sponsor, you should not be asking any questions of the
FDA because you'll have an opportunity to do that later this morning.
So
questions from the committee. Dr.
Benowitz.
DR.
BENOWITZ: I have a couple of
pharmacologic questions. The first one
is the way this drug is supposed to be given is one dose based at 12 hours. The drug has got a long half-life. There certainly are reasons to think that 12
hours is not important.
One
question is whether even having two doses is important, and the second one --
and I know it's not part of this proposal -- but in reading the background
material it seemed striking that 1.5 milligrams in a single dose was just as
effective and no more toxic and certainly easier to comply with.
And
so one question is about the dosing issues, and then I've also got a second
question.
DR.
BEN-MAIMON: The variations in dose have
been studies in other parts of the world, and WHO has actually done some
studies looking at single one and a half milligram doses. The issue really is that what's approved
today is one dose within 72 hours followed by a second dose 12 hours later.
The
safety and efficacy of that product is well documented, and so what we're
seeking today is to move the prescription to OTC for that regimen, recognizing
that maybe in the future there would be a reason to develop alternate dosing
regimens.
DR.
BENOWITZ: And what about the first
part? What if someone doesn't take a
second dose? Will it still work?
DR.
BEN-MAIMON: Well, there is not a lot of
data on 1.75 milligram dose, but clearly women do take the second dose. I mean, the actual use study demonstrates
that, and there's a failure rate for all of these products.
I
mean, this is not a foolproof method to prevent pregnancy. It prevents most or a lot of the pregnancies,
but it doesn't prevent all pregnancies.
DR.
BENOWITZ: Okay, and then a second
question. The efficacy data that you
showed were quite striking in that taken within 24 hours, the pregnancy rate
was .4 percent. On the third day it was
2.7 percent.
The labeling really doesn't make that
point very well. It says take as soon as
possible, but it clearly doesn't tell a woman that you could have a six or
sevenfold difference in efficacy rate if you take it within 24 hours versus 72
hours, and why have you not really emphasized the importance of 24 hours?
DR.
BEN-MAIMON: Well, I think we have
emphasized the importance of taking it as soon as possible. You can see from what's happening here it's
not possible all the time even to get it within 24 hours, and so as soon as
possible is, I think, as much as we can say.
In
addition, we don't want to discourage women that after the first 24 hours have
passed, you know, you might as well give up because it is clearly
effective. As you get out even past 72
hours, there's some data to support, as Dr. Dickerson said, there's some data
to support that it may be effective out as long as five days.
But
clearly, we want women to take it as soon as possible, but we also want them to
take it at 24 to 48 and 48 to 72 hours, as well, and not just throw up their
hands and give up.
CHAIRMAN
CANTILENA: Okay. Thank you.
Over
here, Dr. Macones and then Dr. Hewitt.
DR.
MACONES: You mentioned about some post
marketing information on rates of ectopic pregnancy. I was wondering if you'd just expand on that
a little bit more because the numbers are fairly small even from the clinical
trials that you've done.
DR.
BEN-MAIMON: Okay. Can I have Slide ‑- yeah.
What
you see here are the exposure numbers throughout the world. There are over six million women who have
been exposed to Plan B throughout the world.
Total pregnancies reported are 340, but again, pregnancies are not
likely -- remember this is pharamacovigilance data. This is not data from clinical trials. So women are not reporting every normal
pregnancy clearly.
There
have only been 21 ectopic pregnancies, and when you do the calculation based on
the number of uses, the expected number of pregnancies, you would expect to
have with a two percent risk 585. So
there is significantly fewer reported ectopic pregnancies.
Again,
we recognize, again, these are pharmacovigilance data. So they have their limitations, but you get
similar numbers when you look at the clinical trials, and although the clinical
trials are small, you still have over 7,000 women in 133 pregnancies. So they're not negligible, and those are
clearly pregnancies that were followed up.
So
I think if you combine this data alongside the data that was presented from the
clinical trials, there really is no reason to expect an increase. There is no data to suggest that there's an
increased incidence of ectopic pregnancy.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Hewitt. and then Dr. Wood.
DR.
HEWITT: Yes, I have a couple
questions. The first one is about when
patients call in on the hotline or attend the Web site and how their questions
will be answered. The first question has
to do with multiple acts of intercourse and taking multiple doses of emergency
contraception.
I'm
thinking specifically if a patient has missed a couple of birth control pills
in a pill pack and has not had contraception for an extended period of
time. How will she be counseled when she
calls in over the phone?
And
then secondly, when she calls in with questions about dosing intervals, will
they be giving any information on options with dosing of the two emergency
contraceptive pills in terms of the 12-hour window? Will they be given options of taking both
pills at once?
How
will they be counseled with those phone calls?
I know when I counsel patients I tell them, you know, you don't need to
set an alarm clock for 3:00 a.m. to get up and take your second dose, but how
will those kind of questions be answered?
And
then my second question has to do with communicating this information to and
supporting team use. I know that
literacy studies were not done on women less than 18. Do we have any information besides what you
gave about how they answered the questions to the 11 points you were trying to
convey?
Will
any of the materials be sort of teen friendly or be developed specifically to
reach younger women?
DR.
BEN-MAIMON: Your first question about
counseling, and if I don't answer it all, please feel free to come back because
I may have missed some of it.
We
will have trained professionals, first of all, health care professionals,
women, you know, with nursing degrees or pharmacy degrees staffing the
phones. Those people will be have a
script, and they will counsel women on the different -- we'll have all the
different scenarios laid out, and they will counsel women based on a script
that will be designed with physicians in order to tell women what to do.
I
think if women have missed three or more birth control pills, they would be
instructed to take Plan B and to use a
routine form of birth control at least for the first week, depending upon where
they were in their cycle and what the labeling says for oral contraceptives.
And
of course, if there's any concerns, it would be recommended that they follow up
with a health care practitioners.
But
those scripts would be designed with physicians and would be provided and these
people would be trained in order to deal with those types of questions.
With
regard to teens, we all want our teenagers to refrain from sexual activity
prematurely. I don't think any of us
want our teenagers to be sexually active before they are comfortable and should
be. And clearly we will be reinforcing
the messages of abstinence and all of that, but it is clear that there are
800,000 pregnancies in teenagers every year, and so we really do have to deal
with that issue.
The
label comprehension study, as you saw, had women in it from 12 to 50, and there
were actually a significant number of teenagers 12 to 16 years of age in that
study, and I think we presented the objectives, and we can put that graph up
again. It is number 24, please.
And
you can see here that these are the objectives.
The 12 to 16 year olds scored actually quite well for the vast majority
of the objectives, and so the materials seem to be pretty appropriate for them,
and they do seem to understand and be able to comprehend.
DR.
HEWITT: And what about my middle
question about the dosing interval? You
know, if a patient literally says -- you know, I mean, are they going to be
explained any leeway on dosing the second interval, or do you anticipate the
scripted response will be 12 hours, period?
Are you able to answer that question at this point?
DR.
BEN-MAIMON: Yeah, I think it would be 12
hours. I think that's what the labeling
says. That's what the data
suggests. This is a product that will be
taken once. So we're not talking about
having to wake up in the middle of the night for, you know, the next week and a
half or six weeks.
I
think for one time we would recommend that people take it at 12 hours, and that
the 12 hours, if it occurs in the middle of the night, they get up and they
take their dose.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Wood.
DR.
WOOD: Yeah, I have two questions that
relate, I guess, to access. The first
one relates to the paper that's Tab 8 in our briefing book from Anna Glasier
and David Baird that was published in the New England Journal, and they
encouraged the patients or, in fact, they provided patients with the equivalent
of Plan B to keep in their bathroom cabinet, and that seems to me the obvious
way to go. I mean, there's not much
point in telling people to buy a fire extinguisher once the fire starts
burning. You tell them to get a fire
extinguisher and keep it in their kitchen.
And
similarly, we've had a lot of medical experience now with defibrillators that
the effects of defibrillators are much more effective if they're on site and
readily available for use.
So
my first question relates to that. Are
you going to encourage in the promotion material that people obtain the Plan B
and have it available in their bathroom cabinets and for use in the case of an
emergency, and if not, why not?
DR.
BEN-MAIMON: Well, I think that there is
no question that the data suggests that women who have emergency contraception
use it more frequently.
There's
also no data to suggest that women who have emergency contraception have more
unprotected sex. It's just that when
they have unprotected sex, they use the product because it's available to them.
And
so the materials, I think, will be designed to make sure that women are aware
of how to access and how to get emergency contraception. I don't think we've contemplated having
specific statements in there that say, you know, "Make sure you have one
of these at home."
Again,
there's situations of expiration dating and other things that have to be taken
into consideration, but of course, we can consider that.
DR.
WOOD: My second question related to your
comment near the end of your presentation about making it behind the
counter. That seemed to me totally
counterintuitive, and that seemed to me to raise all of the access issues that
you quite eloquently addressed earlier.
So
it would seem to me that that would totally obviate the benefits of making Plan
B over the counter, and I can't imagine how that would be advantageous.
DR.
BEN-MAIMON: We appreciate your comments,
and that's one of the reasons we raised it, because we think there are opinions
both ways, but we are concerned about putting it behind the counter simply
because of the issue of barriers, and that's why we're interested in hearing
what the panel thought about that.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Trussell and then Dr. Montgomery Rice.
DR.
TRUSSELL: I want to follow up on Dr.
Wood's question.
In
the pharmacies in my hometown now, condoms, spermacides, KY jelly are all
locked in cabinets that can be opened only by the pharmacist, and when I've
asked repeatedly why they do this, it's because they were being stolen blind.
(Laughter.)
DR.
TRUSSELL: So my question is in your
conversation with the pharmacy chains, do you have an indication that this
product is going to also be locked in that cabinet? Because my pharmacists are certainly going to
lock it in their cabinet.
DR.
BEN-MAIMON: Well, what we are proposing,
there's a thing called a Planigram, which is the pharmacies lay out where they
have all of these products, and you know, they figure out where they're going
to place them.
Our
recommendation to the pharmacists will be that it be placed in the female
health care sections along with pregnancy kits and things like that, which are
not locked behind cabinets.
DR.
TRUSSELL: In my pharmacies, they are
locked behind cabinet.
DR.
BEN-MAIMON: Oh, I don't know where you
live, Dr. Trussell.
CHAIRMAN
CANTILENA: Okay. Thank you, Dr. Trussell.
(Laughter.)
CHAIRMAN
CANTILENA: You should consider moving to
another neighborhood.
(Laughter.)
CHAIRMAN
CANTILENA: Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: I thought in the
literature that I read that you were removing the vaginal bleeding from
contraindication to warning, but when I looked at the package on the back you
do not have vaginal bleeding in the warning section. You actually have it under the side effects,
which if I was a lay person I would think that that means I was going to have
vaginal bleeding after unintended -- unintended vaginal bleeding after taking
the medication.
I
think that should be clarified because it wasn't clear to me.
DR.
BEN-MAIMON: I may be mistaken. I thought it was in both, but it's
conceivable that I'm mistaken.
DR.
MONTGOMERY RICE: I don't see it on the
back.
DR.
BEN-MAIMON: Okay. Well, we'll check.
DR.
MONTGOMERY RICE: And I think that needs
to be clarified.
The
other thing that I'm concerned about is that you roll out this wonderful
program called the CARE Program and you say you're not going to give out any
coupons, samples, or rebates, and so I'm concerned about the lower
socioeconomic patient who really requires this medication and the reason the
patient may not be taking a reliable contraceptive is because she can't afford
oral contraceptive pills.
So
I'm wondering what's the reasoning for not having some type of assistance
program with obtaining the medication.
DR.
BEN-MAIMON: I would like to make a
distinction between coupon samples and an assistance program. An assistance program I don't think is
something that we've considered. I think
we would consider it.
We
will be continuing to supply it to clinics at a discount. So it will continue to be available at
clinics for women who source it there and who are used to using clinics as
access for their medical care.
But
I don't want to imply that samples and coupons are related to an assistance
program, and that's not something that we've considered, but we would be
willing to.
CHAIRMAN
CANTILENA: Okay. Thank you.
Thank you.
We
actually are out of time. So what I'd
like to do is ask you to hold your questions until this afternoon. We will have the opportunity to ask questions
of the sponsor after lunch as well.
And
what we'd like to do now is to pause for 15 minutes. We'll take a 15-minute break, and we'll come
back with the FDA.
Thank
you.
(Whereupon, the foregoing matter
went off the record at 9:50 a.m. and went back on the record at 10:09 a.m.)
CHAIRMAN
CANTILENA: It's now time for the FDA
presentations, and our first speaker for the FDA will be Dr. Davis.
Dr.
Davis.
DR.
DAVIS: Thank you.
Good
morning. My name is Dan Davis, and I'm a
medical officer in the Division of Reproductive and Urologic Drugs.
I
did the primary clinical review for efficacy and safety for the original Plan B
submission and have followed the sponsor's periodic safety reports and the
medical literature on emergency contraception since the approval of Plan B as a
prescription drug in July of '99. My
responsibility for the current Plan B submission is to evaluate any safety
concerns relative to the requested change to a nonprescription status.
The
topics to be presented are in the following order: the points to consider for the switch from
prescription to nonprescription status; marketing data on U.S. and global use,
as well as distribution patterns and availability of levonorgestrel for
emergency contraception, which I will often refer to simply as EC throughout my
talk; the sponsor's safety data from both the original submission and the
subsequent post marketing data; findings from the current FDA safety review;
the potential for misuse and abuse; contraindications; and I will close with a
summary of the FDA safety conclusions for levonorgestrel.
Occasionally
I may mention the term "postcoital contraception," which is a more
routine primary method of contraception for women used, taken after
intercourse. The topic today is really
emergency contraception, which is single use, but a lot of our data for safety
comes from original studies dealing with postcoital contraception.
The
prescriptions to nonprescription, which has already been carefully discussed by
Dr. Rosebraugh and the sponsor, I will concentrate on the first two items here,
namely, an acceptable margin of safety and the potential for misuse and abuse.
Dr.
Chen will discuss whether the product was safe during the actual use study, and
finally, the committee members here will be asked to discuss the benefits
relative to risk after all of our morning speakers have presented.
The
sponsor's exposure data comes from many different sources, but first of all, I
want to just remind people that Plan B is levonorgestrel 0.75 milligrams taken
times two doses. The sponsor estimates
the U.S. exposure at 2.4 million uses since the approval of Plan B in
1999. Worldwide, emergency contraception
pills are available in 101 countries.
The
levonorgestrel products in the U.K. and France are identical to Plan B. Exposure is estimated to be at 2.1 million in
the U.K. and 1.8 million in France.
Most
recent 12-month data that's available from Canada shows 72,000 uses in a
one-year period of time.
The
above exposure data clearly shows that levonorgestrel for EC has been used by
several million women in at least four countries in the recent years.
The
distribution patterns show at least four methods of availability. Most common is a routine prescription for EC
as needed. Sixty-eight countries,
including the U.S. have EC availability by prescription.
Advanced
provision of a written prescription or the actual product is becoming more
common and is promoted worldwide by many organizations and clinics. Globally EC is available directly from a
pharmacist in 33 countries, and as discussed earlier, in five states.
Barr
has already covered the availability in the U.S. The largest and longest program is obviously
from the State of Washington. The
California pilot program started in the year 2000, and by January of 2002, the
California legislature passed a law allowing a statewide effort as outlined.
The
other three states are Alaska, New Mexico and Hawaii.
The
fourth method availability is that EC pills are truly available over the
counter in Sweden and Norway. Clinical
trial data are considered to be the gold standard for safety data because
trials are often use strict protocols, control arms, added visits, more safety
monitoring, and good data collection.
The
original Plan B submission contains safety data from several clinical
sources. The pivotal blinded and
comparative World Health Organization Trial included 1,955 women. The primary data sets were submitted with the
NDA application and reviewed by our reproductive division, basically by myself,
and for both safety and efficacy.
Levonorgestrel
alone in that study was compared to the m ore traditional Yuzpe regimen, which
is a combination of levonorgestrel and an estrogen.
From
three ongoing World Health Organization trials, plus some introductory trials
of prescription levonorgestrel in three European countries for use as EC, and
the pivotal WHO large trial, no serious events commonly called SAEs had been
reported by the approval date for Plan B.
From
the literature review, more than 15,000 women from 29 countries in clinical
trials using various doses of levonorgestrel for either EC or postcoital
contraception had been studied. The data
showed that levonorgestrel taken for contraception after intercourse was well
tolerated.
This
data from the extensive review did not uncover any deaths, cardiovascular
problems, thromboembolic events, or serious adverse events. Those adverse events that were reported were
consistent across all studies and reflected the AEs that are listed in the
current Plan B label.
In
summary, the FDA review of the sponsor's clinical trial safety data did not
find any safety signals of concern.
We
next rely on post marketing data which has been obtained since the approval of
Plan B. In contrast to clinical trial
data, it is important to note the limitations of post marketing data. They're outlined here.
The
use or exposure data is often estimated.
The likelihood of reporting adverse events may be greater or lesser,
depending on the nature of the event.
Third,
we know that there's considerable under reporting of adverse events.
And
fourth, many of the post marketing AE reports lack complete clinical information.
There
are many different post marketing sources of safety data, but overlapping of
the reports often makes it difficult to interpret the data. The sponsor provided different sources of
post marketing data.
First
were the FDA required periodic safety reports covering from the time of
approval up till January of 2003. This
contained 345 reports. Reported most
often were 123 pregnancies and 64 cases of bleeding. Most of the reported events were mild and
short term. All were labeled events, and
there were no reports of transfusions, SAEs or deaths.
Many
of the reports actually did come from European sources, even though reported to
our periodic safety update to the FDA.
The
global safety databases included national pharmacovigilance agencies in key
European countries and Canada, the World Health Organization Drug Monitoring
Program, reports from the manufacturer of Plan B, and several other databases.
From
these various global databases there were no reported deaths, no strokes or
thromboembolic events. There was one
case reported in France in a 22 year old woman who was hospitalized with
phlebitis, but did not have any further problems.
In
summary, based on all of the safety data from clinical trials involving 15,000
women and from several post marketing data sources worldwide, the sponsor's
conclusion is that Plan B is an appropriate candidate for a switch to a
nonprescription status.
Our
division requested a consultation from the FDA Office of Drug Safety with a
focus on serious adverse events and ectopic pregnancies. The consultation reviewed the FDA adverse
event reporting system, commonly called AERS, A-E-R-S, and data from the
U.K. In the AERS database there were 116
unduplicated cases, and 60 percent of these were for nonserious labeled events,
such as vaginal bleeding, pregnancy, abdominal cramps or pain, and nausea and
vomiting.
Many
of the reports had incomplete information and are, therefore, hard to
interpret.
From
this data set there were no deaths, serious cardiovascular or thromboembolic
events or transfusions reported to AERS from any country. As already noted, we have over four million
uses of levonorgestrel from the U.S. and the U.K. since 1999, and this data is
primarily U.S. and U.K. data.
There
were ten cases of an allergic reaction that were reported. Three were from the United States. Most were minor, although two women did have
some difficulty breathing. Nobody was
hospitalized.
Under
fetal risk, there are eight reports that included five cases of a spontaneous
or inevitable abortion, and three cases with congenital anomalies, all reported
from Europe. This number of cases is
well below what we would anticipate, given the spontaneous abortion rate of ten
to 15 percent of all pregnancies and the congenital anomaly rate of 0.85
percent.
The
other finding on the AERS database was
ectopic pregnancy. There were 28
reported cases. None were from the
United States, and there were no deaths.
Because the incidence of ectopics is dependent entirely on the total
number of reported pregnancies relative to the number of ectopics, we like to
use a database where the number of ectopics and total pregnancies is as
reliable as possible. For this type of
information we look at randomized clinical trials as mentioned earlier.
From
the six large randomized clinical trials involving the 7,889 women, we see that
there were the two ectopics and a total of 135 pregnancies or an incidence of
1.5 percent. As already pointed out by
Barr Pharmaceutical, this is the same incidence as we would expect in the
general population. So it does not raise
an issue that ectopics should be of concern.
This
slide is a little bit busy, but of all of the potential misuse and abuse
problems, we considered overdose, higher doses, repeat use, and use in
pregnancy, and incorrect dosing.
For
overdose, there were no reports in the literature or safety databases of an
overdose. Overdose is also unlikely with
the expected cost of Plan B.
The
second bullet really should be for higher doses, and the best safety data for
exposure to higher or repeated doses comes from European trials in the 1970s
and '80s, in which levonorgestrel was used for regular postcoital
contraception. In these trials
levonorgestrel .75 milligrams was used up to eight times per month or total
doses of 2.25 milligrams within 24 hours were used and repeated as needed, and
a single dose of .4 milligrams taken on average eight to nine times per month
for an average of nine consecutive months were also used.
From
this database, again, we do not see any safety signals with problems with
serious adverse events, deaths, or hospitalizations.
Repeat
use, there are many, many different studies that could be quoted. I elected to talk about the Rowlands study
from the United Kingdom. The database
was over 15,000 medical records of women who did use EC once. The age range was 14 to 29, and these women
were followed for four years.
Rowlands
found that repeat EC use was uncommon per year or over a four-year period of
time. For example, only three percent of
the women, 15,000 women used EC twice in the four-year period of time. One percent used EC three times in the
four-year period, and .8 percent used EC greater than three times over a four-year
period of time.
We
also are aware of this one-year study by Glasier and Baird of 1,000 women in
Scotland, where EC use was used more often with advanced provision, but for the
women using the product more than once in the entire year, 11 percent of the
women with advanced provision used EC more than once, and 13 percent of those
without advanced provision used EC more than once.
Use
during pregnancy shows no clear evidence that inadvertent use of levonorgestrel
during a pregnancy will result in abortion or cause fetal problems.
For
incorrect dosing, in other words, not using the product strictly according to
the label, there are recently published randomized clinical trials that report
on a single dose of 1.5 milligrams levonorgestrel being safe and effective. The second dose can be taken later than the
labeled 12-hour dose, and we do have information on the first dose being
started between 72 and 120 hours.
I'm
not going to discuss these further because that's really not the point of our
meeting today.
Contraindications
from the prescription Plan B label has already been addressed somewhat. The current label for prescription lists
three contraindications based solely on the class label for progestin only oral
contraceptive pills, which are taken daily for routine contraception. The prescription label clearly states that it
is unknown whether these same conditions apply to the Plan B regimen.
Hypersensitivity
to any component of Plan B is certainly a contraindication and should be
listed. It is a rare event, and there
have been no reports of death or hospitalization due to allergy.
Known
or suspected pregnancy is not a contraindication. It is listed primarily because the product
will not work if the user is already pregnant, and this is really not a safety
issue.
The
sponsor has talked about removing the undiagnosed abnormal genital bleeding
from the label. Our division is in
general agreement with that principle, but we still do not have the final label
and the final approval of the product.
So
our evidence of safety comes from many different sources: the original NDA trial data, which we have
discussed; and since that time, there have been four additional published
randomized clinical trials enrolling 6,503 women in levonorgestrel only arms
and using the same total dose as Plan B.
This
gold standard for drug safety and efficacy had the following findings: no reported deaths; no vascular events; no
thromboembolic events; and as mentioned earlier, there were two ectopics in 135
pregnancies, which is the same incidence that would be normally expected.
Post
marketing data since July of '99 shows the following. There has been obvious extensive EC exposure
in the U.S., U.K., and France, and over six million estimated uses. There have been no deaths, heart attacks, strokes,
or thromboembolic events reported with EC use in the medical literature or post
marketing surveillance.
There's
only one report of phlebitis in the 22 year old woman from France. No reports of overdose, and I found no
evidence for abuse or misuse.
Of
the eight fetal AEs reported in the FDA AERS database, there were the three
congenital anomalies and five miscarriages.
This is very low compared to the background rate as mentioned earlier.
We
have reviewed the data submitted by the sponsor in the current NDA
application. We have done our own review
of randomized clinical trials, the voluminous medical literature on EC, the
FDA's AERS database, and other databases.
Levonorgestrel
has been used extensively worldwide for over 35 years, in combination oral
contraceptives, levonorgestrel oral contraceptives and for postcoital
contraception, and EC.
Plan
B, with a total dose of 1.5 milligrams levonorgestrel, has a safety profile
that includes no deaths, strokes or thromboembolic events. Single doses up to 1.5 milligrams, repeated
doses of .4 milligrams up to 25 months, and repeated doses up to 2.25
milligrams in a 24-hour period of time have been studied.
There
is a low potential for misuse and abuse.
The safety risks are very limited.
We believe that allergy is the only contraindication which is rarely
seen, and there are no reported deaths or hospitalizations.
Finally,
there are no clear risks to a pregnancy or the fetus that have been
demonstrated.
This
concludes my presentation. Thanks for
your attention, and Dr. Karen Lechter will be our next speaker.
DR.
LECHTER: I will first talk in general
about label comprehension studies, what they are, and how they're used. Then I'll discuss the Plan B label
comprehension study. I'll finish with
the agency's primary conclusions from that study.
The
purpose of label comprehension studies is to test the proposed labeling with
potential consumers. Questionnaires
should be based on communication objectives that are the messages in the label that
should be communicated, and that should be tested in the study.
The
results of the studies are used to refine the labeling, which is sometimes then
retested. The improved label is usually
used in an actual use trial, which tests the overall use of the product. However, label comprehension studies can test
issues that can't be tested in the actual use trial, such as whether people
understand what the most common side effects are.
Label
comprehension studies test potential consumers and also sometimes those who
should not use the product. These
studies are usually conducted in shopping malls. Mall participants may be supplemented with
participants from other locations.
We
ask sponsors to include a substantial number of low literate participants. Some studies deliberately recruit specific
populations that have particular medical conditions or who use particular
drugs. These participants may be
recruited by telephone or by other means.
Label
comprehension studies begin with a collection of initial data about
participants who then usually take a literacy test. The interviewer shows the labeling to the
participants and then asks questions based on the communication objectives.
The
types of questions used can be yes/no, true/false, multiple choice, checklists,
or open ended styles of questions. We
discourage the use of yes/no and true/false questions, but if they are used, we
encourage follow-up questions to determine the nature of the participant's
understanding about the issue.
We
encourage the use of scenario questions in which participants have to apply the
labeling information to hypothetical situations, and we usually ask for a
question to determine if participants can correctly decide whether the product
is appropriate for them to use themselves.
The
way the questions are posed can affect the responses. So we watch for biases in the construction of
questions. For example, we try to
eliminate leading questions and series of questions that all require the same
response.
In
the Plan B label comprehension study, of the 663 women interviewed, 656 were
eligible to participate. They ranged in
age from 12 to 50. Those who were age 18
or older who had graduated from college were not tested, nor were those under
age 18, not tested for literacy.
We
categorized those participants who have an eighth grade reading level or below
as low literate.
The
first question about the indication was asked with the package removed from
site. After that question was answered,
the remaining questions were asked with various parts of the label in
view. After questions about the label
participants were asked about their own sexual activity and contraceptive use.
Before
I present the results to you, I'd like to make some comments about scoring and
issues affecting the results. In
addition to presenting results of individual questions, the sponsor presented
results organized by communication objective.
For some objectives, all questions relating to that objective needed to
be answered correctly for the objective to have been successfully communicated.
However,
for other objectives half of three-fourths of the questions needed to be
answered correctly. In some cases,
partially correct responses were scored as acceptable or correct. For example, responses to the question about
the purpose of the product, for that
question credit was given to a partial response that it is for contraception
even though a full response was that it is for contraception after sex.
Finally,
one question about using Plan B for regular contraception was dropped from the
analysis because the sponsor said it was confusing. However, another apparently confusing
question on the same topic was not dropped.
There
are no perfect questionnaires or methodologies.
Every study has weaknesses that may affect the results and the
interpretation of the results. In this
study there were two primary aspects to the questioning that left gaps in our
ability to interpret the results.
First,
because there were no follow-up questions for some of the questions we don't
know if they were answered correctly or incorrectly for the wrong reasons. Also, there were no follow-up questions for
incomplete or ambiguous responses.
Another
problem with the methodology is that not all participants were categorized by
literacy level. Despite these
shortcomings, it is likely that these weaknesses did not have a substantial
effect on our ability to draw useful conclusions from the study.
The
next four slides present the results organized by communication objective. For purposes of shorthand, the tables refer
to those with a reading level of eighth grade or below as low lit. and those
with a higher than eighth grade reading level as high lit.
Keep
in mind, however, that not everyone was tested for literacy. The total column does reflect the total
number of participants who were in the study altogether.
In
two places, and one of them is on this slide, I have two numbers in a box. The first number represents the fully correct
response, and the second number indicates the combination of correct and
acceptable responses for that item.
In
the low literacy and high literacy column for that question, that represents
the acceptable and correct responses for that question. For nine of the 11 communication objectives,
the low literate group scored statistically significantly lower than the higher
literate group. The objectives for which
there were statistically significant differences are indicated with an
asterisk, and as you can see, all four of those on this slide had statistically
significant differences.
It's
not unusual in a label comprehension study for the low literate group to score
significantly different than the higher literate group on many of the
communication objectives.
This
slide shows the communication objectives that score 90 percent or higher
overall. These objectives are that the
product is not for use by pregnant women.
It doesn't prevent STDs, including AIDS and HIV. The purpose is to prevent pregnancy, and it
should not be used by women allergic to its ingredients.
I
want to point out that the objective about using the product to prevent
pregnancy after sex had four different questions associated with it. However, only one of them had the potential
to permit participants to indicate that the product is for use after sex rather
than before. This was the open ended
question about what the purpose of the product was.
Although
90 percent said that the product was for contraception, 45 percent mentioned
that it was for use after sex.
This
slide shows the communication objectives that scored 85 to 89 percent. Eighty-nine percent understood that the side
effects include nausea and vomiting.
Some
responses about taking the second pill 12 hours after the first were
incomplete, with 69 percent giving a totally correct response of 12 hours after
the first pill and 87 percent giving acceptable or correct responses. The acceptable responses usually said 12
hours without specifying 12 hours after the first pill. Eighty-five percent understood to take the
first pill within 72 hours.
This
slide shows the communication objectives that scored 80 to 84 percent. Eighty-two percent understood to take the
pill as soon as possible after sex, and 81 percent understood that if severe
abdominal pain develops, the woman should seek immediate medical care.
There
were no differences between the literacy groups for this item. As you can see, no asterisks for both of
these items.
Two
objectives were understood by the full sample at less than 80 percent. The low literate group also scored the lowest
on these two messages. We don't know if
these two issues were not well understood or whether flaws in the questionnaire
prevented us from determining how well they were understood.
Understanding
that Plan B should not be used if there's unexplained vaginal bleeding was at
75 percent for the full sample and 69 percent for the low literate. Sixty-seven percent of the full sample
clearly understood that the product is for backup, not for regular contraception. Forty-six percent of the low literate
understood this message.
For
this communication objective, participants had to score correctly on three out
of four questions. Scores for these
questions ranged from 47 percent to 85 percent.
We agree with the sponsor that one question might have been
misinterpreted by participants, and we don't give a lot of weight to the
results for that question.
Participants
who answered these question incorrectly would have had to answer all the other
questions in this group correctly to get credit for this communication
objective. In the spirit of caution, we
should deal with this communication objective as if it needed improvement.
There
were no effects of previous sexual experience and no difference due to
experience with emergency contraceptives.
However, this last finding may be due to the low number of participants
with prior EC experience.
So,
in summary, some concepts may be less well understood than others. However, some of the lower scores here may have
been artifacts of the questionnaire design.
There were lower scores for the concepts that Plan B is not for regular
use. Do not use it if there's
unexplained vaginal bleeding. Get
medical help if there's severe abdominal pain, and take the first pill as soon
as possible after sex.
Some
questions were well understood, including the fact that Plan B is for
contraception. It does not protect
against STDs. Don't take it while you're
pregnant. Don't use it if you're
allergic to the ingredients. Nausea and
vomiting are side effects, and take the first pill within three days.
Results
of the actual use study help assess how well the label communicates in real use
situations. However, the actual use
study cannot provide information about certain issues that are best tested in
label comprehension studies, such as the side effects.
The
label comprehension study shapes the label, but it is not the final
determination of approvability.
Dr.
Jin Chen will now discuss the actual use study.
DR.
CHEN: Good morning. My name is Jin Chen. I'm a medical reviewer from the Division of
OTC Drug Products.
I
will summarize FDA's review of the Plan B actual use study, the pivotal
clinical trial that the sponsor submitted with this NDA. This will be followed by a brief literature
review of contraceptive behavior studies associated with emergency
contraception.
First
of all, I would like to briefly go over some basic principles of a typical
actual use study. The actual use study
intends to simulate OTC setting to assess if potential OTC consumers or users
can self-diagnose the medical condition for which an OTC candidate product is
indicated. To assess if potential OTC
users can self-select the product, that's their understanding of the indication
and warnings in a proposed OTC label, and to assess if potential OTC users can
self-medicate according to label directions.
The
study also evaluates the safety of the product when used under OTC-like
setting.
Efficacy
is rarely assessed in this kind of clinical study. The study is generally designed as
multi-center, open label, single arm, uncontrolled trial.
The
study population in the actual use study should represent the anticipated OTC
users. Therefore, subjects are generally
recruited from geographically diverse OTC-like settings with minimal exclusion
criteria. The study may be reached by
inclusion of specific subgroup, such as low literacy population and a certain
age category.
Subjects
may have unlimited access to study product during the study. They should receive minimal intervention from
health care professionals during whole study process.
Now,
let's look at the sponsor's Plan B actual use study. The primary objectives of this study were to
test if anticipated OTC population can correctly self-select the Plan B and it
can time both doses of Plan B based on their understanding of the proposed OTC
label.
The
second objective of this study were assessment of adverse events, frequency of
multiple use, and pregnancy rate.
As
an additional observation, sponsor compared contraceptive behaviors in the
study population before and after study or before and after Plan B use.
This
study was conducted in five family planning clinics across five states in U.S.,
and five pharmacy stores in Washington State.
Female subjects of reproductive age who presented requesting emergency
contraceptive only were recruited. They
made that decision to participate in this study after review of the proposed
OTC label. They were allowed to purchase
one package of Plan B at the study site during enrollment, and they could
re-enroll and purchase additional Plan B during the three-month open study
period.
Subjects
were followed for four weeks with two contacts, at the first week and the
second week, after their enrollment. For
those subjects with unknown pregnancy studies or unresolved adverse events as
four-week contacts, additional follow-up work was given. Data were collected by phone interview during
the follow-up contacts, and a diary card that was provided to each subject with
Plan B package.
Of
the 665 screened subjects, 585 were enrolled.
Eighty subjects were not enrolled.
Of the 585 enrolled subjects, 94 percent came from family planning
clinics, the remaining six from the pharmacy stores.
The
age range of the enrolled subjects was 14 to 44 years. The average age was 22 years. Eighty-seven percent of the enrolled subjects
completed at least high school education.
Thirty percent had ninth to 11th grade education. Forty percent of the enrolled subjects had
previous experience with using emergency contraception, here EC.
Ninety-three
percent of the enrolled subjects completed at least one follow-up contact. Most of them, 86 percent, have two follow-up
contacts. About seven percent of
subjects lost to follow-up.
Based
on the follow-up information provided by 543 subjects, 540 used the Plan B
during the study, which was 92 percent of the enrolled subjects.
Now,
I'm going to briefly summarize each of these five results. First, about self-selection, of the 540
users, 95 percent correctly self-selected Plan B by the following reasons.
Forty
percent of users had intercourse without any contraception. The others had a problem with their regular
contraception methods, such as condom use failure, missed taking oral
contraception pills, and four percent of users had a problem, had accident when
using withdraw methods as a contraception.
Five
percent of users represented 26 subjects incorrectly self-selecting Plan B
during the study. Seven subjects had labeled
contraindications, such as unexplained vaginal bleeding, one already pregnancy.
There
were two subjects who took Plan B before unprotected intercourse. About three percent provided nonspecific
reason for using Plan B.
Timing
of doses. According to the dosing
instruction, in the proposed OTC label 92 percent of users took the first pill
within 72 hours after intercourse.
Seventy-two percent of users took the second pill at 12 hours
later. Overall 68 percent of users took
both pills following the label dosing regimen.
The
sponsor realigned second pill timing data using different dosing
definition. Ninety-three percent of
users took a second pill between six to 18 hours after the first pill. If needing the first pill timing criteria the
same, overall 87 percent of users took both pills according to alternate second
dosing interval.
Adverse
events. There were no serious adverse
events and no new safety signal reported in this study. The most common adverse events were transient
abdominal pain, nausea, headache, and fatigue.
Contraceptive
behaviors. This table shows overall
change in contraceptive behaviors of the enrolled population during the
one-month study as compared to one month before study. At least one such act without any
contraception decreased from 60 percent before study to 20 percent during
study. User withdraw method decreased
from 28 percent to ten percent. Condom
use slightly increased from 79 percent to 90 percent.
Remember
those behavior changes were based on one-month observation during this study.
During
the one-month observation subjects tended to use more effective contraception
methods. One, point, seven percent,
which was ten subjects, requested the Plan B more than once during three-month
enrollment period through the re-enrollment process.
Pregnancy
rate. Ten subjects, which is 1.9
percent, had a confirmed pregnancy. In
addition, there were 40 subjects, which was 2.6 percent, that had unknown
pregnancy studies, and at the end of the study they were lost to further
contacts.
In
summary, the Plan B actual use study shows that 95 percent of users correctly
self-selected Plan B. Sixty-eight
percent of users took the first pill within 72 hours and the second pill at 12
hours later. Eighty-seven percent of
users took the first pill within 72 hours and the second pill between six to 18
hours after the first pill.
There
were no serious adverse events and no new statistic loss (phonetic). Subjects tended to use more effective
contraceptive methods within one month observation. There were no significant differences among
demographic subgroups in self-selection, timing of doses, adverse events, and
contraceptive behaviors.
However,
there were some limitations in this study.
The formal period was only four weeks.
Subjects were allowed to purchase only one package at the enrollment,
although they can come back to the study site to get another package of Plan B,
but they had to go through reenrollment process.
There
was no literacy testing in this study.
Finally,
94 percent of subjects were recruited from clinics. Due to those limitations, it may be difficult
to extrapolate the actual use study results to the OTC setting, particularly to
assess non-tour (phonetic) contraceptive behaviors in target OTC population.
To
address these concerns, the sponsor submitted eight literature reports
regarding contraceptive behaviors related to the advanced provision of
emergency contraception. The literature
enclosed five published studies, two unpublished manuscripts, and one
abstract. Five studies were conducted in
the United States. The remaining three
studies were conducted in outside the U.S., one study each from U.K., India and
Ghana. There were no raw data submitted
with these studies.
The
study populations were recruited from either family planning clinics or
hospital based clinics. Subjects were 15
to 45 years old who come to the clinic not for emergency contraception purpose. Sample size ranged anywhere from 160 to
around 1,000 subjects.
Most
of those studies were of randomized controlled design, and I have two groups,
treatment and control. Treatment groups
received in advance one of three courses of emergency contraception pills. Many subjects had emergency contraception
pills on hand before unprotected intercourse.
In
the control group, subjects were told to obtain emergency contraception pill
through prescription in clinics. In one
study, subjects had pharmacy access to emergency contraception as an additional
control group.
All
subjects in both treatment and the control group received EC education,
emergency contraception education, and supervision from health care providers.
The
formal period among those studies ranged from two to 12 months.
Here's
a summary of the results from those behavior studies. The 08 studies, such as with advanced
emergency contraception provision, were more likely to use emergency
contraception pills. In most of those
studies, such as with the advanced EC provision, didn't have more frequent
unprotected sex, didn't decrease condom use, didn't switch to mass effective
contraception.
The
behavior studies are complementary to the Plan B actual use study in some
degree. For example, those studies had a
longer follow-up period. The sample size
in some of the studies were relatively large, and finally, the advanced EC
provision is the better part in those studies.
However,
there is some limitations in those behavior studies, such as all studies were
conducted in clinical setting instead of simulated OTC setting. All of he subjects in those studies received
EC education. Three studies were
conducted in foreign countries, which may not represent U.S. population.
Six
studies provided only one course of emergency contraception pills in
advance.
This
completes the FDA summary of behavior study.
Thank you very much.
CHAIRMAN
CANTILENA: Okay. Thank you, Drs. Chen, Lechter, and Davis.
We
now have time for questions for FDA presenters, and I would actually like to
start with a question for Dr. Lechter.
In
the review in the document, you actually talk about concepts which were not
clearly understood or for which the data were inconclusive, and really a couple
that jump out at me are things that really drive the primary efficacy in terms of the ability to take the
first tablet as soon as possible after intercourse and the second in terms of
the timing of the second dose.
And
I guess overall if you do sort of the score card, I guess I have according,
you know, to your information that
really four of the 11 objectives in the comprehension study, you know, were not
met.
And
my question is: was your office involved
or was the over-the-counter office involved in sort of going forward with the
actual use after a study which I think if you look at other studies that, you
know, we've heard about in the past for
statins and the heartburn drugs, the overall success of the comprehension study
was really not that good?
So
my question was, you know: were you
involved with shaping the label for the actual, you know, use, and if you were,
I would ask, you know, why you didn't ask for a second comprehension study that
was done in advance of the actual use study.
DR.
LECHTER: Actually I had no
involvement. There may be someone else
on our team who's more appropriate to answer that question.
DR.
ROSEBRAUGH: I'll take a swing at it
anyway. We were not involved with the
label that went into the actual use study, and it's usually the sponsor's call
on when they feel like they're ready.
Typically what you will see is somebody will do a label comprehension
study, make changes that they think are necessary, and then they'll go into an
actual use study.
CHAIRMAN
CANTILENA: Okay. Over here.
Dr. Hager.
DR.
HAGER: I have a couple of quick
questions. One, since only 29 of 585 of
the subjects in the actual use study were 14 to 16 years of age, and since
those 18 years of age and younger were not tested for literacy, indicating not
tested for understanding, are there any considerations about age restriction on
the availability?
Number
two, the comment was made that there was failure to understand the need for
getting medical help for abdominal pain.
The Washington State data, if you look at the pharmacy data, indicates
that the pharmacist said that 85 percent of the subjects needed medical
follow-up, needed medical information.
Is there concern about failure to diagnose ectopic pregnancy among this
population?
And
finally, I have a question about effectiveness.
Since you accepted an extension from 12 hours for the second dose to 12
to 18 hours, can you tell us about effectiveness with that six-hour delay?
CHAIRMAN
CANTILENA: Does someone from FDA want to
handle those in order?
DR.
ROSEBRAUGH: Well, in order, I think
Questions 1 and 2 are things that we are awaiting panel discussion on. So I think it would be premature for us to
comment.
Section
3 or Question 3 is also something that I think we are awaiting the panel to
comment. I don't know.
CHAIRMAN
CANTILENA: Okay. So the short answer is that you have no
comment at this point.
DR.
ROSEBRAUGH: Correct.
CHAIRMAN
CANTILENA: Okay. Dr. Trussell and then Dr. Tinetti.
DR.
TRUSSELL: I wanted to follow up on two
questions that were asked before, including now a third by Dr. Hager, and it's
a question, I think, to Dr. Davis.
On
page 8 in Tab 5, Table 3, you have the results of two randomized clinical
trials, both of which showed that a single 1.5 milligram dose, both pills taken
at once, was just as effective with no greater incidence of side effects.
We
saw both from the label comprehension and from the actual use study that one of
the sources of problems is people taking the pill exactly 12 hours later, which
was declared to be the correct answer, and
now the sponsor has even volunteered to put in a card showing the time
of the first dose and the time the second dose is supposed to be taken.
We
now have these data from two randomized clinical trials that show that they can
be taken at once. We can eliminate all
of these problems by just simply changing the instructions to take both at one
time. You have ample data to support
it. This change has already been made
based upon the same two studies in France and in the United Kingdom.
CHAIRMAN
CANTILENA: Okay. That question, I guess, was for Dr. Daniel
(sic), but I guess anyone from the FDA.
Would you like to comment on that?
DR.
GRIEBEL: Yes. We're aware of those data as well. The regulatory process for changing the
label, however, requires us reviewing those data, the primary data, and that
would be our process for doing that.
We
do not have those data at this time to go through the formal review that is
required to do that. So we have the
prescription product before us, which had the primary data reviewed, and that's
what we're working with.
DR.
TRUSSELL: But the consequence is going
to be unfortunately that most other medical authorities in the United States,
including Planned Parenthood Federation of America, all have switched to taking
both pills at once.
So
there's going to be a great source of conflicting data out there to the
consumer with both of these sets of instructions.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Tinetti.
DR.
TINETTI: My question relates to the
actual use study and which I suppose we're supposed to extrapolate from the
results on the knowledge and effectiveness and appropriate use. My question is 94 percent of those people
were recruited from clinics, and do we have data on how many of them were
actually instructed in the purpose, the timing, the dosing, and so is it really
an accurate reflection of what's going to happen in real actual use when people
aren't necessarily getting it from clinics?
DR.
ROSEBRAUGH: The whole purpose of an
actual use study is to try to mimic OTC environment as much as possible, and so
that they were not supposed to be instructed in any use of it other than what
they could get out of the labeling.
CHAIRMAN
CANTILENA: Okay. Dr. Davidoff.
DR.
DAVIDOFF: Yes. I had two questions. The first has to do with limitation of most
of the studies, at least the published studies, and that is that an actual use,
that they did not charge for the drug.
The drug was supplied to the participants. As I understand it, the drug was charged for
in the sponsor's actual use study.
It
seemed to me that the lack of information on the effect of charging for the
drug is a substantial limitation. It
could work in one of two directions and possibly others. One is charging would, of course, potentially
decrease the potential for repeated use and substitution of emergency
contraception pills for other more conventional methods of contraception.
On
the other hand, charging obviously can and probably would decrease access to
some degree. I wondered if you would
comment on that particular limitation of the data that's available. That's the first question.
The
second has to do with the issue of abdominal pain because it seemed to me from
the labeling the significance of abdominal pain is very ambiguous. It is directed primarily at the concern about
ectopic pregnancy, quite appropriately, but it seemed to me that this lack of
information and the ambiguity of the message about abdominal pain could be
interpreted by women as potentially a side effect of the drug, even though it's
not mentioned under side effects, and I wondered if there isn't an argument to
be made for spelling out in a little bit more detail why there is concern about
abdominal pain.
CHAIRMAN
CANTILENA: Okay. So if I can then try to summarize, your
questions for FDA are to address the issue of charging or not charging in the
studies, and the other is the interpretation of the finding of abdominal pain
or the message.
Curt.
DR.
CHEN: Well, I can answer the first
question. I guess the second question
maybe give somebody else.
Actually
he brought out a very, very important point to FDA. This is a big issue, either charge or not
charge. For this study particularly,
actually such as were reimbursed in the end of -- after second contact from my
understanding, but they were told they
would get reimbursed after enrollment for this one.
So
somehow this confining factor here, definitely, but if you don't pay, if you
don't reimburse, then you probably bring up another issue as you just
mentioned. So this is very tight
(phonetic), and we certainly would like to hear your suggested opinion on that.
For
the second question, I guess I have to pass to -- this is related to ectopic
pregnancy, I believe, right? So probably
--
DR.
DAVIS: Since abdominal cramping, pelvic
cramping is a normal and common side effect of the medication, there is then a
fine distinction between how much cramping and pain would be then synonymous
with or a potential warning signal for an ectopic pregnancy.
Our
general feeling was that if severe symptoms persist for greater than 48 hours,
that certainly that should be in the label for a reason to contact your health
care professional, or even potentially we could label for pelvic pain on one
side greater than the other. In other
words, we're certainly open to a label change that would reflect the potential
risk of an ectopic pregnancy.
CHAIRMAN
CANTILENA: Okay. We have Dr. Crockett and then the last
question from Dr. Benowitz.
DR.
CROCKETT: Yes, thank you.
My
question is for Dr. Chen, and it's concerning the actual use study. It struck me in reviewing the actual use
study that the company did a really good job of following the Weight Watchers model. They applied education and accountability to
taking their product and saw behavioral changes that were very favorable.
And
my question to you as an FDA member is:
how did an actual use data get done?
I want to go back to before it was done.
How did it go through the FDA?
And what kind of input did you as a group have concerning the design of
that study that doesn't actually show actual use patterns at all?
DR.
LEONARD SEGAL: Excuse me. I think I can take this question if it's all
right.
I'm
the medical team leader in the Division of Over-the-Counter Drug Products,
Andrea Leonard Segal, and I was part of that earlier process.
And
we met with the sponsor on more than one occasion, and it was clear that, see,
what we try to do in actual use studies is we try to get an all comers
population. If somebody wants to go into
a drug store and purchase a decongestant, we would like to know that they can
differentiate the product that we're interested in studying from the product
that they might actually have sought to purchase.
So
consequently, we would like to have a mall setting where we would garner people
from all different kinds of realms with all different kinds of purposes. However, this product deals with a very
intimate issue, and the agency recognized at the time that we were discussing
the protocol design that it might be very difficult for anyone to recruit this
kind of a population that might be interested in this kind of an issue in a
general mall setting.
So
we agreed that it would be okay to use a more precise environment. This is not the first time we've done this in
actual use studies. We've done this kind
of thing to help sponsors target specific populations at risk when we've been
concerned about perhaps somebody with heart disease who might be at risk for a particular product or somebody with kidney
disease. That kind of a thought runs
through our minds. So that's what we did
in this particular case.
Does
that address your issue?
DR.
CROCKETT: Yes, partially it does. I have less issue with the fact that it was
done in a clinic setting than I do with the study structure where the patient
received education and had some accountability.
They knew that they were going to have to fill in a card. There were going to be contacts, and that
accountability in and of itself affects behavior.
And
when we're talking about taking something over the counter without that
education and that behavior it seems like the sponsor's actual use study is
more supporting a behind the counter or prescription setting for this drug.
DR.
LEONARD SEGAL: The participants in this study
were not supposed to be targeted to receive specific education. That was only the label was supposed to
educate them. That's how this study
differed from the behavioral studies that were used as supportive evidence for
longer use where consumers or participants did receive education, both in the
control groups and in the advanced provision groups. In this study education was not a specific
element.
With
regard to follow-up contact, all actual use studies suffer from this
weakness. We are always debating how to
derive our data without influencing consumer behavior, and we try to do it in
the least obtrusive manner.
But
we recognize that it's a flaw. I don't
think that it is possible; at least we have not figured out yet how it is
possible to conduct a perfect actual use study that would not in any way
influence a consumer.
What
we often try to do is to not establish routine follow-up visits as much as
possible. We try to allow the consumer
to have as much rein as to determining when he or she will choose to follow up,
but we need some means of data collection.
Does
that answer the question?
CHAIRMAN
CANTILENA: Okay. Thank you.
And
the final question from Dr. Benowitz.
DR.
BENOWITZ: My question is to Dr. Chen.
In
your review of the contraceptive behavioral studies that were not done by the
sponsor but published elsewhere, you talked about emergency contraception in
general, and it's my recollection, but please correct me if I'm wrong, that
these included both combination estrogen/progestin, as well as progestin only
products.
And
it's also my impression that the side effect profile is different; that there's
much more nausea and vomiting and much more aversive to use the combination
products rather than progestin alone.
And
do you think that that difference has any impact in terms of how people use
this repetitively, in terms of contraceptive behavior?
DR.
CHEN: Regarding behavior, actually I
believe you referred to a literature study, right?
DR.
BENOWITZ: Yes.
DR.
CHEN: Okay. Yeah, some study definitely use combination
products. Probably most of them, they
use Yuzpe regimen.
Do
you have another question?
DR.
BENOWITZ: Well, my question was the
toxicity of the combination product is different and more adverse than the
progestin only.
DR.
CHEN: Yes, in general, yes.
DR.
BENOWITZ: Many women I know have taken
the combined product, find it very uncomfortable and really don't want to use
it again if they can ever avoid it because they get really sick.
The
progestin product does not do that, and my question is does that difference in
the product influence your interpretation of the contraceptive behavior and
repetitive use behavior.
DR.
CHEN: Yes, it could be it could impact,
you know, in terms of compliance to take a pill, you know. In general, single ingredient has had less
side effects from previous clinical safety trial. So that probably somehow increased compliance
in terms to take both pills or one pill, whatever.
DR.
BENOWITZ: So, again, a follow-up. Is there any evidence that there's a
difference in behavior if you're using combined versus progestin only?
DR.
CHEN: We don't have this information
from those literature.
Dr.
Davis, you may have something?
DR.
DAVIS: Just to make a quick comment
since I did the review of the original data for Plan B and it was comparative
to the Yuzpe trial from the large World Health Organization trial. There's no doubt that the safety profile, and
you're referring to nausea and vomiting, was really superior for levonorgestrel
only, and that, in fact, superiority claim was granted to Women's Capitol
Corporation, and it is labeled such in the Plan B product.
We
did not grant a superiority claim for efficacy because it wasn't statistically
significant, but the data certainly strongly suggests that the levonorgestrel
only is a better product for efficacy than the Yuzpe regimen.
But
in comparing the behavior studies, we really -- I'm aware of the fact that many
of them were Yuzpe only. One of them
switched from the Yuzpe regimen to levonorgestrel only about halfway into the
study, but we didn't really look at a comparison then of the two.
But
it would be to me logical to conclude that the levonorgestrel only would have a
better compliance profile because of the less side effects and reuse profile,
too.
CHAIRMAN
CANTILENA: Okay. Thank you very much.
And
we'll now move into the section of the committee meeting, the open public
hearing, and Dr. Templeton-Somers will read a statement before we start this section.
DR.
TEMPLETON-SOMERS: Hello. We have a very full open public hearing
today. In the interest of both fairness
and efficiency, we're running it by some strict rules.
To
make the transitions between speakers more efficient, all speakers will be
using the microphone in front of the audience.
That's at the end of the table there.
Each
speaker has been given their number in the order of presentations, and when the
person ahead of you is speaking, we ask that you move to the nearby next
speaker chair, which is in the corner by Dr. Alfano there.
Individual
presenters have been allotted two minutes for their presentations. The two group presentations have been
allotted three minutes. We will be using
a timer, and speakers who run over their time limit will find that the
microphone is no longer working.
(Laughter.)
DR.
TEMPLETON-SOMERS: We apologize for the
need for the strict rules, but we wanted to give as many people as possible an
opportunity to participate and to be as fair as possible.
Thank you for your cooperation.
CHAIRMAN
CANTILENA: Okay. Both the Food and Drug Administration and the
public are trying to have this a transparent process for information gathering
and decision making. To insure
transparency at the open public hearing session of the Advisory Committee
meeting, FDA believes that it is important to understand the context of an
individual's presentation.
For
this reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the committee of any
financial relationship that you may have with the sponsor, its product, and if
know, its direct competitors. For
example, this financial information may include the sponsor's travel lodging or
expenses, you know, covering your testimony.
Likewise,
the FDA encourages you at the beginning of your statement to advise the
committee if you do not have any such financial relationships. If you choose not to address this issue of
financial relationships at the beginning of your statement, it will not stop
you from speaking.
And
I think we're ready to start. I will
just go over one more thing. At the end
of the table, you'll find a box with some lights. The lights are a code to tell you 90 seconds
the light will be green. For the last 30
seconds it will turn yellow, and when your time is up at two minutes, it will
change to red, and that's the point where you will no longer find the
microphone is working.
Okay. We have a technical holdup here. Stand by.
Okay. I think we're ready to start. Go ahead, our first speaker.
DR.
GOLD: Good morning. As an associate professor in adolescent
medicine in the Department of Pediatrics in University of Pittsburgh, I'm
delighted to be here today to present our research on providing emergency
contraception, or EC, in advance to adolescent girls.
The
results of this study will be published this February in the Journal of
Pediatric and Adolescent Gynecology.
Next
slide, please.
I
first want to acknowledge our funding sources as well as the collaborating
students who held with the project.
Next
slide when you get to it.
We
conducted a randomized study comparing the sexual and contraceptive behaviors
of girls given education, plus one packet of advanced EC versus those who got
education only. By advanced EC, I mean
we gave the girls the medicine to have on hand in case they had unprotected
sex.
We
recruited 301 sexually active girls between the ages of 15 and 20 from an urban
adolescent clinic in Pittsburgh. At
enrollment, we conducted a 15-minute interview to collect demographics and
sexual and contraceptive history.
Then
the girls were randomized into the advanced EC or education only group. We then conducted monthly ten-minute
telephone interviews for six months.
Next
slide, please.
The
two groups were well matched on relevant demographic, sexual, and contraceptive
history variables. We found no
difference by groups in rates of unprotected sex or in the use of hormonal
contraception at the one and six-month follow-up interviews.
There
was also no difference by group in condom use at the one month follow-up.
Next
slide, please.
However,
at the six-month follow-up, more girls in the advanced EC group used condoms in
the past month compared to those in the education only group. The advanced EC group used EC nearly two
times more than the education only group at the one-month follow-up.
More
importantly, the advanced EC group started their EC course sooner after
unprotected sex compared to the education only group. EC is 50 percent more effective when taken
within 12 hours of unprotected sex.
Next
slide, please.
These
findings imply that having EC easily available does not cause adolescents to
have more unprotected sex or to stop using hormonal contraception or
condoms. It does help adolescents use EC
sooner.
Thank
you.
CHAIRMAN
CANTILENA: Just made it.
(Laughter.)
CHAIRMAN
CANTILENA: Okay. Next speaker, please.
(Applause.)
DR.
CULLINS: Good morning. I'm Vanessa Cullins, Vice President for
Planned Parenthood Federation of America.
I
have no financial relationships with the sponsor.
Planned
Parenthood Federation of America wholeheartedly supports Plan B emergency
contraception becoming over the counter.
As you have heard, Plan B emergency contraception is ripe for
over-the-counter availability.
Planned
Parenthood Federation of America has followed the extensive body of published
literature about emergency contraception pills which consistently shows that
emergency contraception is safe, effective, and is used responsibly. Based upon this evidence, the federation has
striven to make emergency contraception easily accessible through such programs
as Dial EC, through which a prescription is phoned into a pharmacy; Emergency
Contraception Online; advanced provision of emergency contraception pills or
prescription; and emergency contraception to go through which a walk-in visit
results in express availability of emergency contraception.
Since
2000, over two million emergency contraception kits have been purchased from
Planned Parenthood affiliates. Based
upon affiliate experiences, we confirmed that emergency contraception is used
as intended, and women do not use emergency contraception as regular
contraception.
Within
the federation, which consists of over 850 clinical sites, there have been no
reports of serious adverse events attributable to emergency contraception.
Over-the-counter
availability insures timely access to a safe medication which works best the
sooner it is taken. Continued
prescription or over-the-counter status encumbers timely access to emergency
contraception.
Even
in Washington State where collaborative pharmacy agreements create an
environment that's similar to behind-the-counter access, consumer need is not
satisfied. All Washington State family
planning affiliates have had a marked increase in the amount of emergency
contraception that has been purchased and used by women.
Over-the-counter
status --
CHAIRMAN
CANTILENA: I'm sorry, ma'am. Your time is up.
DR.
CULLINS: -- important and timely.
(Laughter.)
CHAIRMAN
CANTILENA: Thank you, ma'am.
The
next speaker, pease.
DR.
STUART: Good morning. My name is Dr. Gretchen Stuart. I'm an assistant professor at the University
of Texas Southwestern Medical Center in Dallas, and I'm a practicing OB-GYN,
and I'm testifying today on behalf of the National Family Planning and
Reproductive Health Association, known as HFPRHA.
I
have no financial or other conflicts of interest with Plan B or any other drug
companies to disclose.
NFPRHA
represents a network of 4,600 clinics which provide family planning services to
low income women across the country and are supported with federal funds, such
as Title X.
Title
X clinics have been on the forefront of efforts to provide emergency
contraception in a timely fashion. We
salute Barr for making a public commitment to continue selling Plan B at a
reduced price to Title X providers.
However,
based on first-hand experience, this is not enough. For many uninsured women and teens, the
barriers to EC access remain insurmountable.
Many have little experience with the medical system and may be too
intimidated to make a call to a health care provider to ask for a prescription.
Many
clinics are closed on nights and weekends, and many pharmacies fail to stock EC
as a prescription product.
For
these reasons I couldn't be more supportive of removing any barriers to
accessing Plan B for teens. Currently 80
percent of all teen pregnancies are unintended.
This statistic necessitates action based on the reality of teens' lives
rather than our collective wish that teens postpone sexual activity.
Like
it or not, nearly half of all teens are sexually active by the time they
graduate high school, and like all women, teens are not always effective
contraceptive users and can experience failure.
The
economic and social consequences of unintended teens specifically are
devastating. Less than one third ever
finish high school and leaving many unprepared for the job market and likely to
raise their children in poverty.
Fifty-two percent of all mothers on welfare had their first child as a
teenager.
Given
the clarity of the science and the enormous potential to advance the important
public health goals of reducing unintended pregnancy and abortion, I strongly
recommend that FDA allow Plan B to be placed over the counter on pharmacy
shelves and not behind the counter restricted.
Thank
you.
CHAIRMAN
CANTILENA: Thank you, Dr. Stuart.
Next
speaker, please.
MR.
MARSHALL: My name is Robert
Marshall. I'm a state legislator from
Virginia.
As
I look around the room today, one name that should be on this NDA is Hugh
Hefner. Playboys, adolescent adult males
are going to be the primary beneficiaries of this. In fact, I will suggest to you they may be
the major purchasers of this, who in turn will sell it to high school kids that
we're going to have to deal with with appropriations from the State of
Virginia.
Cokie
Roberts says, "I always love the demographic figure on abortion. The most pro choice group in the country,
young men between the ages of 18 and 25, the most responsible group well known
for taking, you know, responsibility for their actions."
Why
isn't NDA even considered here? The U.S.
Defense Department authorized this for one month, then pulled it off its
formulary. At the University of
Virginia, these pills are passed out up to 120 hours after intercourse. Physicians there at the medical school are
refusing to pass this out.
You
all said it was safe. You said it's effective.
Perhaps this causes abortion and perhaps of them have a conscience about
this and don't want to be forced into this like they will be.
This
drug was never proven safe in the first place.
Industry watchdogs have, in fact, become industry lapdogs. The FDA did not rely upon any independent
test conducted for safety or efficacy.
You cited 21 studies, 19 of which dealt with efficacy. One maybe dealt with safety dealing with
blood clotting. One from Kaiser
Permanente showed that almost 50 percent of women had moral questions about
what was going on.
Additionally,
I found out the incidence of abortion will not be reduced. I looked at your Web site this morning. Interestingly, the definition of pregnancy
has been changed even by the Bush administration from fertilization to
implantation, and I've got the proof back here.
This was from May 13th to yesterday.
The
definitions of abortion and pregnancy were defined and acknowledged by Dr.
Abraham Stone, who said, "Measures that prevent implantation are measures
that cause abortion." He's from
Planned Parenthood. I loved quoting my
opponents.
You
all are doing a disservice, and you will disrespect the rights of women to be
informed as patients to call this --
CHAIRMAN
CANTILENA: I'm sorry. Your time is up. Thanks, Mr. Marshall.
The
next speaker please.
MS.
LASER: My name is Rachel Laser, and I'm
senior counsel with the National Women's Law Center.
I
have no financial or other conflicts of interest with Plan B to disclose.
The
mission of the National Women's Law Center is to reduce barriers for all women
with special attention to the needs of low income women. Making Plan B an over-the-counter drug
removes barriers to access of this critical contraceptive drug for women and,
in particular, low income women.
Women
do not use EC in great part because they lack access to it. Barriers to access include gaps in knowledge,
obstacles to obtaining a prescription, time constraints and costs, factors that
are all exaggerated for low income women.
In
order to obtain EC as a prescription drug, a woman must first know that it is
an option. Low income women are more
likely not to have heard about EC.
Positioning EC over the country where it is easily accessible helps to
educate all women about its availability.
Next,
the woman wanting EC must visit a physician to get the prescription. Nearly one in five women, however, and nearly
one-half of uninsured women do not have a regular health provider. These women are hard pressed to obtain an
appointment with a physician on such short notice.
A
woman must also be able to pay for the visit, plus transportation both to the
doctor and then the pharmacy. Secondary
costs might include missed work and babysitting. Making EC available over the counter would
eliminate many of these hurdles.
Finally,
we note that the cost of EC over the counter relative to the sometimes lower
cost of EC as a covered prescription drug could impede access for some low
income women. For women who have
insurance coverage though EC might be off formulary and cost at least as much
as it would over the country, and many of the low income women do not have
prescription coverage for this product.
Nearly one in five women lack health insurance, the majority of whom are
low income women.
And
although all state Medicaid programs must cover family planning services,
almost half of the states do not cover emergency contraception and Medicaid
programs.
Finally,
public funding could help minimize the cost of EC over the counter.
In
summary, although some low income women may benefit from prescription coverage
of --
CHAIRMAN
CANTILENA: I'm sorry. Your time is up. Thank you, Ms. Laser.
The
next speaker, please.
DR.
STEWART: Good morning. My name is Felicia Stewart. I chair the board of directors for the
Association of Reproductive Health Professionals, an organization of 12,000
reproductive health researchers, educators, and clinicians in the United States
and internationally.
I
also am an adjunct professor in OB-GYN and reproductive sciences at U.C.-San
Francisco.
On
behalf of ARHP, as well as the 3,000 members of the National Nurse
Practitioners in Women's Health and the 10,000 members of the American Medical
Women's Association, I'm pleased to have an opportunity today to speak in
support of switching Plan B to over-the-counter status.
ARHP
manages the first national emergency contraception hotline and Web site
established in 1996 to provide women with information about emergency contraception
and referrals to providers. To date our
Web site has received over two million visits and approximately 500,000 phone
calls.
ARHP
also received calls and E-mails from women seeking help. The preponderance of these, and I have to
deal with my fair share of them, is not because of problems they have using the
medication, but because they have problems finding access to the medication.
Better
access is needed. Seeing a provider is
not necessary and certainly can be a barrier since this option can be used
safely and effectively without prescriber intervention.
We
also note that there are some ethical issues involved. It would be unethical to withhold from women
a safe, effective treatment that affords a second chance and also unethical to
reinforce the idea which woman naturally would assume on the basis of FDA
restriction, that there would be some scientific evidence that unrestricted use
would be unsafe or dangerous for their health.
Finally,
there is unprecedented support for this.
ARHP, along with 70 organizations --
CHAIRMAN
CANTILENA: I'm sorry. Your time is up, Dr. Stewart.
The
next speaker, please.
MS.
WRIGHT: I'm Wendy Wright with Concerned
Women for America, which is the nation's largest public policy women's
organization. We have no financial ties
to the sponsor, to the product, or to its competitors, and we're very disturbed
by Plan B's promoters' emphasis on access, but not on women's safety.
There
have been no studies done on the long-term effects of women after taking Plan
B. There have been no studies on the
effects of multiple use. In fact, Plan B
promoters liberally encourage multiple use.
On Plan B's Web site in the Q&A section, it asks how often can Plan
B be provided. The answer is Plan B can
be provided as frequently as needed.
Additionally,
there have been tests done in the pediatric population which is now required by
federal law. The Pediatric Equity Act of
2003, just signed into law on December 3rd, requires this.
Consumers
are more influenced by ads than they would be by labeling, and the ads that
have been put out by Women's Capitol Corporation for Plan B have actually been
found in violation of federal law. I
will quote from the FDA's letter to Women's Capitol Corporation.
The
FDA has concluded that Women's Capitol Corporation's ads are false, lacking in
fair balance or otherwise misleading, in violation of the Federal Food, Drug,
and Cosmetic Act. Specifically, the
direct to consumer radio and print ads overstate efficacy, fail to convey important
limitations on use, and minimize important information about risks associated
with the use of Plan B tablets emergency contraception.
As
a result, the ads raise significant public health and safety concerns. We have provided a full testimony that refutes many of the claims made today by
Plan B's promoters that I'll not be able to include in this short
testimony.
We've
also raised concerns not addressed by the promoters. I would encourage you to please read our full
testimony.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
The
next speaker, please.
MS.
FREEMAN: Hello. My name is Linda Freeman.
I am the co-chair of the NOW New York State Reproductive Rights Task
Force. I am speaking to you today not
only as an activist, nor as someone who has used the morning after pill, but
most importantly I'm speaking to you today as a woman, a woman who has found
access to the morning after pill to be a challenge.
I
had just moved from Ohio to New York City and was in my first year of graduate
school. My boyfriend had come up for the
weekend to visit and our Plan A method of birth control failed and I found
myself in need of the morning after pill.
What I found may or may not surprise you. It was sure a surprise to me.
Many
of the health clinics I phoned wanted between 50 to $150 for a doctor's visit
and a prescript for EC. As a graduate
student, which all of you were at one time or another, you know that a
student's budget is extremely limited. I
cannot afford such exorbitant costs.
I
continued to phone health facilities throughout the New York City area, hoping
that I would find some place that was much more reasonable. Unfortunately I did not. what I did find, however, was the student
health center at the school that I was enrolled in. They had the pills in stock, and I was urged
to come into the center immediately.
I
was lucky but many women are not so lucky.
Now that I am out of school I have no longer the peace of mind knowing
that the morning after pill is available to me when I need it as long as it's
Monday through Friday from nine to five, the hours in which the clinic is
open. The cost is now a bit more for me
than as a student. Unfortunately my health
insurance does not cover birth control pills.
It does, however, cover Viagra.
In
the past, on Friday, I had an appointment with my OB-GYN, who refused to write
me a prescription for the morning after pill, stating that I needed to contact
him first to make sure that the need for the pills was warranted, as if I
wouldn't know when I needed to take them.
Please
keep in mind as you are making your recommendations today that we women are
aware of when we need to take the morning after pill. Please do not insult our intelligence nor
belittle us. We as women are capable of
following directions.
Most
importantly, we as women should and must be allowed to make reproductive
decisions for ourselves without interference from others, without judgment from
others, and without the need for someone else' approval.
Thank
you for your time.
(Applause.)
CHAIRMAN
CANTILENA: Thank you.
Next
speaker please.
MS.
DENNER: I'm Carole Denner. I'm a registered nurse with 35 years'
experience, and I'm a volunteer with Concerned Women for America.
Over-the-counter
labeling conveys the impression a drug has been proven safe as user's labels
without any hidden health risks. Neither
the 21 studies cited by the FDA in the 1997 invitation for new drug
applications, the 39 studies cited by the Women's Capitol Corporation in this
over-the-counter application, nor the studies referenced by Dr. Daniel Davis
this morning address the long-term potential health consequences to America's
women and girls.
What
is the maximum safe dose of levonorgestrel monthly or yearly? None of the clinical trials cited were
designed to determine any long-term risks based on expected variables for
adolescents, women over age 35, concomitant medical conditions.
It
was mentioned this morning under need that 43 percent of U.S. pregnancies will
experience problems. The greatest
percentage of these occur in immigrant or in educated populations, women who
choose not to avail themselves or who delay the available prenatal care that is
available in the United States. None of
the studies cited follow the participants beyond the immediate time frame of
levonorgestrel usage. Are there
long-term risks?
Taking
only one and a half times the recommended daily dose of Tylenol for more than
ten days can result in hepatotoxicity, but this wasn't even determined until
Tylenol had been on the market for years.
What
is the risk to America's women and girls?
The
American Medical Association and the American College of Obstetricians and
Gynecologists both recommend Plan B go over the counter. Yet they continue to recommend that low doses
of the same drug given as a normal birth control pill be given only by
prescription. That's how logical and
inconsistent.
For
the safety of American women and girls, I and the over half a million members
of the Concerned Women for America of Virginia, the nation's largest public
policy women's organization, ask and recommend that high dose hormone therapy
after unprotected sex be available only by prescription by those capable of
evaluating women for their health risks.
Thank
you.
CHAIRMAN
CANTILENA: Thank you. Time's up.
Next
speaker, please.
MS.
MAHONEY: Hi. My name is Erin Mahoney. I am the Co-chair of the National
Organization for Women, New York State Reproductive Rights Task Force.
There
are many reasons why the morning after pill should be over the counter, but in
these two minutes I have with you, I want to talk about my experience with the
morning after pill and why I needed over the counter.
When
I needed the morning after pill, I was in Detroit, Michigan for the first
time. I had just helped my boyfriend
move and we didn't know a sole. We used
condoms as our birth control method, but this time I needed the morning after
pill. I was luckier than other women in
this place. I had gone to a feminist
gynecologist that year, and she had insisted that I take a prescription for the
morning after pill with me in case I ever needed it.
However,
that pill was not cheap. That doctor's
visit cost me $150 because my insurance didn't cover annual gynecological
exams. It does cover Viagra.
I
had the prescription for the morning after pill filled that day and kept it in
my medicine bag until that night when I needed it. If I had not had the morning after pill with
me, I would not have had the first clue where to start looking for a doctor's
office in Detroit, let alone one open on a Saturday night when I needed it.
I
read the instructions. I followed them
exactly, took the first pill with food and then the second 12 hours later. I didn't get sick or throw up. I was just relieved I wasn't going to get
pregnant.
But
what really bothers me about this whole process is that if I happen to go to a
good doctor that is willing to write me a prescription just in case I need it,
I'm lucky. If I go to a doctor who
refuses to prescribe it in advance, I'm out of luck.
I
shouldn't have to rely on luck to control my life. I shouldn't have to rely on a doctor for a
drug that is safe and effective within the first 24 hours after sex.
We
have a lot of experts in the room today, but I have taken the morning after
pill, and I know what could have happened if I hadn't had it on hand, and I
know what could happen to me if it isn't over the counter. I think that makes me an expert.
Because
many of us who have experienced the morning after pill have so little time to
talk here, we're going to speak outside at the lunch break for the press about
our experience taking the morning after pill.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Our
next speaker, please.
MS.
HARRISON: Good morning. My name is Teresa Harrison of Ibis
Reproductive Health, a nonprofit organization that aims to improve women's
health choices on autonomy. I'm also on
the board of directors of Our Bodies Ourselves, a women's health advocacy
group.
Neither
organization receives funding from pharmaceutical companies.
Both
Ibis and Our Bodies Ourselves support the switch of Plan B to the over the
counter. In particular, we support the
switch because what we have learned about women's efforts to obtain emergency
contraception.
Ibis
research shows that women cannot get emergency contraception when they need
it. America's ERs turn women away in
their hour of need. Recently we surveyed
over 1,200 hospital emergency rooms across the country. Less than half would provide emergency
contraception to women, even those who have been raped.
Just
16 percent would provide it to any woman who needed it, and an additional 18
percent would only provide it to women of sexual assault.
Our
research also found that ERs staff are frequently judgmental or even hostile
towards callers. Some ER staff do not
value women with contraceptive emergencies.
If
Plan B were available over the counter, women without health insurance, women
without private doctors, and women who need it on weekends could get EC
directly, discretely, and with dignity.
They could also avoid an unpleasant and expensive, time consuming visit
to the ER.
Please
allow Plan B to go over the counter.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you.
Next
speaker please.
DR.
KLAUS: I'm Hanna Klaus. I'm an obstetrician-gynecologist with
extensive experience in natural family planning and teen sexuality education.
I
have no financial relationship with Plan B.
I
object to changing the status of Plan B for the following reasons, which are
documented in detail in my testimony.
There's no time for documentation here.
Progestin
slows tubal motility. Both U.K. and New
Zealand have warned doctors when they had a 5.9 percent rate of unintended
pregnancies which were ectopic. To make
a drug with that potential for an increase in ectopic pregnancy available
without medical supervision is the height of medical irresponsibility.
When
Plan B was the sole contraceptive of women with infrequent coitus, their unplanned
pregnancy rate was 6.8 percent with a 33 percent dropout rate due to side
effects within six months. People take
the course of least resistance to interact to take the drug more than once per
cycle, irrespective of warnings, and will likely turn away from it when they
experience side effects leaving them even more vulnerable to pregnancy and STD.
The
chlamydia and gonorrhea rates have risen nearly 20 percent in this country in
the last four years, concomitant to the high profile advertising of the morning
after pill which, intended or not, promote the notion that taking Plan B will
make up for the lack of sexual responsibility.
Women
also have a right to know that Plan B, if taken after conception, prevents
implantation. If they have ethical
objection to aborting an embryo at any stage, they have a right to the right
information.
And
finally, conception can only occur in six days in the cycle, making the pills
unnecessary for at least 24 days out of each cycle, and that may be fraudulent
advertising.
I
suggest you teach people their fertility cycle so that they'll know when to say
yes and when to say no.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker, please.
MS.
MOORE: Hello. My name is Kirsten Moore, and I'm President
of the Reproductive Health Technologies Project, a nonprofit advocacy
organization based here in Washington, D.C.
We
do not have a financial interest in this product. We do not accept any money from
pharmaceutical companies of any kind.
We've
been working on the issue of emergency contraception for ten years. We have greatly enjoyed our work in this
field trying to raise awareness, reduce barriers to access. We've been involved in dozens of initiatives
to promote advanced provision, pharmacy access, public education campaigns, et
cetera. These have all been fun, but
they've cost a lot of money. They've
taken a lot of money. They've taken a
lot of time. It takes a great deal to
get buy-in from the professional medical community, and our take-away message
is that medical practice is slow to change, and that it is time to put the
decision about emergency contraception, when and where to use it, in the hands
of women.
There
is no medical or public health rationale which justifies preserving a
prescription access or otherwise restricting access to this product.
Though
we are not service providers, we do have first-hand knowledge of the need for
better access to EC. Our HTP was the
original home of the hotline, and all too often has been on the receiving end
of panicked phone calls from women who were desperate to find EC, but could not
find a provider, did not wish to see their own provider, or were refused EC by
a provider.
We
know the prospect of an OTC switch prompts questions about the consequences of
nonprescription access and the fear of misuse, overuse, or general
irresponsibility. We understand these
concerns and fully support effort to insure informed responsible use of EC
among women of all ages.
However,
concerns about consequences of too much access cannot overshadow the real
consequences of the current situation:
difficult access, limited access, or no access to health care in EC
specifically lead to distress, unintended pregnancies, and abortions. It does not have to be this way. Every woman including young women deserve a
second chance to prevent an unintended pregnancy.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker, please.
DR.
JORDAN: My name is Dr. Beth Jordan. I'm the Medical Director of the Feminist
Majority Foundation, a leading feminist think tank, grassroots organization,
and publisher of Ms. Magazine.
We
have no financial incentive or relationship with Barr.
With
the largest pro choice student activist in the U.S., the Feminist Majority is
committed to working with students and providers to maximize access to
emergency contraception on the nation's campuses. Other speakers are to discuss EC safety and
efficacy in reducing unintended pregnancy and the abortion rate. I can unique inform you of the situation on
campuses by discussing the results of a recent social science study conducted
by the Feminist Majority Foundation documenting the lack of availability and
inaccessibility of emergency contraception.
College
age women are at particular risk for engaging in unprotected intercourse,
experience contraceptive failure, and being sexually assaulted. To the maximally effective, EC must be taken
within 24 hours. Barriers to timely
access place unnecessary and unacceptable burdens upon students.
In
2002, the Feminist Majority Foundation conducted a comprehensive nationwide
random sample survey of EC access on campus health clinics. The survey found that only 61 percent provide
EC or prescriptions for EC, and only 16 percent have weekend hours.
Anti-reproductive
rights politics is an obstacle threatening access to EC on campuses. Anti-abortion legislators and activists who
wilfully or naively can cite contraception with abortion increasingly infringe
upon a woman's right to choose even contraception.
Leading physicians of the 2002 American
College Health Association Conference reported to me that through intimidation,
protests from anti-reproductive rights legislators, office holders, and
activists discourage student health clinics from offering or advertising
EC. Our students deserve better.
ED
access must not be dependent on right wing politics, restrictive clinic hours
or the individual provider or the clinic provider. Empowering young women to be responsible in
preventing unintended pregnancy requires over-the-counter access to emergency
contraception 24 hours a day seven days a week.
In
2002, the Feminist Majority Foundation launched a petition gathering support
for over-the-counter access to EC. I
present more than 30,000 petitions to you as your token of support on behalf of
legions of Americans supporting this public health measure.
The
scientific evidence and public health imperative is strong and undeniable. Access delayed ‑-
CHAIRMAN
CANTILENA: Our next speaker please.
DR.
CARROLL: My name is Robert Carroll. I'm a retired physician. I'm here as an individual, not representing
any group or organization, and I have no financial involvement.
My
interest in the question of permitting over-the-counter sales of the morning
after pill stems from my concerning regarding the epidemic of sexually
transmitted disease, especially among young people.
I
practiced medicine as a general internist from 1949 to 1995. The increase in STDs in the last several
years of my practice was startling and disturbing. For the past eight years I have been
presenting elective classes on STDs to students at the local senior high
school.
As
everybody knows, our society has undergone a sexual revolution in the last 30
or 40 years. Our young people have been
encouraged to engage in sexual activity with the understanding that it was safe
and morally acceptable as long as contraceptives were used.
They
were not and are not now being adequately informed of the significant danger of
acquiring STDs with or without the use of contraceptives. There are more than 15 million new cases of
STDs every year in this country. Not all
the news is bad. For the past ten years
there has been a slow, but steady increase in sexual abstinence. This trend has been accompanied by a similar
slow but stead decrease in abortions and teen pregnancies.
It
is self-evident that over-the-counter availability of the morning after pill
will lead to increased promiscuity and its attendant physical and psychological
damage.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
The
next speaker, please.
DR.
ENGLE: Thank you for the opportunity to
present the views of the American Pharmacists Association.
I'm
Jan Engle, Associate Dean for Academic Affairs and clinical professor of
pharmacy practice at the University of Illinois at Chicago and the immediate
past president of APHA.
Decisions
to classify products as either prescription or nonprescription are best made by
the FDA incorporating a review of safety and effectiveness utilizing clinical
research information.
Part
of the review must include examining the risks and benefits associated with
increasing access to the product.
Specifically, the FDA should evaluate how this product has been used in
the prescription only environment to assess prescribing patterns and patient
use patterns that may support expanded access of the product to an OTC basis.
The
provision of the product by pharmacists under the purview of collaborative
practice agreements, agreements between pharmacists and physicians detailing
the conditions under which a pharmacist will initiate or modify a patient's
drug therapy may support the expanded availability of a product. EC is a therapy commonly prescribed under
these agreements.
Pharmacists
in more than 37 states have the authority to initiate or modify therapy under
collaborative practice agreements with physicians and other prescribers. In the case of levonorgestrel, five states
explicitly allow pharmacists to prescribe and/or dispense emergency contraception
directly to patients under collaborative practice agreements.
A
number of other states allow pharmacists to provide the therapy under
collaborative practice agreements as well.
Washington State was the first state to allow pharmacists to provide EC
in a two-year pilot. By the end of the
pilot nearly 12,000 patients consulted pharmacists for EC, 40 percent of which
were during weekends and evenings or holidays.
It's
important to note of the 12,000 interactions, many times pharmacists did not dispense
the drug because it was not appropriate.
Sixty percent of pharmacists referred at least one patient for further
care; 75 percent referred patients because of concerns of eligibility; 50
percent referred for contraceptive services; and seven percent for rape
counseling.
Clearly,
pharmacist provision of EC under collaborative agreements significantly improve
--
CHAIRMAN
CANTILENA: Thank you.
Next
speaker please.
MS.
FLOWERS: My name is Hillary
Flowers. I am 23 years old, and I
recently moved to New York City from Madison, Wisconsin. I am fully employed, and I have no health
care benefits.
When
I needed the morning after pill, I was a sophomore in college. I called tons of doctors, but they did not
want to see strangers who did not have an appointment. I finally found a female doctor who would see
me.
She
explained to me that the morning after pill was basically a higher dose of the
regular birth control pills. She gave me
a pack of regular pills and told me how many to take. I had no side effects.
The
cost of my doctor's bill was between 150 to $200.
A
few years later, I was in a serious relationship and the condom broke. In this circumstance I was contemplating
whether or not to go on birth control pill.
So I had birth control pills at my house.
I
knew from my previous experience from talking to my doctor that the morning
after pill was a higher dose of birth control pill. So I took the same amount of birth control
pills as I had taken before, and I recently learned that the number of pills
changes depending upon the brand of birth control pills you are taking. The brand of pills I had at the time was
probably not the same as I had taken, but I couldn't afford to pay $200 for a
doctor's visit, nor did I want to call 20 doctors who did not want to see
strangers.
I
risked my health in order to take the morning after pill which was so hard to
get. I'm a very healthy woman. I have no health insurance, and I am paying
student loans. What am I supposed to do
if a condom breaks? Not pay rent so I
can pay a doctor to get the morning after pill?
Take a bunch of birth control pills that I have on hand or that a friend
has that I can try to borrow and take 12 hours after?
I shouldn't have to risk my health to prevent
pregnancy. I must have the right to
control my body and my life with directions in order to know that I'm taking
the right kind of pill.
CHAIRMAN
CANTILENA: I'm sorry, ma'am. Your time is up.
Next
speaker, please.
MS.
MANGAN: My name is Kelly Mangan. I'm the Vice President of the University of
Florida Chapter of the National Organization for Women.
Women
should not be told when or under what circumstances we can control our
bodies. Yet here I stand ironically
before a panel many of whom are men having to ask for the right to control my
body and direct my life.
I
have used the morning after pill twice after condoms came off inside me while I
was having sex. I didn't get pregnant,
and I also didn't have any of these overhyped side effects I keep hearing
health professionals talk about.
I
got the morning after pill from my campus infirmary to have if I ever needed
it, but the nurse who prescribed it asked prying questions about my
relationship with my partner and how long I had known him. She also discouraged me from taking the
morning after pill again because of possible side effects, while at the same
time encouraged me to go back on birth control pills which could have far more
serious side effects than the morning after pill.
If
the morning after pill was available over the counter, I wouldn't have to spend
time and money making doctor's appointments when I needed it. I also wouldn't have to justify myself to
nurses and doctors because they disapprove of my sexual relationships, which
are none of their business anyway.
If
I could really control my fertility, meaning 24 hours a day and without having
to bed a doctor or a pharmacist for permission, then I would have more time,
more money, and more personal freedom.
Basically I would have more control over my life.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker please.
DR.
BRUCHALSKI: My name is Dr. John
Bruchalski. I'm a practicing OB-GYN in
Fairfax, Virginia and here with the Catholic Medical Association.
The
points I want to make today refer to teenagers and Plan B. Point number one, not all women have regular
cycles, especially teens. Forty-three
percent of girls have irregular periods the first year after menarche. For as long as five years one-fifth of
adolescent girls have irregular menses.
Point
number two, it's these same women with irregular cycles who are sexually
active, suffering from pregnancies and sexually transmitted diseases. We all know that two-thirds of twelfth grade
women have had sexual intercourse. We
also know that three to four million of the new STD cases this year will be
teens.
Most
teens rely on a single contraceptive to prevent pregnancy and infections when
they're using anything at all. The
reduced contraceptive efficacy relates to improper use and frequent
discontinuation of contraception.
Conversation
and counseling can help prevent this.
Therefore, without medical advice from a health professional, the use of
Plan B by teens will be disastrous.
Current
thought also says that a physical exam is unnecessary before treatment. We are educating our patients about their
options presently. Why put this potent
medication over the counter and bypass an opportunity for counseling,
especially in this affected subgroup, teen women?
I
know of no study specifically looking at teens and Plan B.
We
are sincerely passing up an opportunity to engage our teen patients about the hazards of sexual intercourse. You've heard these stories from these
presenters prior to me. It is in this
conversation and counseling that they will become more open and honest with
their medical providers.
Conversations
lead to trust. Trust leads to following
advice. Over-the-counter status
decreases conversations.
Over-the-counter status for Plan B is bad medicine.
CHAIRMAN
CANTILENA: Our next speaker, please.
DR.
KAHLENBORN: Chris Kahlenborn, Altoona,
Pennsylvania.
No
financial interests.
I'd
like to make four points against Plan B.
First, there have been no trials on the long-term effects of Plan B on
children who will be conceived if Plan B fails to prevent or abort a pregnancy. Obviously children will be conceived and
brought to term in women who take Plan B.
There has never been a single study going out ten, 15 years on what will
happen to those children, and many of us physicians and internists know well
what happened with dioethylstilbesterol when it was given to women and resulted
in an increased risk of vaginal cancer in their daughters
Secondly,
the claim that emergency contraception has a 75 percent efficacy rate could be
artificially inflated since it is based on studies whose control groups were
not properly matched against the case groups.
Usually older control groups or control groups that had lower rates of
infertility are not properly matched. That would overinflate that statistic.
Third,
women could theoretically begin using Plan B as a type of birth control. An experience from Jamaica which made
emergency contraception over the counter this past May may serve to remind us
of this possibility. Quote, pharmacists
from across the land as we have reported are ringing alarm bells. Some people are using it as sweets. People are using it more than twice a
month. Some are using it up to five
times a month.
And
lastly, the evidence clearly shows that Plan B works by causing an early
abortion, a post fertilization effect.
A
leading professor wrote to me and said ‑- a leading advocate of
emergency contraception -- "I think women should be told how emergency
contraception works, including it might work by inhibiting the
implantation" --
CHAIRMAN
CANTILENA: Sorry, sir. You're out of time.
Next
speaker, please.
DR.
HUSSAR: I'm Daniel Hussar. I'm on the faculty at the Philadelphia
College of Pharmacy, but speaking as an individual. I teach the nonprescription drug therapy
course.
I
do not have any financial or other working relationships with any of these
companies to disclose.
I
urge the members of the committee to recommend against unrestricted OTC
availability of Plan B and to recommend OTC availability of this product only
following a woman's consultation with a health professional as the pertinent
expertise regarding its use.
And
we have heard about the Washington and California models.
I'd
identify the following reasons in support of these recommendations. First of all, regarding the mechanism of
action, the package insert for Plan B notes that it may inhibit implantation,
an action that is considered by some to be an abortifacient action. To my knowledge, there are no definitive data
to identify the approximate percentage of women who may experience inhibition
of implantation.
Secondly,
safety. Some of the women who might
consider the use of the Plan B may be pregnant but do not yet realize it. A question then exists regarding the safety
of the product for the developing fetus.
To my knowledge, there are not sufficient data to demonstrate safety for
a fetus. Plan B is contraindicated
during pregnancy.
In
reviewing the package insert for Plan B, I was very surprised to observe that
unlike the vast majority of other products, there is no pregnancy category
identified, and I would urge the committee to ask why that is the case or not
the case.
Certain
other progestins, as well as the combination oral contraceptives, are
classified in pregnancy Category X, signifying the highest level of risk for a
fetus. It's reasonable to think that
Plan B should be classified in pregnancy Category X also.
To
my knowledge, no drug that is classified in pregnancy Category X is available
without a prescription.
Third,
other implications, as others have mentioned.
I have concerns about the extent of the risk of sexually transmitted
infections. I think the availability of
Plan B without restrictions would increase or would reduce safe sex precautions
which could lead to the increase in consequences, such as STDs.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker, please.
MS.
BOONSTRA: On behalf of the Alan
Guttmacher Institute, I thank you for this opportunity to comment on the new
drug application proposing over-the-counter use of Plan B, the FDA approved
emergency contraceptive.
AGI
is an independent, not-for-profit organization focusing on reproductive health
research, policy analysis, and public education in the United States and
internationally. The institute does not
have any financial relationship with Plan B, the sponsor, or its direct
competitors.
Moreover,
Sharon Camp, founder and former President of WCC and now President and CEO of
AGI, has no financial interest in WCC.
Timely
access to emergency contraception is one of the most promising avenues for
lowering unintended pregnancy and reducing the need for abortion in the United
States. Most U.S. women at risk of
unintended pregnancy over nine and ten are using contraceptives. But some have difficulty using contraception
correctly or consistently, and contraceptive methods do fail.
Approximately
half of unintended pregnancies in the United States occur among couples who are
using contraceptives in the month they become pregnant. Data indicate that emergency contraceptive
use has already played a significant role in reducing U.S. unintended pregnancy
and abortion rates.
Even
with limited access to and awareness of the method, recent AGI research finds
that emergency contraception averted 100,000 unintended pregnancies in the year
2000, including an estimated 51,000 abortions.
We
ask the committee to give full and fair consideration to the question of OTC
status. The panel should make a science
based recommendation, treating the pending application as it would any other
proposed switch from prescription to OTC status.
This
application should not be held to a different standard simply because the
product involved is a contraceptive method.
We
thank the committee and would be happy to respond to any questions it may have.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker, please.
DR.
COLLITON: My name is Dr. William
Colliton. I'm a retired OB-GYN professor
from the George Washington University Medical Center. I understand that you have copies of my
statement, which time prohibits getting into.
I
do want to draw your attention to the appendices behind the statement. The first one is a page containing two graphs
that show the incidence of divorce and the incidence of gonorrhea encountered
over time, the time frame beginning in 1920 and ending in 1980. You can see that there was a blip in both
graphs during World War II, very, very understandable when young people are
torn from their families and from their loved ones and get into extramarital
intercourse and the love bug jumps up and also the rate of divorce jumps up.
Then
you see that these curves beginning in 1960 take a dramatic turn up to the
upper right-hand corner of the graph going out of sight. This is because in 1960 the birth control
pill and the IUD were marketed and being efficacious contraceptives and
abortive agents. They gave rise to the
ability to have a sexual revolution.
The
second graph that I wanted to draw your attention to is a demonstration of the
total ineffectiveness of the approach to eliminating teenage pregnancy under
Title X. The data begins in 1971 and
ends in 1999.
You
should understand that during that time frame 4,085,000,000 of your tax dollars
were expended in an attempt to eliminate the problem of teenage pregnancy with
no effect whatsoever, except to worsen the problem.
The
problem got so bad that the Alan Guttmacher Institute and the federal
government stopped putting the data out in 1990.
It
turns out that since --
CHAIRMAN
CANTILENA: I'm sorry, sir. You're out of time.
Next
speaker, please.
MS.
COLEMAN: Good afternoon. I'd like to address you from three
perspectives. First, as a forensic
nurse.
In
New York State, it is estimated that only 16 percent of women who are raped
ever tell anyone. Even less than that
seek medical attention.
How
many women are missing the opportunity to prevent a pregnancy as a result of
being raped because they don't go to a hospital?
Second,
as an advocate, violence against women is a public health issue as well as
crime victims issue. Access to emergency
contraception is a public health service, as well as standard medical care
following a sexual assault.
While
New York State has finally passed legislation requiring all hospitals to have
EC available on site to those rape victims who request it, this law does not
benefit those victims who avoid or opt not to seek medical attention
immediately after being raped.
Making
EC available over the counter will increase access to those thousands of women
who opt not to go to the emergency department.
And,
third, as a rape survivor, nine years ago I was tied to my bed, gagged, and
raped at knife point. I know first hand
about the shame, the humiliation, the degradation, the fear, the guilt, and the
self-blame that rape victims go through.
It
has been said by some that by providing emergency contraception over the
counter this will decrease reporting of rape to criminal justice services. I disagree.
It's the same, the degradation, the self-blame, and what victims have to
go through when they disclose publicly, especially the perpetrator is someone
famous, that decreases reporting.
Should
these women also have to endure unwanted pregnancy because they choose not to
speak out or not to seek medical attention in a public forum? I urge you on behalf of past, present, and
future rape victims to please help increase this access to a much needed public
health service and to a standard of medical care.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker, please.
(Applause.)
MS.
LEADER: Hi. My name is Alexandra Leader, and I'm 35 years
old. I am co-chair of Red Stockings
Allies and Veterans, a New York City based women's liberation group.
I
got pregnant when I was 23. My boyfriend
and I used condoms for birth control. I
used condoms, and I still do, because I thought they were my best bet at
protecting me from STDs.
After
a year of us going out, the condom came off inside of me while we were having
sex. I knew I was midway between my
periods, and so there was a good chance I could get pregnant, but I decided not
to get the pill that time because I heard it makes you throw up a lot, and also
I was very busy and didn't want to take the time to wait at the doctor's office
for a prescription.
Well,
I got pregnant. The side effects of
pregnancy were feeling tired and awkward for weeks and weeks until I could have
an abortion, which then cost me over $400.
A year earlier, I had led my NOW chapter in a campaign at the University
of Florida to get a pharmacist fired for refusing to prescribe the morning
after pill.
But
even with my activist experience with the pill, I still didn't know that its
side effects had been wildly exaggerated.
I hadn't heard women talk about taking it like we're doing here today.
This
is why women need to speak out from our own experiences with the morning after
pill and birth control to find out what's really going on.
I
have since taken the morning after pill six times over the course of ten years
when my birth control did not work. It
actually allows me to use condoms because it's my backup to a slipped or broken
condom.
I
now make sure I always have it at home.
I've gotten it for free through friends in the health care
professions. I've never thrown up and
had little or no side effects each time, and I haven't been pregnant again.
Twice
I experienced mild jitters. That's
it. And it's much cheaper with much less
side effects than weeks of waiting and feeling like your body isn't your own if
you get pregnant --
CHAIRMAN
CANTILENA: I'm sorry, ma'am. You're out of time.
Can
we have the next speaker, please?
MS.
ALLINA: I'm Amy Allina from the National
Women's Health Network. The network
accepts no financial support from pharmaceutical companies and has no financial
stake in Plan B or its competitors.
The
network is here to urge the committee to recommend approval of the application
to make Plan B available without prescription.
Our brief comments will focus on consumer understanding and awareness of
the product and how this affects the question of whether the prescription
requirement can be removed while still insuring that the product is safe and
effective for women.
Though
EC has been known for decades to prevent pregnancy after sex, it has not been
widely used. Even with two dedicated
products on the market and despite national education campaigns, awareness of
EC in the United States is still low among women and among health care
providers.
Because
EC is not widely known to consumers, there may be concerns about whether women
have enough information to use it correctly
without the assistance of a prescriber.
The
network has a longstanding commitment to insuring that women have good information
about drugs they use, dating back to our earliest work advocating for the
inclusion of patient information with oral contraceptive pills in the 1970s.
In
the case of a nonprescription product, patient information is even more
important. For a nonprescription product
to be used correctly, consumers must be able without the assistance of a health
care provider to understand the approved indication, any contraindications and
safety concerns, and instructions for correct use.
We
believe Plan B easily meets that standard in actual use and label comprehension
studies women have shown that most can understand the product information
without the assistance of a health care provider. By including young women and over sampling
women of low literacy in the studies and by amending the proposed labeling to
respond to concerns about the understanding of those women, the company has
provided additional assurance that women of varying ages and educational
background will be able to use the product correctly.
Moreover, there's no additional
information that prescribers or pharmacists are providing to women which would
make EC safer or would make actual use more effective.
This
is a safe and effective product, and ‑-
CHAIRMAN
CANTILENA: I'm sorry, ma'am. You're out of time.
The
next speaker, please.
MS.
JUDIE BROWN: Good morning. My
name is Judie Brown. I am the
President of American Life League. We
represent over 350,000 American families, and because my testimony includes as
a backup all of the clinical information to which I will refer in my comments,
I would invite you to read that.
Emergency
contraception, first of all, is not contraception. So-called emergency contraception can by
definition abort a child before that child implants. A human being begins at conception, not at
implantation. Pregnancy begins at
conception. It does not begin at
implantation.
If
a human zygote cannot implant, he or she will die. This means that the pills act to prevent
pregnancy by aborting a child. For this
reason alone the pill should not be available under any circumstance and
certainly not over the counter.
The
composition of Plan B, the particular brand of pill being discussed today, is
such that two pills contain a lot of levonorgestrel, a chemical that can
contribute to heart problems, circulatory problems, blood clotting, ectopic
pregnancy, and more. There is more than
adequate documentation in the medical literature to suggest that these pills
are not only dangerous, but if given without access to a complete medical
history, potentially deadly.
As
you are, no doubt, aware, a medical history is required prior to the
dispensation of the birth control pill.
Why isn't the same being required of the morning after pill?
Over-the-counter
status immediately removes this safeguard.
Who is going to be liable if a woman who ingests these pills suffers a
deleterious side effect? It won't be the
U.S. government.
Pills
such as Plan B are designed with one purpose in mind: to destroy the evidence that a sexual
encounter has occurred that could result in the conception of a child. The emergency in this case is a baby. If these pills are made available over the
counter, adolescents who might have given such a result a second thought will
not be inclined to take pregnancy into consideration before engaging in risky
sex --
CHAIRMAN
CANTILENA: I'm sorry, ma'am. You're out of time.
Next
speaker, please.
MS.
SEGUIN: My name is Stephanie
Seguin. I'm the Vice President of
Gainesville, Florida National Organization for Women. I'm also the chair of the Florida NOW Young
Feminist Task Force.
In
1999, I studied abroad in France. I was
sitting outside late one night at a bar when these men rode up on bicycles
wearing tee shirts that said "Help" in French. They were handing out condoms and packets of
pills. I didn't know what the pills
were. So I asked my host mother the next
morning and in broken English she explained to me that it was the "if you
think you might be pregnant and don't want to be" pill.
I
figured it was the morning after pill I had heard of and was happily amazed at
how easily you could get it. It made me
think of the time I had needed the morning after pill here in the United
States. My boyfriend at the time, who is
now my husband, and I had had sex and the condom came off. The following morning, which was a Saturday,
I braved the football game day traffic, which in Gainesville can be rough, to
go to the campus infirmary which was closed.
I had no idea where else I could possibly get it. So I just crossed my fingers and hoped that I
wouldn't be pregnant, have to drop out of school, and move back home with my
parents.
How
great it would have been if I could have just had it in my bathroom cabinet or
ran to the local drugstore to get the morning after pill.
Women
deserve access to the morning after pill any time, anywhere, and for any
reason. And as for an age restriction,
unwanted pregnancy is much more disruptive and dangerous when you're young. As a result of not taking the morning after
pill when you're 14 means having a baby when you're 14. The morning after pill should be easily
available to women of all ages, any time for any reason.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Next
speaker please.
MS.
BOGGESS: I'm Jane Boggess with the
Public Health Institute.
Our
organization in California has sponsored legislation to allow direct pharmacy
access in that state. We currently have
about 800 pharmacies that provide EC and current usage suggests that we serve
about 150,000 women a year.
Pharmacy
access may look good from here, but remember that when it was first started, it
was considered radical. Policy makers
and others raised all kinds of concerns and worse case scenarios. None of them have come to pass.
Instead
the EC pharmacy program in California and in other states -- and I'd like to
note that the both Republican and Democratic governors have brought up EC
pharmacy programs -- EC usage in California, direct access, has shown the
tremendous need for this product.
Contraception
fails at all times of the week, and often it's not consistent with access to a
clinic or access to a doctor's office.
Despite
the advances and successes, gaps remain in California. One million dollars later and still about a
third of the rural counties don't provide emergency contraception.
Further,
these programs have passed on costs to consumers. The pharmacists, rightfully so, believe they
should be paid for their time in providing the service. It's still a prescription setting in
California, and this has been a prohibitive cost to many especially low income
consumers.
While
it has been helpful to have pharmacists involved, the bottom line is that in
California we've always viewed this as transitional. State authority to expand access to EC is
limited. It's both costly and very
cumbersome to implement, and it's no substitute for federal FDA action.
In
short --
CHAIRMAN
CANTILENA: I'm sorry, ma'am. You're out of time.
Next
speaker, please.
MS.
HENRIQUEZ: Hi. My name is Silvia Henriquez, and I'm with the
National Latina Institute for Reproductive Health, and we do not have any
financial relationship with this pharmaceutical company or any others.
The
National Latina Institute for Reproductive Health fully supports making Plan B
available over the counter. We believe
that the availability of over-the-counter emergency contraception can play a
dramatically important role in reducing unintended pregnancies, abortion, and
sterilization rates among Latinas.
Additionally,
it is likely to benefit an especially vulnerable population, namely, the
disproportionately high numbers of young, low income, and underinsured Latinas
with limited access to family planning and reproductive health care services,
who may experience contraceptive failure or unprotected sexual intercourse.
We
believe Latinas are a key constituency whose reproductive options could be
greatly improved by the provision of over-the-counter emergency
contraception. At present, accessing EC
is made difficult for many Latinas who do not have a regular health care
provider, are unable to take off from work within the 72-hour time horizon, and
who cannot afford the cost of a health care visit in order to secure a
prescription for emergency contraception.
Latinas
face formidable obstacles to procuring reproductive health services. At present the promise of emergency
contraception is exactly that, a mere promise.
Latinas are disproportionately poor and uninsured, and many must rely on
understaffed, financially distressed public health institutions for their care,
sometimes waiting weeks or months for an appointment.
Against
this backdrop, it is unlikely that many Latinas will be able to access
emergency contraception within the required hour time frame. Over-the-counter EC presents a safe and
equitable solution that will enable many more Latinas and low income women to
make use of this important reproductive option that can substantially reduce
the number of unintended pregnancies and abortions in this country.
For
these reasons the Latina Institute for Reproductive Health fully supports
making Plan B --
CHAIRMAN
CANTILENA: Thank you, ma'am.
Next
speaker, please.
MS.
VERA BROWN: My name is Vera Brown, and
I'm a sophomore at the University of Florida.
I'm also a committee chair for the Campus National Organization for
Women.
Last
spring was my first and only experience with the morning after pill. As a college freshman, I wasn't able to have
a child or afford the $500 needed to have an abortion. Luckily, a few weeks before that I had
attended a Campus NOW meeting where I learned about the morning after pill, and
I was told that it was available at my college infirmary.
The
morning after pill didn't give me any side effects at all. In fact, I'm not on any birth control pill at
all because they don't offer one birth control pill for a woman suffering from
hypertension, as I do.
After
hearing stories of other women who tried to get the morning after pill, I
realized that I had a somewhat positive experience, but I also realized that it
was through the feminists before me who fought continually to make sure that I
had a positive experience, as you should.
But
the problem that I have is what happens when I'm not a student anymore. What happens when I'm a mother, a
professional, a grandmother? Does that
mean that I have to go through the same horror stories that I heard other women
go through?
As
a woman, I deserve equal accessibility to the morning after pill no matter what
station in my life. Any compromise for a
woman to have the right to get the morning after pill is discrimination of all
women and her right to control her body.
Thank
you.
(Applause.)
CHAIRMAN
CANTILENA: Thank you.
Next
speaker please.
MS.
PETRAITIS: Hi. Good morning.
I'm Carol Petraitis of the Clara Bell Duvall Project, and unfortunately
the co-author of my paper, Wendy
Bennett, was unable to be here today.
She's seeing patients at Bayview
Hospital in Baltimore.
But
I'm grateful to be here to tell you about our study of community pharmacies in
Pennsylvania, and we have no financial disclosures with the sponsor of the
drug.
Our
study was designed to determine knowledge and attitudes about EC among
pharmacists. We surveyed about ten
percent of the pharmacies in Pennsylvania.
The study was IRB approved, and it was published in Contraception
this October.
Hopefully
all of you received copies of it in your briefing packets.
Part
of our motivation for conducting the study came from our work with rape
victims. Many victims who visit
emergency departments in Pennsylvania do not receive EC there, but leave with a
prescription, and we wanted to learn how easily they could fill that
prescription.
Of
course, our findings apply to any woman seeking emergency contraception,
whatever her reason.
Unfortunately
our results were very discouraging.
Sixty-five percent of the pharmacists that we spoke to said that they
could not fill a prescription for EC that day.
The majority, 79 percent reporting that the product was not in
stock. Thirteen percent confused EC with
RU-46, the French abortion pill, or abortion.
Six
percent said that dispensing EC was against the store's policy. Seven percent said it was against their
personal beliefs, and finally, pharmacists in rural areas were much
significantly less likely to be able to provide EC than those in urban areas.
In
conclusion, our findings demonstrate that pharmacists pose a significant
barrier to emergency contraception both for victims of rape, incest, and for
women experiencing contraceptive failure.
Therefore,
we strongly endorse the proposal to make emergency contraception available over
the counter.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you.
Next
speaker, please.
MS.
GUBRIUM: My name is Erika Gubrium. I'm 30 years old and a member of Gainesville,
Florida National Organization for Women.
I've
been taking birth control pills for the last six years. Recently, however, due to financial
difficulties, I decided to stop taking the pill.
Last
month I had sex and the condom broke.
This occurred during a vulnerable time in my cycle. So I was worried that I might get
pregnant. Not having the money or time
to see a doctor to get the morning after pill, I waited for my period, which
was supposed to come within the next few days.
It didn't come.
After
several days I was even more worried. I
had heard that home remedies, like taking a bunch of birth control pills could
work in the same manner as taking one lower dose morning after pill. So I took several pills that I had left over
from my prescription, which caused me to feel nauseous and irritable, and then
I waited.
A
week later, with extreme relief, I got my period. I can't imagine what I would have done had I
been pregnant. As a full-time Ph.D.
student, I'm also working three jobs just to pay my rent. I can't afford to have an abortion right now,
much less have a child.
Because
of lack of access and the well kept secret of how the morning after pill works,
I was forced to come up with my own homemade remedy. As I see it, the only difference between
taking a pill once a day every day and taking a pill once after contraceptive
failure or unprotected sex is that a woman like me doesn't have to hand over
half her paycheck to buy a daily birth control pill or schedule an expensive
appointment with a doctor to protect herself from an unwanted pregnancy.
Based
on my experience, I can tell you that requiring women to get a prescription for
the morning after pill poses severe obstacles to its availability. Women must have unrestricted over-the-counter
access to the morning after pill.
Thank
you.
CHAIRMAN
CANTILENA: Thank you.
Our
next speaker, please.
MS.
STANEK: Hi. My name is Jill Stanek. I'm a registered nurse with ten years'
experience, the bulk of which is in the hospital labor and delivery department.
I'm
here on behalf of Concerned Women for America.
I'm
focusing my testimony today on the disastrous effects that ECs would have to
minor girls if they were made available without prescription. Because there have been no long-term EC
studies performed, endorsement of their over-the-counter use by the AMA, ACOG,
and Family Planning Centers must be to thwart getting sued for not providing
informed consent. I can see no other
logical reason why responsible physicians would intentionally forego the
opportunity to assess, diagnose, treat, and educate their patients.
There
is significant potential for abuse and misuse of ECs. Making ECs available would be a welcome tool
for adult sexual predators who molest family members, children of friends or
students. They could keep a stash in
their bedroom drawer or their pocket to give their victims after committing
each rape.
Alan
Guttmacher Institute reported the younger women are, when they first have
intercourse, the more likely they to have had nonvoluntary sex. Planned Parenthood reported teenager girls
with older partners are more likely to become pregnant than those with partners
close to their own age.
NARAL
identified the link health care professionals provide girls who seek EC
use. They stated, "The need for
emergency contraception can bring young women into family planning centers
where they can receive other health care services and counseling."
Dr.
Jocelyn Elders co-authored a commentary in JAMA that said, "Pregnancy may
be the sign of ongoing sexual abuse."
She concurred with Planned Parenthood --
CHAIRMAN
CANTILENA: I'm sorry, ma'am. You're out of time.
Next
speaker, please.
MS.
GANDY: My name is Kim Gandy. I'm President of the National Organization
for Women, and we have no financial interest in this proceeding.
Our
organization has for nearly four decades advocated and supported the wide
availability and accessibility and affordability of all forms of safe and
effective contraceptives. Therefore, it
is our very strong urging that these committees recommend to the Food and Drug
Administration that they make emergency contraception available over the
counter.
As
its name suggests, this is about responding to emergencies, emergencies that
are the result of unprotected sex or contraceptive failure. Making Plan B available over the counter
would significantly reduce the stress and trauma experienced by women in these
emergency situations while preventing thousands of unwanted pregnancies.
You've
already heard from several of our activists about their experiences in the
United States and abroad.
EC
is not only a safe and effective method to prevent unwanted pregnancy. It can also empower women who have been raped
with a sense of control and provide an important means to help them cope with
the trauma of sexual assault.
In
one survey when calls were made to health providers during business hours, only
three out of every four attempts to obtain emergency contraception resulted in
appointments or telephone prescriptions within the key 72 hours. Because EC is more effective when it's used
earlier and most effective within 12 hours, these obstacles pose a serious
threat to women's health.
Women
need to have access 24 hours a day, seven days a week.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you.
Next
speaker please.
MS.
McGRAW: Thank you very much.
I'm
Deven McGraw of the National Partnership for Women and Families. We're a nonprofit, nonpartisan advocacy
organization that promotes quality health care for women. We have no financial interest in Plan B, the
sponsors, or these proceedings.
I
can't speak to the interest of Hugh Hefner, young playboys or sexual predators
in these proceedings, but I can tell you that the women we represent are very
much in support of making Plan B available over the counter for two primary
reasons. One is the access issue, which
has been discussed a lot. So I won't use
my dwindling time here to go into that.
But
the one I want to draw attention to is the issue of increased opportunities for
education. I have two postgraduate
degrees. One of them is a Master's of
Public Health. I've been fortunate
enough to always have a regular health care provider. Until I started doing work on this issue for
my organization, I didn't even know about emergency contraception.
If
you make Plan B over the counter, it
will provide a significant, quite frankly, financial incentive for the sponsors
to educate women both about how this product is to be used, what is the
mechanism of action, what are the side effects, if any, what are the
contraindications, which as far as I can tell are none, and how its appropriate
use as a contraceptive device for emergency purposes.
The
other thing I want to speak to is this notion that if you make it available
over the counter it will somehow be misused or abused by women, and quite
frankly, we think that that is both insulting to women's intelligence and
mischaracterizes how they make reproductive health care decisions.
We
trust women to make decisions about use of over-the-counter medications, both
for themselves and for their families, including children, for a range of
products for which the side effects and the potential adverse effects for
misuse are much more serious than those for Plan B, and we encourage you to
judge this product based on those same standards as you would for any
over-the-counter medication, based on the scientific criteria.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you, ma'am.
(Applause.)
CHAIRMAN
CANTILENA: Next speaker, please.
MR.
ULMANN: My name is Andre Ulmann, and I'm
the CO of HRA Pharma. We have no
business relationship with Barr.
HRA
Pharma is the French pharmaceutical company which has registered Norlevo, a
levonorgestrel only emergency contraception, in over 50 countries. Norlevo's first registration in France in May
'99 was soon followed by a switch to a nonprescription status, a move
subsequently made by a majority of European countries.
In
all but two of these countries Norlevo is delivered by pharmacies without
prescription. Only in Norway and Sweden
is Norlevo available directly over the counter.
Today
women in 27 countries worldwide can obtain Norlevo without a doctor's
prescription, which corresponds to over 27 million women of childbearing age in
Europe and a total of nearly 80 million women worldwide. As part of a country that facilitated the use
of Norlevo, especially in nonprescription settings, HRA Phara recently obtained
approval for administration of two tablets in a single intake.
Here
we wish to make public information that confirms the safety of nonprescription
emergency contraception which is presented by Dr. Erin Gainer.
DR.
GAINER: My name is Erin Gainer. I am in charge of research and development at
HRA Pharma.
Our
post marketing safety database now contains information on over seven million
levonorgestrel emergency contraception treatments, and all of the periodic
safety update reports filed since first registration have concluded that the
benefit-risk ratio is positive.
In
addition, HRA Pharma has undertaken a series of studies to evaluate the process
and outcomes of this switch to nonprescription status. A retrospective prescriber based study in
France confirmed the safety and efficacy profile of Norlevo in real world
use. French, Norwegian, Portuguese and
Swedish women interviewed following use of Norlevo on a nonprescription basis
confirmed that they were able to diagnose their need for emergency
contraception understand how to use it and comfortably manage any side effects.
Furthermore,
these users expressed their comfort with and praised the practicality of
nonprescription access to emergency contraception. Ongoing research will assess the experience
and practices of emergency contraception users during the six months following
dispensation in a pharmacy.
Emergency
contraception has been held as one solution to prevent unwanted pregnancy and
pregnancy termination. HRA Pharma has
been closely following abortion figures since Norlevo launch in European
countries.
Recent
official statistics from Finland show a six percent decrease in pregnancy
terminations in the first half of 2003 as compared to the same period in 2002,
with the largest decline of about ten percent of parented women under 20 years
of age. According to a Finnish official,
the decrease in abortions is likely a consequence of, among other things, the
fact that emergency contraception has been available in pharmacies without a
prescription since May of 2002.
We
testify today to the consistently positive benefit-risk profile we have
observed over four years of experience with nonprescription access to Norlevo
emergency contraception.
CHAIRMAN
CANTILENA: Okay. Thank you.
Next
speaker, please.
MS.
CHURCHILL: Hi. My name is Candi Churchill. I'm with Gainesville Women's Liberation out
of Florida, and I have a display with them, not yet.
Some
argue that -- not yet. Oh, well -- some
argue that making the morning after pill over the counter like aspirin and cold
medicine is going too far and although the morning after pill is safe, women
should be able to obtain it only through a pharmacist prescription.
I
disagree. The morning after pill should
immediately be made over the counter, and it should be affordable and
accessible to women of any age, particularly young women.
The
United States should follow the lead of at least 37 other countries which
already provide women access to this safe backup birth control method without
restriction. The science and the studies
have been done. It's time to catch up
with most of the world.
Requiring
women to reveal the details of sexual activity to a pharmacist who may be a
stranger, or worse, a friend of your family, is humiliating and
unnecessary. Women should be able to
have the morning after pill around before a problem arises.
Will
pharmacists be willing to give women the woman after pill just in case? Some will; some won't. It shouldn't be in their hands. It should be in the hands of women.
In
1991, a pharmacist at my college, the University of Florida, refused to
dispense the morning after pill. If over
the counter women will make sure we have a current dose in our medicine
cabinets at home for ourselves and friends who need it, just like women have
other medical supplies for their families.
Finally,
we should be able to send a man to pick up the morning after pill. After all, they're at least half of the
problem that we're in this situation.
(Laughter.)
MS.
CHURCHILL: The only way a man can go
pick it up for us is if it's over the counter.
I
hope you will vote to make the morning after pill over the counter. Women will settle for nothing else.
Thank
you.
(Applause.)
CHAIRMAN
CANTILENA: Okay. Thank you.
The
next speaker, please.
MS.
TAYLOR: Hi. My name is Jennifer Taylor, and I'm the
Director of Communications for Human Life International, an international
educational postulant, and I'm prepared to read a statement today, but it's in
your packet and I'll let you read it, and instead I decided to speak from my
heart.
Most
of the women who have spoken here today from the National Organization of Women
and other groups have said they obtained the pill from the recommendation, encouragement,
and sometimes even pleading of their physician, admitting the benefit of having
access to such a physician. And some of
these women even said, "And thank God for these doctors."
Yet
they're asking you to keep other young women from the advice they might
otherwise receive from their physicians.
Also
today we've heard a lot about the failure of the condom. In fact, I think every one of these young
women mentioned the condom failed them.
Yet the organizations these young women represent are the same
organizations that applaud the condom and work overtime to make it available in
such places as Africa where HIV and AIDS rates are only increasing. Do they think the condom works better in
Africa?
My
point: these young women have very
touching testimonies. Their emotion
behind their stories may want to make you, incline you to support
over-the-counter use of Plan B.
Another
common thread that runs through these stories is the inability to control
themselves in sexual situations. As a
young woman how sad it is to know that these women are slaves to their bodies
and that the organizations they represent lead them to believe that they
themselves cannot control themselves, but have to rely on pumping themselves
full of drugs.
I
am 30 years old and I've been married for two and a half years. I don't believe in contraception, and I don't
use it, and I've never been pregnant, and my husband and I don't abstain as
much as people might want to make you believe they do when it comes to NFP.
I've
been taught natural family planning, and I know how to use it. I'm the one who's truly free because I'm not
on the pill. I'm not a slave to my body,
and I'm not a slave to the ideology of any organization. I don't have the stress and the worry and the
anxiety that these other young --
CHAIRMAN
CANTILENA: Okay. Thank you.
I'm sorry. Your time is up.
Next
speaker, please.
REV.
TILLER: My name is Reverend Robert
Tiller, and I represent the Religious Coalition for Reproductive Choice.
I
have no financial relationship with Plan B or other conflict of interest to
disclose.
The
coalition is a 30 year old organization whose members include agencies of the
Episcopal Church, Presbyterian Church USA, United Church of Christ, United
Methodist Church, Unitarian Universalist Association, and Reform and
Conservative Judaism.
There's
broad consensus that unintended pregnancy is a serious public health problem,
that it has a negative impact on family life, and that reducing unintended
pregnancy will strengthen families.
Emergency
contraception has been proven to be a safe and effective way to reduce the
rates of unintended pregnancy, and we urge the FDA to approve this application.
Objections
to this application come from groups opposed to abortion because of their own
particular religious view that a fertilized egg is a person. Their objections can be ignored because it
has been shown that emergency contraception does not cause abortion.
These
groups also claim that women cannot be trusted to use EC without supervision
and that EC causes promiscuity. Such
claims are not only unfounded, but they also deny that women can make moral
decisions, and they attempt to incorporate narrow religious views into health
care regulations that affect us all.
Currently
obstacles in the health system hinder women's ability to decide in a timely
fashion whether to take EC or not. The
role of the FDA after ascertaining the safety and efficacy of this drug should
be to remove unnecessary barriers to its access. Women must be trusted to make moral decisions
about its use according to their own beliefs and circumstances.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you.
Our
next speaker please.
DR.
THOMAS: Amen, Reverend.
My
name is Albert G. Thomas. My specialty
is OB-GYN. I'm a member of PRCH,
Physicians for Reproductive Choice in Health, and we have no financial
interest.
I
strongly encourage the U.S FDA advisory panel to grant over-the-counter status
to emergency contraception pills. Given
the unacceptably high annual number of three million unintended pregnancies
every year, the extensive scientific research in the efficacy of EC, and my own
clinical experience of almost 19 years, I believe that the over-the-counter
availability will remove unnecessary and harmful barriers of a highly
effective, entirely safe product that has proven integral to decreasing the
U.S. abortion rate.
I
am an attending physician at Mount Sinai Medical Center in New York City. Just two weeks ago a 25 year old patient came
to me for routine yearly exam. At the
end of her exam, she thanked me for being her doctor. I asked her why.
She
then related a story that occurred on a Sunday morning that January, last
January. At that time she experienced a
condom break at 3:00 a.m. She called me,
and of course, I called the pharmacist who dispensed the medication from one of
New York City's all night pharmacies.
She
then proceeded to explain that she was hesitant to contact me at that late
hour. I repeated my usual spiel about sleeping
near the telephone with high expectations of receiving calls from pregnant and
laboring patients, in addition to patients with reproductive emergencies,
especially broken condoms.
I
then began to consider the nearly three million women in the U.S. who didn't
call their physician, who became pregnant against their wishes under similar
circumstances, who chose to have an abortion or who felt forced to make the
heart wrenching decision to give the unwanted child up for adoption.
Imagine
the impact of unfettered access to EC in
all of those couples. Imagine their
avoidance of emotional stress that will result when a woman is allowed to walk
into any pharmacy and obtain this postcoital contraceptive with any of our
permission. I hope that you, the
Advisory Commission experts, will heed the medical and scientific data strongly
suggesting the increased EC access will decrease death resulting from pregnancy
related complications. This fact alone
should establish over-the-counter availability of EC for all women as a crucial
public ‑-
CHAIRMAN
CANTILENA: Okay. Thank you very much.
That
concludes the open public hearing. I
wish to thank all of the speakers for staying on time, and I apologize to the
ones who we had to cut off for time.
We
will now break until 2:00 p.m., an hour and eight minutes for lunch. Just before we go to lunch, let me remind the
committee members to refrain from discussions of the topic of the meeting
during lunch, and any committee members who want to go to the back door of the
restaurant, please gather up here at the head of the table.
And
the committee members are having lunch in the Tack Room, and if you come up
here, we'll show you how to get there.
Thank
you.
(Whereupon,
at 12:50 p.m., the meeting was recessed for lunch, to reconvene at 2:00 p.m.)
AFTERNOON
SESSION
(2:01
p.m.)
CHAIRMAN
CANTILENA: Okay. Let's go ahead and get started if the
committee members can please take their seats.
This
afternoon what we plan to do is start out by allowing the committee to ask
clarifying questions of the sponsor or FDA for issues that have come up during
the morning, and I would ask the committee members to hold themselves to one
question each time on each round, so to speak, so that everyone has a chance to
speak.
Then
after we do the clarifying questions, we'll have a general discussion about the
safety and the actual use studies, and then we'll actually go to the questions
for the committee at the end.
The
format for the questions for the committee will be that everyone has a chance
to answer individually and explain their answers either way so that you'll all
have a chance to comment on each and every question, and I know that does add
some time, but I think that's very important in terms of what the FDA is hoping
to gain from this committee meeting.
So
let's first open it up for clarifying questions for the sponsor and for FDA
that have to do with the safety of the switch.
Yes,
Dr. Uden.
DR.
UDEN: During one of the presentations we
had by Daniel Hussar, he talked about the pregnancy X status or what is the
status of this product in terms of pregnancy?
CHAIRMAN
CANTILENA: That's for FDA.
DR.
GRIEBEL: I'll start the answer, and then
I think Dr. Kweder will want to add on.
The
current prescription Plan B labeling includes information on pregnancy. There is under precautions a subsection,
"pregnancy." It does not have
a so-called pregnancy category assignment, and in fact, we have a guidance that
we're working on where we are removing pregnancy category assignment to the
oral contraceptive labeling.
I
think Dr. Kweder may want to follow up.
DR.
KWEDER: I think Donna has covered it.
The
reason for that is that the only reason that the oral contraceptives carry
pregnancy Category X, which is that not
because they are a risk; it's only because you wouldn't intentionally use an
oral contraceptive if you knew you were pregnant. And so it's really a quirk of the regulation
and how they're written that they have the Category X.
We've
endured a great deal of criticism from the medical community about having that
category on oral contraceptives, and so as Dr. Griebel stated, we're going to
be removing it and just putting information about what to expect or to be
concerned about, if anything, should an exposure in pregnancy occur.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Lockwood.
DR.
LOCKWOOD: I actually had a guess, I
guess, for both the FDA and the manufacturer about the labeling specifically as
regards breast feeding. It says,
"If breast feeding, ask doctor before use," and I'm unaware of any
literature whatsoever that even long-term progestin only contraceptives have
any ill effect on breast feeding. In
fact, they seem to have some beneficial effects in breast feeding.
Certainly
there shouldn't be any beneficial effect whatsoever from a short course like
this. So why is the labeling there?
DR.
GRIEBEL: Could I clarify? Is that in the prescription label or is
that -- it's in there. Okay.
Dr. Ganley just sidebarred me and told me that that is actually required
labeling for an OTC product, but we would be interested in hearing your
comments on whether you think it's necessary.
DR.
LOCKWOOD: No.
(Laughter.)
CHAIRMAN
CANTILENA: Well, thank you for being
brief.
Any
further questions concerning clarifying?
Yes, Dr. Hager -- I'm sorry. Dr.
Clapp first.
DR.
CLAPP: My question was about breast
feeding, the same question. But I would
add that as a pediatrician who receives those calls all day and night, I don't
think it's necessary to include it on the labeling because it, first, suggests
to the potential buyer that there is a reason for concern, and I don't think
there is.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Tinetti.
DR.
TINETTI: -- or for the sponsors, and it
has to do with safety to the fetus and/or child if there is a pregnancy, and
for the packet there was some illusion to the fact that there hasn't been any
identified problems with it, but I guess my question is how systematic has been
the evaluation and follow-up of pregnancies that come to birth and safety in
that population.
DR.
DAVIS: I can just say that it is
extremely difficult to get accurate data on pregnancies and their follow-up
with exposure to literally any drug, but certainly to your, you know,
contraceptives, steroidal hormones.
Now,
we do know from large epidemiologic studies with oral contraceptives where
women have taken the oral contraceptive literally for three months in the beginning pregnancy, and there has
been no hard data that has shown an association or risk factor with oral
contraceptives taken for several weeks or months in a pregnancy.
And
there is no data that I'm aware of of a teratogenic risk with levonorgestrel
only from oral contraceptives or emergency contraception.
CHAIRMAN
CANTILENA: Other comments from the
sponsor?
(No
response.)
CHAIRMAN
CANTILENA: Okay. Dr. Hager.
DR.
HAGER: Yes. I have a question about the self-diagnosable
aspect which is one of the indications as far as going OTC. It would be my contention that the diagnosis
is not unprotected intercourse, but rather unprotected intercourse just prior
to and at the time of ovulation.
So
my question is are there data available on the unnecessary uses. Does the sponsor have any information? Does the FDA have any information about how
excessively used this product is beyond that window?
DR.
GRIEBEL: We're not aware of any. I don't know if the sponsor has.
CHAIRMAN
CANTILENA: Okay. If you can use the microphone at the podium.
DR.
BEN-MAIMON: Can I have Slide 543 please?
What
you can see here is that in some countries Plan B is actually approved or
levonorgestrel emergency contraception in these doses is actually approved for
postcoital use in women who are of low coital frequency, and that's defined as
less than four times a month. And so you
can see in over 2,800 women and over 13,000 cycles in 14 studies, there's a
good bit of data.
There's
been only one ectopic reported. There
have been no serious adverse events, and these women have taken up to ten
tablets per cycle.
With
regard to the issue of ovulation and taking it around ovulation, could I have
slide 375, please?
You
can see from this slide, and this is by Dr. Croxatto, they looked at when women
ovulate and what day of the menstrual period, and clearly predicting this is
very difficult and can occur anywhere from day ten all the way out to day 23.
In
addition, there have been studies done looking at women in consecutive cycles,
and it's almost impossible even from consecutive cycles to predict when women
are ovulating.
And
so if people are taking it based on a calculation of when they anticipate their
menstrual period, there's a lot of risk and they really could become pregnant
inadvertently.
DR.
HAGER: Which basically means that the
recommendation is to take it with every act of unprotected intercourse; is that
correct?
DR.
BEN-MAIMON: That's correct.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Trussell.
DR.
TRUSSELL: Another direct answer to that
question, Dr. Hager, is that we recently published a paper where we compared
the risk of pregnancy by cycle day relative to ovulation, and it is true that
there's only that six-day window, but when you then convert that into the risk
of pregnancy by cycle day where cycle day one is the first day of bleeding,
then there is no day except for the first two days where the risk of pregnancy
is zero.
And
of course, the problem is that since women don't know when they're ovulating,
the only guide they have to go by is cycle day measured in the normal way, not
relative to day of ovulation.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Giudice.
DR.
GIUDICE: I don't know if we'll get to
this at some other time, but in terms of in the actual use study, there was for
the lower literacy group a 46 percent comprehension or reporting by reading the
package that this would be used for contraception, not necessarily for
emergency contraception.
And
at some point are we going to be talking about the print in the package?
CHAIRMAN
CANTILENA: Yes, that will come up later.
DR.
GIUDICE: Okay. Thank you.
CHAIRMAN
CANTILENA: Okay. Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: I wanted to get some
clarification on the Washington State experience with the pharmacist. I don't know who brought this up. I don't remember, but I'm trying to get some
clarification of what were, in that survey, what were the number one reasons,
other than the contraindication of vaginal bleeding or that the patient may
suspect that she was pregnant that the pharmacist gave when they didn't give
the emergency contraception?
DR.
BEN-MAIMON: When they did not?
DR.
MONTGOMERY RICE: When they did not give
the woman the emergency contraception.
DR.
BEN-MAIMON: That was in the actual use
study actually, and in that study women came in -- and can I have Slide 389,
please, or the ones we looked at this morning? -- the women came into either
the pharmacy or to the clinic, whichever was the appropriate place, and
basically said, "I had unprotected sex, and I need emergency
contraception."
And
I would like to clarify from this morning there was a question about
counseling. These women received no
education at all. They basically were
given the product, asked to read the drugs facts panel. It was sealed, and then they made the
decision whether or not they wanted to use the product or not.
And
if they thought the product was appropriate for them, they were then told that
they had to sign an informed consent.
And what happened here is I don't know if you remember, but there were
663 patients, and there were the 500-plus that were in the trial, and then
there were the 80 that were not enrolled.
Eleven
of these did not meet eligibility criteria, and that was why. Of the 69 who would not sign an informed
consent, nine actually received nothing.
They walked out with nothing.
Two
received other medications, such as Lo/Ovral or Ovral, and 58 got a
prescription for Plan B. The reasons
were that they did not meet the eligibility criteria, which included that they
had to speak English because the packages were in English. They had to be willing to be followed
up. They had to be available and/or
that they would not sign an informed consent.
And clearly, for those women we don't have a lot of information.
But
what I can tell you is in this 58, of the women who provided us information,
the vast majority wanted additional information, and because it was an actual
use study, we couldn't provide the additional information prior to signing the
informed consent.
So
they sought additional information, and then with that additional information
they got Plan B.
DR.
MONTGOMERY RICE: I guess I'm trying to
get outside of sort of a study, that when you look at surveys from like, let's
say, the California experience have you done any surveys of those pharmacists
and what the percentage of them actually filled a prescription and what reasons
they give that they don't fill the prescription? Do you have any of that type of information?
DR.
BEN-MAIMON: We don't have quantifiable
data, but we do have anecdotal data which says that a lot of them don't fill
the prescription. One, they don't have
it. It's not stocked because, again,
remember from Washington, the pharmacy access programs, only 26 percent are
actually participating in the pharmacy access program.
So
many pharmacies don't either stock it still and are not participants and,
therefore, can't dispense it.
The
women may not meet the criteria. They
actually have to go through a questionnaire, and the other thing is that the
pharmacist chooses not to dispense for whatever reason.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Crockett.
DR.
CROCKETT: Thank you.
First
I'd like to start by saying thank you for being a company that's concerned
about lowering the induced abortion rate, and you should be applauded for
that. That's a wonderful objective.
We've
had a lot of discussion or some discussion about the low literacy groups and
their comprehension, and I agree with those concerns, but I wanted to raise
another issue, and that is my high literacy group.
We
heard from some of them in the open public hearing this morning, and although
your labeling labels this as an after intercourse or emergency contraception,
several of them indicated that they would want to use it as a primary form of
birth control because they didn't want to use other forms of birth control.
In
addition, my high literacy population of patients smart enough to figure out
that this is not just Plan B, an indication coming over the counter; it's a
drug, levonorgestrel, which is a progesterone, which can be used for lots of
other things. There are women that use
it for menopausal symptoms. There are
women that use progesterone for luteal phase defect, when they're trying to get
pregnant and infertility issues, and it's not going to take them very long to
figure out that levonorgestrel is now over the counter and they can go get it,
and that raises a lot of concerns for me.
In
your handouts to us, you indicated that one of the ways that you wished to
consider controlling how this was dispensed was by pricing it high enough so
women would not use it as a regular contraceptive or as a progestin only
contraceptive, and I wanted you to address that a little bit because I'm
wondering how you plan on handling these concerns about the high literacy group
and about how you could raise the price high enough to not preclude our lower
socioeconomic group from having access to the medication at the same time.
DR.
BEN-MAIMON: I think there's two
responses. First of all, there's really
two deterrents to using this for routine use.
One is the menstrual irregularities associated with it.
The
studies that I showed you earlier in women of low coital frequency where they
are using it is routine birth control.
The reason it was never pursued in this country, in particular, is
because there are so many menstrual irregularities, and we all know women don't
like to bleed irregularly. They like
much more a predictable time for bleeding.
And
so that in and of itself, I think, worked as a deterrent.
Second
of all, I don't think that we're talking about using price as a deterrent. I think though that just given the
circumstances, the fact that one package -- first of all, it's a single use
package as you saw -- one package is comparable in price to one month's worth
of oral contraceptives.
And
so clearly repeated use is difficult, and as we did hear in the public hearing,
many of these people who are using -- many of the women using it are on a budget. They are either in school or going through
school or newly in jobs, and so price, although I don't think we intend to
utilize it as a deterrent, may very well act that way.
With
regard to the lower income women, we will be providing it, as we said earlier,
to clinics at a discount, and so it will still be available in clinics to women
who cannot afford private practice or who don't have medical insurance.
CHAIRMAN
CANTILENA: Okay. Just a quick follow-up.
DR.
CROCKETT: I would just like to make a
statement to the FDA that I disagree with using pricing as a manner of
controlling how a medication is dispensed over the counter. That's not a reliable mechanism.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Benowitz, please.
DR.
BENOWITZ: This morning there were two
safety concerns raised that I would like to ask a question about. One was if Plan B was to be used repetitively
for a long period of time, and the second was use in adolescents.
The
first question which could be FDA or sponsor or the panel, because I'm sure you
know better than I, is a summary of the safety data on just progestin only
contraceptives. We've had a lot of
experience with that, used for years and years and years, and I think that
would be useful for me to know.
And
the second thing is: are there any
studies of progesterone in adolescent animals to look at development or to look
at brain development and look at behavior as there are for other sorts of
drugs?
DR.
DAVIS: Dan Davis for the FDA.
I
certainly can address the question about the repeated use. All of the clinical data that I presented was
levonorgestrel only. None of that was
from combination oral contraceptives, and we have studies that go back to the
'70s and '80s where they really were doing dose ranging to find out what dose
would be most effective for levonorgestrel starting at .15 milligrams and going
up to one milligram. And those were for
women using the levonorgestrel after intercourse on a regular basis for regular
postcoital contraception so that we have thousands of women who use the varying
doses on repeated.
Probably
the best day or one of the best data was the Kesseru study from Lima with over
2,800 women for an average of nine months using the .4 milligram dose for an
average of nine times per month. So if
you multiply the .4 by nine, you get 3.6 total dose every month for an average
of nine months.
That
study actually went up to 25 months. So
we do have, you know, some participants who used that dose up to 25 months.
For
adolescent studies, I would simply say I'm not aware of a study that has been
published for adolescent use, but perhaps the sponsor has some more specific
data on that issue.
DR.
BENOWITZ: Can I just ask a follow-up?
The
other question is just for the ordinary progestin daily use oral contraceptive,
what's the safety profile for that?
DR.
DAVIS: Extremely high. The only issue that has been raised is that
of ectopic pregnancies with the progestin only daily contraceptive pills, and
the incidence there, although it appears to be higher, it's not higher than
what we would expect in the general population, and that's why I presented the
data on ectopic pregnancies from the randomized clinical trials for
levonorgestrel specifically for emergency contraception.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Lockwood or are you satisfied, Neal?
DR.
BENOWITZ: I just wondered had the
sponsor looked at the question of progestins in adolescent animals.
DR.
BEN-MAIMON: No, we had not.
CHAIRMAN
CANTILENA: Okay. The answer was they had not.
DR.
LOCKWOOD: I don't want to use up my
question, but I want to help answer his question because my NIH grants are on
this topic. So I have some knowledge of
this area.
Depo-Provera
and the implantables, particularly Depo, are associated with a higher rate of
osteoporosis, and most of these women develop abnormal uterine bleeding. There's about a 15 pound weight gain on
average after use, and there's a higher rate of depression. So those are the long-term consequences.
But
that was not my question. If I could beg
you to put back up the slide that showed the pattern of ovulation, and the
question I'm going to ask is as follows.
We
know from the published literature that the earlier in an ovulatory cycle prior
to ovulation that the drug is used, the better the contraceptive effect and the
greater the likelihood of ovulatory either dysfunction or frank disruption.
My
question to you is: do we have data on
the efficacy of the agent after ovulation?
So, for example, if a woman ovulates on day 14 and she has unprotected
intercourse on day 17 and uses this agent, what is the likelihood of her being
pregnant? It should be eight percent or
so if the drug had no effect.
DR.
BEN-MAIMON: This is actually very
difficult to do. Obviously in randomized
trials you can't randomize women to get pregnant or not, and so the studies
that have been done are complex. The
only real data post ovulation besides the statistical data generated by Dr.
Trussell is that there is clear data in the Kesseru by Kesseru that the sperm
motility, the cervical mucous, as well as uterine pH, change within hours of
taking levonorgestrel, but the connection between that and an impact on
fertilization has not been shown.
There
have been some very early studies on combination therapy, and I think that's
really important that there may be some changes in the endometrial lining, but
again, that's combination, and when you give estrogen and progesterone, as you
all know, the ratio is highly important in maintaining t he integrity of the
endometrial lining.
And
there are really no studies to date that have been published that show that
levonorgestrel has any impact on the endometrial lining post ovulation.
In
addition to that -- can I have 362? -- again, estrogen containing products are
of limited value because of the impact of estrogen. As somebody said earlier, progestin
traditionally is used to maintain the integrity of the endometrial lining, and
is used in women with a luteal phase defect just for that purpose.
In
addition, anti-progestins, such as RU-486 or mifepristone, are detrimental to
the endometrial lining. So, again,
anti-progestins work to destroy the endometrial lining, not progestins.
And
so clearly, the only real evidence of how levonorgestrel works is that it
prevents ovulation; it impacts sperm motility and sperm migration through
changes in the cervical mucous and the pH, and there really is no data to
suggest that there's any impact on implantation or fertilization.
DR.
LOCKWOOD: Just a point of
clarification. When one gives
progesterone for luteal phase defect, you usually begin it around seven days
after ovulation. You don't begin it in
that immediate periovulatory period.
I
raise the issue because of obviously the issues of whether this is a
contragestive or contraceptive, and also because we know that progesterone
given at around the time of attachment can affect HOXA-10 expression. It can affect integrin expression. It can affect Lith expression by endometrial
glands, et cetera.
So
the issue becomes not does it necessarily create a hostile environment in the
endometrium such that you would be able to affect advanced implantation because
I agree with you. Progesterone is good,
not bad to do that.
But
the issue becomes does it affect attachment, and does it act, in other words,
like an IUD rather than an anti-fertilization agent. And it sounds like you're telling me no one
has done the studies, and I couldn't find any that at least I could discern
from a Medline search or from looking through your data.
DR.
BEN-MAIMON: The studies are not
available. The biggest issue here though
is that Plan B or levonorgestrel only emergency contraceptions work like other
oral contraceptives in that way, and so especially progestin only containing
oral contraceptives, and so the data is clearly there's no data that's
definitive in either way.
But,
again, I think logic precludes us from assuming that that's the mechanism of
action.
CHAIRMAN
CANTILENA: Okay. Dr. Stanford.
DR.
STANFORD: I'd like to offer a little bit
of a different opinion on that issue, and I think it is an important issue for
women who want to have a clear idea of the best evidence of how this works and
for their informed consent for use.
I
don't think it's quite as clear-cut as has been presented that there's no data
on one side and all data on the other side.
If you look through all of the studies we have got in our background
book, there's data on both sides.
But
I don't think we have time to discuss all of the nitty-gritty, but I would like
to point out what I think is probably the most to date compelling piece of data
on the side that says this may work after fertilization at times, and that is
the data that it's effective up to four or five days after.
Now,
I understand that it's not being proposed for that indication, but there are
certainly people proposing that use based on studies showing that, yes, the
effectiveness is less the farther out you go, but there's still fewer
pregnancies than you would expect, and the pregnancy rate is still lower than
the expected pregnancy rate of four or five days in a couple of studies,
including the World Health Organization 2002 study we have here where it was
estimated at 60 percent effective four or five days after.
So
when you understand that there's five or six days where intercourse can result
in pregnancy and you've got five days, four or five or even three days after
administration of a drug after intercourse, there's certainly a good percentage
of those times when it's being given after ovulation because you've got a
five-day window of giving it and you've got a five-day window when intercourse
can result in pregnancy.
PARTICIPANT: Before or after ovulation.
DR.
STANFORD: Right. You've got a five-day window where
intercourse can result in pregnancy up to the five or six day up to day of
ovulation, depending on which study you look at. Studies that have adjusted for uncertainty
and timing of ovulation have suggested it may have even been five days rather
than six.
But
anyway, so you've got this five or six-day window and then you've got a
five-day window where it is shown to be effective. There's no way that -- you know, there's
certainly some epidemiologic evidence from there that suggests that it is
working after fertilization some of the time, and I think it is misleading to say we have no
suggestion of that happening.
CHAIRMAN
CANTILENA: Okay. How about if we go forward from a comment
from Dr. Giudice and then Alfano?
DR.
GIUDICE: Actually I have two
comments. One is that a five-day window
can be interpreted with the sperm being in the reproductive tract for 72 to 96
hours with a very late ovulation and with an effect of the levonorgestrel on a
decreased release of the sperm in the cervical mucous or in the crypts of the
fallopian tubes.
Secondly,
for fertility therapy we commonly begin progesterone administration on post
ovulatory day 2, and for infertility therapy with embryo transfer, we commonly
begin supplemental progestin or progesterone one day before embryo transfer.
So
I just want to make it very clear that administration of progesterone
clinically early and periovulatory has no significant impact upon implantation
rates.
CHAIRMAN
CANTILENA: Okay. Dr. Alfano.
DR.
ALFANO: Yes. I think this question is for Dr. Chen.
And
I realize that the ADR rate is very low for this drug, but my question is: have you been able to discern any differences
in ADRs in jurisdictions where the product is available with an Rx or without
an Rx, be they countries or states?
DR.
GRIEBEL: No, we haven't been able to do
that.
CHAIRMAN
CANTILENA: Okay. Dr. Macones.
DR.
CHEN: Yeah, we actually compare
with ‑-
CHAIRMAN
CANTILENA: I'm sorry. I thought that was the answer.
DR.
CHEN: Oh.
CHAIRMAN
CANTILENA: Is that the answer or is
there more data? There is no more
data. Okay. So it was just a reinforcement of the answer.
Okay. Please proceed.
DR.
MACONES: Just a question about the
actual use study. As I recall from the
numbers that you presented, 40 percent or so of the participants had used
emergency contraception before, and I was wondering if the 670 percent who
hadn't or who were first time users had similar performance, proper
performance, compared to the other 40 percent who were second time or more
users.
DR.
BEN-MAIMON: That is correct. In the actual use study we did have 40
percent of the women who did use the product before, and 412, please. And what you can see here is
contraindications. Remember they were pregnancy,
unexplained vaginal bleeding or allergy, prior users versus naive users. Incorrect use was similar in both groups.
And
you can see this was taking the first pill within the first 72 hours and taking
the second pill at 12 hours exactly were very similar. So there was no difference in the two groups.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Lam.
DR.
LAM: In the actual use study, 32 percent
of the users did not take the second pill correctly. Just a point of clarification. Did the sponsor follow up with those 32
subject or 32 percent of the subjects to find out why they failed to follow
that relatively simple instruction?
And
what type of strategy would the sponsor propose to improve that adherence rate
since the time to take the medicine correctly is critical basically?
DR.
BEN-MAIMON: Can I have Slide 629,
please?
What
you can see here is that 73.8 percent of the women took the second pill exactly
at 12 hours, but 86.1 percent took the pill within 11 and a half and 12 and a
half hours.
So
the reason that there was a very strict definition of exactly, and when I said
12 hours, it was exactly 12 hours. We
did though, however, in order to try and make it even better, a we stated
before, we bolded it in the package where it actually tells them to take it at
12 hours.
And
in addition to that, we are including in the package a reminder card that will
tell them not only to take it as soon as possible, but will allow them to
record the first dose and record the time of the second dose in order to remind
themselves that that's the time to take it.
CHAIRMAN
CANTILENA: Okay. Next is Dr. Johnson.
DR.
JOHNSON: I have a somewhat related
question, and it has to do with how frequently people don't take the second
dose at all, and so, for example, in the label comprehension study, the
question seemed to get at how well they understood to take it within 12 hours,
which gave away the fact that they had to take a second pill at all.
And
so I'm wondering if you can give me any -- if you have any data on how
many didn't take the second pill at all
and if you have data on what the efficacy rate is when they only take 1.75.
DR.
BEN-MAIMON: We have data from the actual
use study that looks at taking the pills.
As we said earlier, 92 percent took both pills. Point, two percent, one person, took only one
pill. One percent, three people, took no
pills. That was the three women -- it
was originally, if you remember, 543 women and we were down to 540. They just didn't use the product, and we had
42 women who were lost to follow-up that we had no information on.
CHAIRMAN
CANTILENA: Okay. Thank you.
Next
we have Dr. Greene and then Snodgrass, Wood and Crockett.
DR.
GREENE: One of the points I'd like to
make with respect to this question that was just asked is there is data with
respect to the efficacy of the regimen, whether it's taken 12 or even as far as
24 hours apart between the two pills, and in fact, in a randomized trial there
was no difference in the contraceptive efficacy whether the pills were taken 12
or 24 hours apart. So that's just one
point of information I wanted to provide.
CHAIRMAN
CANTILENA: Is that information in our
packet, as a reference in our packet?
DR.
GREENE: I don't think so.
DR.
BEN-MAIMON: I can actually show it. We have a slide.
CHAIRMAN
CANTILENA: Is it from a published study?
DR.
BEN-MAIMON: Sorry.
CHAIRMAN
CANTILENA: Is it from a published study?
DR.
GREENE: No, it's not.
DR.
BEN-MAIMON: You can see here that this
was 24 hours apart. This is an overall
efficacy rate for all of the regimens.
It is not broken out, and we don't have access to that data. We've tried to get it, but we do not have
access to it. But the overall pregnancy
rate was 1.7 percent.
CHAIRMAN
CANTILENA: Okay. Dr. Greene, do you have another question?
DR.
GREENE: The other point I just wanted to
make was touched up, and that is although pregnancy can occur within five days
or six days, what we're talking about is the period when the ovum is
fertilizable is extremely short after ovulation so that Wilcox and others' data
have indicated that an act of intercourse after 24 hours after ovulation is
incredibly unlikely to result in pregnancy even without pharmacologic
intervention
DR.
LOCKWOOD: That's not the point. I guess the point I'm trying to make is the
opposite point. If you've documented
ovulation and you then show that there would be -- you've documented
ovulation. The patients had intercourse,
then have intercourse again, and you show efficacy to giving the agent that
second time.
It
would suggest that there was a contragestive effect. From what I can discern, I don't think we
have any data to suggest that that happens or any data to suggest that it
doesn't happen because I don't think anybody has done that study.
That
was my point.
CHAIRMAN
CANTILENA: Okay. Dr. Snodgrass.
DR.
GREENE: Or is ever likely to.
DR.
SNODGRASS: My question is related to the
issue of 1.5 milligrams once, and as I recall there was some discussion earlier
about this was data that was available from outside of this country that had
not yet been reviewed. I guess my
question is more to the FDA.
Are
there plans to review this type of data?
DR.
GRIEBEL: If a sponsor submits it, then
we would review it.
CHAIRMAN
CANTILENA: A sponsor driven process.
Dr.
Wood.
DR.
WOOD: I was going to make the same
point, I think, that Mike just made, but I guess I'm concerned that we're
getting into sort of bureaucratic issue where we have to demonstrate that the
drug should be taken exactly 12 hours after the last dose when, in fact, in
your heart I suspect that the sponsor believes that two doses taken once would
be at least as effective as one dose taken 12 hours apart, and that the data
that says that it has to be taken at 12 hours rather than 11.5 and 12.5, as was
on your slide, just seems to me beyond the pale.
I
mean, to those of us who are giving drugs to regular folks every day, they
don't take their drugs 12 hours apart, and you don't make that a condition for
approval of an anti-hypertensive or whatever.
So
I think we've got ourselves into a bureaucratic trap where we're worrying
ourselves to death about whether to take it 12 hours apart when we don't have
data to support that as being an essential part of the efficacy data.
CHAIRMAN
CANTILENA: Thank you.
The
trap will not actually hold the committee because we will move forward.
(Laughter.)
CHAIRMAN
CANTILENA: Dr. Crockett, please.
DR.
CROCKETT: Yes, thank you.
We
spent quite a considerable amount of time yesterday hearing very compelling
testimony about adding folic acid to contraceptives to prevent spina bifida and
anencephaly in unintended pregnancies, and it strikes me during this
conversation that it would be an optimal time to educate our population about
the failure rate of the emergency contraception and to put a recommendation on
the label that they start taking their folic acid.
Has
your company considered that at all, please?
DR.
BEN-MAIMON: We watched that committee
meeting. No, we haven't, but we will be
happy to discuss it with the FDA.
CHAIRMAN
CANTILENA: At a later date. Okay.
Dr. Emerson.
DR.
EMERSON: This is just a follow-up on
this actual use study. Two points.
One
is the idea that you excluded patients just because they asked for more
information, isn't that part of actual use?
I mean I go to a hardware store and ask how to use tools and still over
the counter.
(Laughter.)
DR.
EMERSON: And so I would think that that
would be there.
And
then it also seems to me that in the actual use study that what we're really
interested in is how the use compares with what the people would be doing with
the medical supervision, and so the point being of noncompliant patients. You know, we have that problem all the time
anyway.
So
I guess I haven't seen very much of this data that suggests that it's
substantially worse than what compliance would be in medically supervised,
prescribed medications.
DR.
BEN-MAIMON: I'll answer your question
twofold. I think the issue of actual use
-- and maybe the FDA can weigh in on this -- is really to try and take a
population that would be using the product.
Obviously
with this product it's difficult because
it's such a private matter and there aren't a lot of women using it
today, and so using the family planning clinics was important.
The
issue here isn't though whether if women want to pursue additional information
whether they can take it. The question
really was if they choose not to pursue additional information, can they take
it correction, and I think that's the question that the actual use study
answers.
The
other question is if they need additional information, can they get it, and I
think that speaks to all of the discussion about the learned intermediary and
the need for a learned intermediary. And
it is clear that women will have a 24-hour hotline staffed by health care
professionals. They will have access to
a Web site, and clearly, they still have access to a pharmacist and their
physician during the same hours that they normally would. It's not that they're going to be prevented
from making that contact.
And
so I think your point is well taken, but because the study was designed to test
whether with no information or no additional information women could use it
appropriately, that's the way the study was designed.
With
regard to the efficacy issues and comparing it to other trials, could I have
Slide 42? And then I'll want 43 in a
minute.
You
will probably recall I presented this morning this slide, and this is really
what this does. We basically said it's
the same regimen, and it's the same dose, and given that, since we know the
efficacy from the WHO study supported the safety and efficacy of the product,
if women are taking it with the same pattern of use as they were taking it in
this trial, it should have the same efficacy and safety profile.
And
you can see that the percent of women taking it at various times is clearly
similar between the two groups. That was
the first pill within 72.
This
is the time between the first and second pill, and you can see again that the
distribution is very, very similar with about four percent of women taking it
after 16 hours and about five percent in the original trial.
So
given the fact that it was safe and effective in the WHO trial the way it was
taken, it should be safe and effective as an over-the-counter product.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Kweder, did you have a comment?
DR.
KWEDER: No. I think that Dr. Ben-Maimon has answered
it. Thanks.
CHAIRMAN
CANTILENA: Okay. Actually I have a question for the sponsor.
On
page 17 of your document, there was just one study that raised a statistical
trend, the San Francisco study, UCSF 2000(b), which talked about a slightly
lower condom use incidence. I was
wondering if you can comment on that.
I
think you're comparing, if I'm reading this correctly, you're comparing the
pharmacy access group as compared to the clinic group; is that correct?
DR.
BEN-MAIMON: Yes, that's correct, and I
think what you'll see there is that that was somewhat offset by an increase,
although it was not statistically significant, in the use of oral
contraceptives.
So
there was no change in the overall use of contraceptives. There was a switch from the use of condoms to
oral contraceptives.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Benowitz and Dr. Stanford next.
DR.
BENOWITZ: We haven't heard anything
about drug interactions, and we know for the usual type of contraceptives that
women who are taking certain anticonvulsant drugs, rifampin, can have
contraceptive failures, and one question is have you looked at the effects of
enzyme inducing drugs on the kinetics or effects of Plan B, and if not, should
these be a contraindication for use?
DR.
BEN-MAIMON: Well, I'll make two comments
with regard to that. The first is that
clearly there is data on levonorgestrel, and there is an interaction with some
of these products. We have not
specifically done it with this particular dose and two doses.
I
think though you have to look again at the benefit-risk assessment and what
you're dealing with here is the act has already occurred, and so these women
are either going to get pregnant or they're not going to get pregnant, and
their last chance to prevent that pregnancy is to take Plan B.
So
I think you have to look at it from a safety perspective, and there is no data
to suggest that any of these drug interactions present any kind of a safety
concern. So even though there may be a
slight reduction in the plasma concentrations or the drug may be slightly less
likely to work, which is not documented, but if we presuppose that, the benefit
still outweighs the risk that they take it and hope that the pregnancy is
prevented.
DR.
BENOWITZ: Well, just if I can follow up
on that, that would be okay if there were only one possible product. If there are multiple products that have
potentially different interactions and different efficacy, I think we need to
give people the rational choice about what would be the most effective.
DR.
BEN-MAIMON: Right, but all of those
products would have to go through the review process and their labeling would
be discussed with the FDA, and then I think they would have to decide what kind
of labeling needed to be put in place, but clearly this is specific for Plan B.
CHAIRMAN
CANTILENA: Dr. Stanford.
DR.
STANFORD: I understand, again, that the
data that we have on mechanism of action
for Plan B is imperfect, incomplete, but I think it's a critical issue for
those women who want to understand how it works and have informed consent for
use.
So
along those lines I have a question from Appendix 6 from the sponsor's
book. They list all of the answers to
Question 7 about -- after they showed the women the package, they said,
"Without looking at the label, tell me what Plan B is used for," and
then classified answers as either correct and acceptable or correct but not
acceptable or not correct and not acceptable, and they list them verbatim.
And
among the ones that are listed as correct and acceptable are a number of women
who said that -- one of them is, for example, an abortion type thing for the
day after. One was them was to kill a
fertilized egg, and basically showing that some women had that understanding,
and it was classified by the company as a correct and acceptable understanding
of what the product is for.
And
so I'm just wondering for the FDA did they also classify those particular
answers as correct and acceptable for what the product is for.
CHAIRMAN
CANTILENA: Dr. Lechter? Is she here?
DR.
LEONARD SEGAL: Dr. Lechter unfortunately
had to leave, and I don't know that I can actually specifically address how she
did her calculation in her review on that particular issue. My assumption is though that she probably
followed the sponsor's categorization.
CHAIRMAN
CANTILENA: There were a few tables that
she showed in her presentation where she had asterisks where there was, you
know, a difference between her, you know, assessment and the sponsors. But I don't recall if that specific issue was
asterisked or not.
Okay. Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: I think that one of the
things that Dr. Stanford is getting to -- and you can tell me if I'm wrong --
is a matter of informed consent such that the patient is as fully informed as
possible based on all of the information that we know about how this product
works.
So
I guess I would ask the sponsor first.
When you've done surveys, if you have -- and you may not have this
information -- in women who have taken emergency contraception and then you've
asked them the question of how they
perceive, first of all, the medication worked, besides one of these
studies because during that time, I think when you are dealing with that
immediate issue of needing emergency contraception or even within the first
couple of weeks while you're waiting for that cycle to come, your perception of
how it works may be different than when you sit down and really think about it. So I think that's one point.
And
then, you know, even with my background, having a lot of experience with
infertility and giving a lot progesterone, et cetera, and I've reviewed the
literature, there is some data out there that really does suggest at very high
dosages that there may be the possibility that you're interfering with the
implantation.
And
so I guess my comfort level would definitely -- I would definitely be a lot
more comfortable making sure that the patient or the woman who makes that
decision is as informed as possible that there potentially is a possibility
that still gives that woman enough information to make an informed decision and
not dilute any of her rights in deciding to proceed with this medication.
CHAIRMAN
CANTILENA: Okay. Doctor -- I'm sorry. You have a comment?
DR.
BEN-MAIMON: We are very sensitive to the
fact that there are differing views not only of how this could potentially
work, but also when pregnancy begins.
And so there are actually statements in the labeling with regard to the
implantation issue in order to provide women information so that they
understand and that they know that this could potentially prevent implantation.
Again,
we believe the data is overwhelming. We
believe the medical definition, which is that pregnancy starts at implantation,
is a critical point to keep in mind, but we are sensitive to the issues that
others -- the opinions of others.
CHAIRMAN
CANTILENA: Okay. We have Dr. Snodgrass and then Dr. Davidoff.
DR.
SNODGRASS: I just wanted to follow up on
the drug interaction question. It seems
that if rifampin, phenytoin and others pose that potential, that this would be
another argument for consideration of the higher single dose since you had
lessened that possibility.
CHAIRMAN
CANTILENA: Any comment from the sponsor?
DR.
BEN-MAIMON: Again, the data is new. It came from the WHO study. We may very well at some point have access to
it and put an application together, but right now the application that's there
is for two single doses.
CHAIRMAN
CANTILENA: Dr. Davidoff.
DR.
DAVIDOFF: Yes. To follow up on the mechanism question, I
also wondered a bit about that because there were some data in the background
packet that did suggest from ultrasound studies that ovulation may occur, but
there may be what was called dysfunctional ovulation as a result of taking
these pills, not that I understood exactly what ovulatory dysfunction is or
does, but presumably it is the mechanism by which fertilization is impaired,
but I'd be prepared to be enlightened.
But
my question that I thought might help clarify the situation had to do with what
is the wording on the oral contraceptives that are the progestin only, the mini
pill. Because in my reading of Novak's
textbook, it says, page 249 of the 2002 edition, 40 percent of those cycles are
ovulatory.
So
presumably there is something else going on besides prevention of ovulation in
the use of the mini pill, and I wondered what the labeling tells potential
users about the mechanism.
DR.
BEN-MAIMON: I would defer to the agency.
DR.
DAVIS: I can read from the Plan B label,
which has really been presented by the --
PARTICIPANT: What's the labeling of the mini pill?
DR.
DAVIDOFF: Depo, Norplant, Micronor.
DR.
DAVIS: I don't know specifically what it
states on the mechanism of action. So
I'm sorry. I'd have to leave a -- maybe
Scott Monroe, my team leader, could comment.
DR.
MONROE: I can't quote it either, but a
mechanism which is likely to be operative when you're taking a continuous
progestin, as we're talking about, is change in cervical mucous and affecting
sperm penetration, and so forth. So that
would not be a likely mechanism here, but it's considered to be a potential
important mechanism with a progestin only contraceptive.
CHAIRMAN
CANTILENA: Do you have a follow-up, Dr.
Davidoff?
DR.
DAVIDOFF: Yes, I understand, but since I
guess there is still some question about the possibility that there might be an
occasional ovulation, an egg that's fertilized, is there wording in the mini
pill that states something along the lines that the Plan B --
DR.
BEN-MAIMON: I don't know the answer to
that.
CHAIRMAN
CANTILENA: We have actually Dr. Greene
and then Dr. Montgomery Rice.
DR.
GREENE: Just a quick point with respect
to the drug interactions. Most of the
drug interactions with combined estrogen-progestin oral contraceptives are
really due to interference with enterohepatic circulation of the estrogen and
permitting breakthrough ovulation.
That
wouldn't be germane to this preparation.
CHAIRMAN
CANTILENA: Okay. Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: I was just going to say
I believe the packaging on the mini pill says something like "out-of-phase
endometrium," along with the cervical mucous and some other stuff. So it may say something like that.
CHAIRMAN
CANTILENA: Okay. Dr. Crockett.
DR.
CROCKETT: Yes, this will be a short
question. In your presentation this
morning on one of your slides you mentioned that there were 133 pregnancies,
and I was just wondering if you have the follow-up data on the outcomes of
those pregnancies for us, please.
DR.
BEN-MAIMON: I actually don't, except for
the fact that the two or three -- I can pull up the slide. Just a second. Sixteen, please.
DR.
CROCKETT: Yeah, I believe it was the one
where you had your ectopic rate of two percent.
DR.
BEN-MAIMON: Yeah, and that's all we
have, is the ectopic rate.
CHAIRMAN
CANTILENA: Yes, Dr. Lipshultz.
DR.
LIPSHULTZ: Just a quick question for the
sponsor. I'm interested in your data
about almost a spermicidal or sperm interference of the drug in that I know in
the human a steady state of sperm ascent has been shown to be reached as early
as 35 to 45 minutes after intercourse. I
mean, so the data that you have on lack of sperm reaching the egg, is this
inferred, scientifically shown? I mean,
where did the data come from that you quote as the mechanism?
DR.
BEN-MAIMON: No, there actually is a
study by Dr. Kesseru -- I can never say his name correctly. Forgive me -- in healthy women where they
administered levonorgestrel in these doses, and within hours afterwards they
then retrieved sperm and cervical mucous from the female genital tract, and
they were able to show decreased motility, changes in cervical mucous, as well
as changes in pH, and it was within several hours, within 16 --
DR.
LIPSHULTZ: There's already sperm in the
tubes. So if there's eggs in the tubes,
then there's going to be fertilization.
DR.
BEN-MAIMON: Well, it's my understanding
that sperm generally resides in the lower female genital tract and then
migrates up in waves, which is why the sperm are sort of waiting for the egg
for ovulation, and why it's actually the days leading up to ovulation where
women are most fertile.
I
defer to the experts on the panel who know this physiology probably much better
than I do.
CHAIRMAN
CANTILENA: Okay. Since there are no takers for a lecture --
(Laughter.)
CHAIRMAN
CANTILENA: -- are there any general
questions for clarification, other than what's already been asked about the
actual use study and the comprehension study?
Dr.
Crockett.
DR.
CROCKETT: In our discussion we talked a
little bit about the menorrhagia that happens, especially if women use this
medication more than one time during a month, and as a practicing OB-GYN, I
already see a ton of bleeding disorders, and I'm not anxious to see a whole lot
of patients coming in with this.
So
I was wondering if you have any estimate on the number of office visits that
this is going to generate from irregular bleeding or the public health impact
on that.
DR.
BEN-MAIMON: No, I don't have data. What we do know is that -- and I'll show this
-- that this is with repeat use, and this is from the women who are using it
for postcoitus, and you can see that intermenstrual bleeding occurs in about 40
percent of women. Again, if they only
use it once during the cycle, it is gone, and then they get back on their
regular cycle, but you can see there's a whole host of bleeding disorders when
used initially.
Most
women have their period on time. It can
be slightly earlier or slightly later.
Clearly if they miss a period, there is a recommendation on the label
that they do a pregnancy test and follow up with their physician, and so again,
if used once within the cycle, then bleeding irregularities should be minimal.
One
other point. You asked about the
follow-up of those pregnancies. The only
point I can make is there were no serious adverse events reported in that trial
associated, and clearly congenital anomalies, those kinds of things, abortions
or requirements for hospitalization would have been counted. So that does speak to that a little bit.
CHAIRMAN
CANTILENA: Yes, Dr. Hager.
DR.
HAGER: Could we put to rest the question
that we've danced around since this morning?
And that is the long-term effects.
We've touched on it; we've gone away from it. We're told that it would be answered this
afternoon, but just some information that you would have for us on long-term
effects with either single use or multiple use.
CHAIRMAN
CANTILENA: I think actually you heard
some information from the FDA. Dr. Davis
had some information from the literature and from other, you know, drugs.
You
know, in addition to that or, you know, on that?
DR.
HAGER: I didn't feel that that was the
final word. Is that it?
DR.
GRIEBEL: That's what we have. I don't know if the sponsor has anything
they'd like to add, any details.
DR.
BEN-MAIMON: No, I think Dr. Davis made a
very nice point. Levonorgestrel has been
on the market for a very long time in continuous use pills. There's data on very high doses, given
repeatedly, and I don't know what more we could propose or show.
CHAIRMAN
CANTILENA: Okay. Dr. Hager any other point on that?
Okay. Are there any questions from the committee
regarding the label comprehension and actual use study?
And
I guess I would ask the sponsor how it was that you ended up with basically a
study that was done in family health, you know, centers and you had such a
small number of, you know, pharmacies.
DR.
BEN-MAIMON: From the actual use study
you're referring to?
CHAIRMAN
CANTILENA: Yes, yes, from the actual use
study.
DR.
BEN-MAIMON: The reason was that this is
a very difficult product to evaluate.
Obviously you can't go advertising for women who have had unprotected
sex to please come, you know, to a counter.
And so there was discussion with the FDA -- sorry. I didn't mean it to be funny.
After
discussions with the FDA, clearly, it was decided that we would try our best to
simulate an over-the-counter environment.
The
one thing I would want to point out is, you know, when you look at it in
contrast to a prescription environment, we actually, I think, did very closely
simulate the over-the-counter environment.
The woman had to determine that she needed something, that she had had
unprotected sex and she had an event that needed intervention.
She
then had to be motivated to go and seek help at a family planning clinic. She walked in and she either said, "I've
had unprotected sex," or, "I need emergency contraception," one
of the two, and she was given no further information except to be told that
there was a study and did she want to participate.
If
she said yes, she was then given the package, and she determined whether or not
taking Plan B was appropriate. If she
did not think that it was appropriate, she was not enrolled. If she did think it was appropriate, she then
signed an informed consent. She was
given the cards, and she went home.
So
in answer to your question, this was the best we felt that we could do in order
to make sure that we could perform the study in a timely fashion and have
adequate numbers of women to be able to give some sort of clear indication as
to whether or not they could take the product appropriately and take it
correctly according to the label.
CHAIRMAN
CANTILENA: All right, but what she was
given actually was the -- I assume she was given a copy of the informed consent
document. Is that true?
DR.
BEN-MAIMON: No, she was just given --
CHAIRMAN
CANTILENA: Just she signed it and that
was it?
DR.
BEN-MAIMON: She signed it, and that was
it.
CHAIRMAN
CANTILENA: Okay, and I guess the only
other, you know, concern I have is because it was such a short study and you go
through the process of sort of enrollment and informed consent, and then the
whole study was only for one month; are there, you know, concerns that you have
that are different from those we heard from FDA with regarding the
generalizability of that short study into the long-term environment of, you
know, over the counter?
DR.
BEN-MAIMON: Well, again, I think that
the issue here is whether or not women could take it without contraindications
and whether they could take it correctly.
And since this product is taken, you know, two doses 12 hours apart,
that was able to be assessed.
The
need for a longer study would have had to have been done if we were looking at
pregnancy as the primary outcome, and here because it's the same regimen and
the same dose as the already approved prescription product, we were able to, I
think, make the determination that it should be as safe and effective as the
prescription product as long as it was taken in a similar fashion, and so
that's how I think you can deal with that.
CHAIRMAN
CANTILENA: Okay. I don't think there are any -- actually, Dr.
Patten has a question.
DR.
PATTEN: Yes.
CHAIRMAN
CANTILENA: Patten and then Montgomery
Rice.
DR.
PATTEN: A question or comment coming
from the label comprehension study. I
note that one of the conclusions that was well understood was that the first
pill should be taken within three days, and a concept less well understood was
that the first pill should be taken as soon as possible after unprotected sex.
And
so when I look at that information on the label, I see that's a fairly complex
sentence, and I'm wondering if that isn't what is contributing. I mean, the most important thing is that the
woman understand that she take it as soon as possible after unprotected sex.
So
I would just suggest that you break that sentence into two sentences or in some
way figure out how to simplify it so that the confusion goes away.
DR.
BEN-MAIMON: We'll take that into
consideration. Thank you.
CHAIRMAN
CANTILENA: Yes, Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: I don't know if you
were alluding to this, but you know, when we give a prescription to a patient
for emergency contraception, we don't necessarily see that patient back in a
week or two in our office. You know, we
tell her if she has a cycle, then she's fine and she doesn't have to come back,
and then you would see that patient for a routine visit.
And
so, I mean, people who prescribe emergency contraception have probably a lot of
experience or a fair number of patients who they have given this and haven't
seen any long-term issues with that or problems with follow-up because
generally the information, you tell them that you should have your cycle. If you don't have your cycle in a couple of
weeks, then you will see them back under those circumstances.
CHAIRMAN
CANTILENA: Excuse me. I guess my point was that's the environment
where you're involved. You're educating
the patient, and I was just sort of trying to get a handle on what the
extrapolation would be to a setting where, you know, there is not that
individual there, and that information will now be, you know, provided through
the outside, well, you know, through the insert and through this program.
So
I was just trying to get a comfort level with the extrapolation of how it's
currently used and the extensive experience in that setting to how it will
apply to the OTC setting, as outlined.
Go
ahead.
DR.
TRUSSELL: Probably the most reassuring part of the actual use study
is that the 40 percent of people who had had a prior encounter with a learned
intermediary to get emergency contraception did not use it any better than the
rest of the people who were naive users.
(Laughter.)
DR.
TRUSSELL: So if there is a terrific
benefit to seeing the learned intermediary, it doesn't last very long.
(Laughter.)
CHAIRMAN
CANTILENA: Not to defend the learned
intermediary, but our committee over many years has heard that one of the
reasons it should be over the counter, X, Y or Z should be over the counter was
because, you know, the regular system is not very good, and I guess I would,
you know, not like to hold that up as a
reason for approval for over the counter, because the other system is not very
good.
Dr.
Uden.
DR.
UDEN: During the public hearing, we
heard from a woman who represented the Latina population, and you did all of
your label comprehension studies with English speaking, English reading
individuals. What information do you
have that this was done in Spanish for the Latina population, that the same
words would be appropriate for that culture, and what would you propose for
Spanish labeling?
DR.
BEN-MAIMON: Well, first, let me show you
that there was a percentage, about 14 percent, which does mirror the U.S.
population for the actual use, and 23 percent of Hispanics in the label
comprehension. So we did have a sample
that mirrors the general population.
Also,
I think the low literacy group may have been low literacy, some of those women,
because of the difficulty they had speaking English, not necessarily because
they were uneducated necessarily.
But
I think you're touching on a very important point, and we have talked
internally about whether or not we should have the label in Spanish, and we
will discuss that with the agency.
DR.
UDEN: Or a number of other languages.
DR. BEN-MAIMON: Yes.
CHAIRMAN
CANTILENA: Okay. Thank you.
I
think unless there are any other questions that need to be clarified -- I'm
sorry? Okay, yes. Dr. Berenson.
DR.
BERENSON: I have two questions. The first one was in the actual use study --
actually I think it was a labeling study -- there was at the beginning a
portion where the woman was allowed to look at the package and then the package
was taken away from her and she had to answer some questions, and I was curious
as to why that was done because in actual practice I don't know why anyone
would ever take the package away from her and then quiz her about it.
(Laughter.)
DR.
BERENSON: It would seem more actual use
if she could have continued to look at the package.
The
second thing was in the packaging that was sent around the room, I don't know
if that's the proposed packaging for marketing, but there were no instructions
on the outside of the box where many over-the-counter medications do have
instructions on the outside of the box, and it could clearly state there things
like "take as soon as possible" and within 72 hours.
DR.
BEN-MAIMON: It is on the box.
DR.
BERENSON: I withdraw the second
question.
DR.
BEN-MAIMON: That's just the way the
study was designed. It may have been
better, but the idea was really it was only one question that was asked
initially, which was what is it for. It
was an open ended question, and that's just the way the study was designed, but
your point is well taken.
CHAIRMAN
CANTILENA: Okay. Dr. Wood.
DR.
WOOD: I want to return to the issue
about the as soon as possible. It seems
to me based on the literature review that we had, the drug will be taken in
potentially one of two ways. It will be
taken by people who seek it out to use as an emergency contraceptive after an
event and by others who keep the drug in their bathroom cabinet to use
appropriately.
That
being the case, it would seem to me that the statement "as soon as
possible" and "within 72 hours" should be separated because for
these individuals they would use it differently. For somebody who already has the drug, they
should use it as soon as possible. For
somebody who has to go and seek it, they should still use it as soon as
possible, but certainly within 72 hours.
And
it seems to me that distinction needs to be made in the label more clearly.
DR.
BEN-MAIMON: Okay.
CHAIRMAN
CANTILENA: Okay. A final question, Dr. Crockett.
DR.
CROCKETT: This is a question to our
over-the-counter committee members. I
wondered regarding other medications proposed for over-the-counter use how you
consider the illiterate population and what impact it would have on them.
CHAIRMAN
CANTILENA: Yes. Other sponsors, I mean, I'll try to answer
it, and then, Curt, hop in, please, but other sponsors with general products
have included, you know, pictograms and things on the label which were, you
know, tested and, I think, have been shown to be helpful, and I can't remember
the products offhand. Perhaps Dr. Ganley
or Dr. Rosebraugh would have some specific examples of what products.
So
they've shown some efficacy in terms of, you know, labeling, you know, with
that tool. Any other comments, Curt?
DR.
ROSEBRAUGH: No, not really. The only distinction I would add is that when
we do pictograms, it's usually on the package insert. You really can't have it in the drug
facts. That's part of the regulation.
CHAIRMAN
CANTILENA: Okay. Well, why don't we, instead of waiting until
3:30 for our break, why don't we take a 15-minute break at this point, and then
we'll come back and get into the questions?
(Whereupon, the foregoing matter
went off the record at 3:13 p.m. and went back on the record at 3:32 p.m.)
CHAIRMAN
CANTILENA: Will the committee please
take their seats?
A
couple of individuals on the committee have asked just for an opportunity for
probably one or two more clarifying questions about the CARE Program. I think the first person was Dr. Benowitz.
DR.
BENOWITZ: One thing that was striking
this morning was despite the enormous public health importance of emergency
contraception and the enormous amount of money spent in the State of California
to try to get people to know about it and use it, that it was used so little
and so few pharmacies used it and so few physicians promoted it.
And
my question is: with the experience in
California, why or how do you plan to do better?
DR.
BEN-MAIMON: It's an important question,
and we actually think that it's a combination of issues and they both have to
occur simultaneously, and that is we need to educate consumers, but we also
need to educate physicians as well as pharmacists, and then we also need to
educate and we also need to make it available so that when people go get it,
when they try to get it, it's there.
And
it's sort of the chicken or the egg.
People don't carry it because it's low volume. People don't go get it because they get
frustrated, as we heard from many docs who called prescriptions in.
And
so I think what we're talking about here is first using three mechanisms to get
to consumers. The first is we have a
sales force because we are actually -- we sell proprietary drugs and a lot of
oral contraceptives. We have a sales
force of 250 sales reps. that visit about 30,000 doctors across the country.
And
so we will be using that as a mechanism to distribute educational materials
with the intent hopefully that when a woman walks into the office there will
either be a display or a receptionist will say, you know, "Here's some
materials we'd like you to read while you're waiting," which may be a way
to outreach in a way that we already see these doctors.
Then
of course, there's radio and advertorials that, like we said, are public
service in nature, that really provide information and encourage discourse
either to call the hotline or to look at the Web site so that women become more
educated and more aware.
I
think also there is somewhat of a word of mouth issue. You
know, the more women that become aware of it, the more likely that other
women will become aware of it because they talk to each other.
And
then finally, from the standpoint of stocking, we will be working with the drug
stores to make sure that they carry the product. We have very good relationships with retail
pharmacies and chain drugstores to make sure that it is available when women
try and seek it out.
CHAIRMAN
CANTILENA: Is that all right, Neal?
Okay. Are there any other questions? Dr. Blaschke.
DR.
BLASCHKE: Well, just as a follow-up to
the question about the CARE Program, one thing that I'm interested in is your
monitoring program. You described it in
a little bit of detail in the briefing book, but I wonder if you could add how
you expect you might use the information you get back during the monitoring
program to modify, for example, the label, which seems to me to be something
that people are concerned about that could be improved.
DR.
BEN-MAIMON: Well, I think, first of all,
we were planning on doing survey type questions, and then obviously using
publicly available information like CDC data, and the issue really is that I
think this would be a hard population to survey the patients themselves.
But
we have lots of contacts, as we've said, with physicians. Through surveys and questionnaires, we hope
we will be able to determine what kinds of questions are actually being asked,
where people are having trouble, where they're having concerns, where they're
having to contact the pharmacist or the health care provider.
In
addition, the data from our hotline itself can be pursued in order to find out
what questions are actually being asked on the hotline and then clearly to
follow that up with discussions with the agency for labeling modifications.
CHAIRMAN
CANTILENA: Okay. Thank you.
Why
don't we now go to the questions for the committee? And the format that we'll use here, as I said
earlier, we'll actually go around the entire table and have you vote and then
state your reasons for your vote because I think that will be very helpful to
the FDA to hear sort of your thoughts behind your vote.
And
I think actually just before we do, I would like to ask Dr. Alfano if he has
any comments. There are 29 individuals
at the table, but 28 voters. So are
there any comments that you'd like to make, Dr. Alfano, before we head into the
vote?
DR.
ALFANO: No.
CHAIRMAN
CANTILENA: Okay, all right. And we're only going to make one sort of
addition to the first question. The
first question: does the actual use
study demonstrate that consumers used the product as recommended in the
proposed labeling?
And
as you answer that, I also would appreciate your stating what improvements
could be made, in your opinion, to the label as it's out there now.
So
why don't we start on this side of the table, Dr. Hager, answering Question 1
and stating your reasons and then talking about the label?
DR.
HAGER: My answer is yes. The data indicate that depending on how you
evaluate it, between 13 and 28 percent of the individuals incorrectly used the
drug, although that did not prove to be deleterious in a large number of cases.
Regarding
inclusions with the labeling, I personally would hope that undiagnosed bleeding
would be reincluded from a gynecologist perspective. It can be a symptom of ectopic pregnancy. It can be a symptom of other gynecologic
conditions that would warrant investigation.
The
potential effect, the mechanism of action on the endometrium, I believe, should
be included so that the patient has adequate informed consent as to the
potential that it may alter implantation.
And
finally, a strong emphasis, an underlined emphasis that abdominal pain is an
indication to seek medical care immediately because of the risk of ectopic
pregnancy.
CHAIRMAN
CANTILENA: Okay. Thank you.
There's a comment over here from FDA.
DR.
ROSEBRAUGH: I just wanted to make a
point of clarification. Since mechanism
of action has come up several times, the way the sponsor is proposing it right
now, as I understand it, the mechanism of action will be on their package
insert. So it would not be at the point
of purchase, and it would be helpful if people would give us their thoughts
about that.
Let
me just explain point of purchase real quick.
I'm sorry. That just means that
when they pick it up, they can't see it until after the buy it and open it up.
DR.
HAGER: Yes, my feeling is that it does
need to be available to the consumer at the point of purchase. The conflicting information that Plan B does
not cause abortion and yet the inclusion that it does have an effect, a
potential effect, on the endometrium, I think, is contradictory, and I would
like to see a very plain statement that is at the point of purchase so that the
consumer can make an informed decision as to whether or not they want to take
this with the potential that it may affect the endometrium and implantation.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Lam.
DR.
LAM: I would say yes to the question
that the actual use study demonstrates that the consumer used the product as
recommended in the proposed labeling, and I actually think that the label is
better than some of the other labels that have come before the OTC committee in
the other study.
And
actually, I am satisfied with the sponsor in terms of trying to improve the
adherence rate by putting the little labels indication for the user to write
down the time in order to remind them when you would be the appropriate time to
actually take the second dose or something.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Lipshultz.
DR.
LIPSHULTZ: Yeah, I also agree that it
does demonstrate as stated.
I
would also say that in the labeling I would like to see likewise on the
immediate packaging some more information for the consumer about mechanism of
action and also somehow clarify the sentence about as soon as possible, as well
as the statement "within 72 hours" so that it is better understood.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Johnson.
DR.
JOHNSON: I feel that the appropriate use
was documented in the actual use study.
In terms of improvements to the label, I think one of the problems with
over-the-counter labels is we always want more information on them than is
possible in the physical space that's available.
And
so while I think in a perfect world it would be perhaps nice to have the
mechanism on the outside, it's probably going to be at the expense of some
other information that's already on here or they're going to have to have a
very large box.
And
so I don't feel strong. I think it's
important that it's in the package insert.
I don't feel strongly that that's available on the outer carton.
CHAIRMAN
CANTILENA: Okay. Dr. Macones.
DR.
MACONES: Yes, I think the answer to this
question for me is yes, that the actual use study did demonstrate that users
can be use this product well.
In
terms of the label, just a couple of points already mentioned. I would favor adding something about the
mechanism of action onto the box itself so that people can look at it in the
store and understand how it works. I think that would be very important to some
people about whether or not they would choose this.
And
I also think I agree with Dr. Hager that I think there needs to be some more
clarification within the box about why abdominal pain is an important side
effect for people to know about and to notify their physicians.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Patten.
DR.
PATTEN: I would say yes to the question,
and my concerns with the label, I've already stated one of them. I think the sentence having to do with when
this product should be used is too confusing, and I would also suggest that a
way be found to really emphasize to users how important it is to take it within
the first 24 hours after unprotected sex because beyond that, as we saw in the
slide, its efficacy diminishes.
So
I'm not sure. I leave it to the experts
to discover what that way would be, but I think it would be very good to
express that to women so they really understand the urgency about using it
right now.
Also
I just would raise a question about the front of the box, Plan B emergency
contraception. I just raise the question
should there be added there the statement that this is for use after
unprotected sex. "Emergency
contraception" can have different meanings to different people. I'm out of birth control pills, you
know. Should I buy this or should I buy
a package of condoms, et cetera?
CHAIRMAN
CANTILENA: Thank you.
Dr.
Williams.
DR.
WILLIAMS: I say yes also to the actual
use study showing the product's capability of performing the task. The concern that I have is, I guess,
twofold. One is to translate the 7,000,
8,000 individuals who have taken the product into the eight to ten million
individuals who are going to be available to use these products, and the second
thing is to make sure that those individuals understand what the product is to
do.
And
secondly, to worry about the potential difficulty, the barrier of, I guess, the
amount of cost of the product for a lot of our underserved individuals in my
community, and I think my individuals, like the community that you talked about
in your drugstores, they have some barriers of getting to the product, and
therefore, I don't think these products will be on the general shelf in my
particular neighborhood either, but that's one of my concerns.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Crockett?
DR.
CROCKETT: I'm going to say no. I don't think the actual use study
demonstrates that consumers used the product as recommended in the proposed
labeling. I think it showed that they
can use it with the proposed labeling in the setting of having access to
education and accountability afterwards, and I think those are important
factors to consider in bringing a product like this from behind the counter to
over the counter.
In
regard to the labeling, I would like to suggest that there be stronger emphasis
on putting the failure rates for the 24 hour, 48 hour, and 72 hour first pill
taking into the product labeling so that patients more clearly understand the
risks and the pregnancy risks from delaying use of it.
And
also, I'm going to reiterate that I think if we're going to go that far, that
we should also put in a statement about needing to take folic acid in case that
there's an intended pregnancy.
CHAIRMAN
CANTILENA: Dr. Uden.
DR.
UDEN: Yes, and I won't say any more.
I'll pass my time along.
CHAIRMAN
CANTILENA: Dr. Stanford.
DR.
STANFORD: I think, yes, it does
demonstrate it for short-term use, short-term study.
In
terms of the label, let me just make the suggestion of something along the
lines of Plan B may work to prevent pregnancy by preventing fertilization or
preventing implantation. Plan B does not
interrupt pregnancy after implantation.
I
think the "after implantation" is important because some women would
understand abortion to mean if it says it does not cause abortion, they would
understand that to mean after fertilization, and I think the language needs to
be unambiguous for people at different points of understanding.
I
also, since we are talking about the label, have one other comment on the
label, and that is how well does Plan B work.
I think the estimate given there is not the most accurate estimate that
could be available. My proposed wording
would be something like Plan B lowers the risk of pregnancy about 84 percent
when used as soon as possible within 72 hours and no further intercourse occurs
during the menstrual cycle. In typical
use, it is about 72 percent effective.
Now,
those percentages are not the point. The
percentages could be changed depending on the study, but the 89 percent that's
quoted is a perfect use quote, and I note that in the package insert later when
they're talking about all of the other contraceptive methods, they quote
typical use for every other method, and they're only quoting perfect use here.
I
think it's important to quote both perfect and typical use if you're going to
quote effectiveness, and it's also important to use the best available
estimates of effectiveness, which I don't think we currently have in the 1998
analysis.
And
there are other experts in this panel, such as Dr. Trussell, who have done more
updated estimates for Yuzpe, and they seem updates with a more reasonable
methodology could be done for Plan B relatively easy by getting the data and
reanalyzing them.
And
I'm suggesting that that should be what's on here, not the 89 percent.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Benowitz.
DR.
BENOWITZ: I would say yes to the
question, but I would also say that I think the goal was not met in that only
37 percent used it within the actual use study within 24 hours, and so I would
go along with the previous panel members in saying that the instructions should
be stronger, and maybe some quantitative data should be provided about how
important it is to use within 24 hours, not to wait for 72 hours. I think that is really key.
With
respect to mechanisms of action, I'm sympathetic with the idea of doing
it. I'm concerned that technical
language like that on the outside of a package will not do very much. Most people won't understand the suggested
language that we've heard so far, and I'm concerned that you can't do justice
to the issue on the outside of the package; that the package insert may be the
only place you can explain it.
CHAIRMAN
CANTILENA: Dr. Lockwood.
DR.
LOCKWOOD: Yes to the question. I would actually eliminate the line "if
breast feeding, ask the doctor before use." That will give you the only person advocating
any elimination of words. That would be
good.
And
I agree wholeheartedly with the emphasis about ectopics. In this internal blue mini insert, whatever
it's called, I would emphasize that all in bold rather than just see a doctor
right away if you have stomach pain. I
think it's critical that they have a sense that they link the possibility of an
ectopic pregnancy with the pain and notify the doctor.
I
would also recommend the language on mechanisms be put in this internal insert
rather than the external one for the same reasons. It would be impossible to describe it.
But
I would eliminate in the first little page of this insert where it says
"pregnant women (in Plan B cannot cause an abortion)," I would just
eliminate "Plan B cannot causae an abortion." I think rather than get into the semantics
and the arguments about what an abortion is, I would just eliminate that
phrase, and somewhere in this little insert, I would explain that the mechanism
of action may be the prevention of fertilization. I think most people know what fertilization
is, and then some lay language that refers to "or implantation."
CHAIRMAN CANTILENA: Thank you.
Dr.
Tulman.
DR.
TULMAN: I would vote yes for the first
question, and I also have some suggestions for the labeling. I think the mechanism of action is better
served in a package insert. I think you
would get to a point that the font would become unreadable on the outside of
the box unless we have a huge box.
I
do think it needs to be emphasized, however, under directions. I think "as soon as possible" is a
rather casual phrase. I think why not
the word "immediately"? I
think it's more precise.
Also,
I think if there's any directions that come with this, and I don't recall
whether the sponsor said anything about whether or not on a full stomach, on an
empty stomach, with water, with whatever, if there's any other types of
restrictions or if you can take it, indeed, full, with food, without food,
juice, water or whatever. I think that
should be on there.
And
also the other question I had on here concerns stomach pain, and you didn't
mention whether that was gastric pain or cramping or what the precise nature of
the pain was.
(Participant
speaking from an unmicked location.)
DR.
TULMAN: Yeah, because that's kind of an
imprecise. You know, is it like pain
like from indigestion or is uterine cramping pain? And I think you could be more precise about
that.
That's
all.
CHAIRMAN
CANTILENA: Okay. Dr. Trussell.
DR.
TRUSSELL: My answer would be yes to the
first question, and the most important change that could be made to the label
is take both pills as soon as possible.
CHAIRMAN
CANTILENA: Which, of course, is not the
way the application has been filed.
(Laughter.)
CHAIRMAN
CANTILENA: So you're voting to reject
the application; is that correct?
(Laughter.)
CHAIRMAN
CANTILENA: Okay. Dr. Giudice.
DR.
GIUDICE: I say yes to the question and I
have the following recommendations for the label.
First
of all, I agree with Dr. Hager with reinstating undiagnosed vaginal bleeding
for the reasons stated and agree with the previous comments on abdominal pain,
seeking immediate care of a physician, and clarifying whether this is stomach,
abdominal or pelvic.
Of
concern in the label comprehension study was in the low literacy group that the
objective for backup, not regular contraception, was only 46 percent. So I would bold and cap the word
"backup" under "Plan B is a backup contraceptive."
In
addition, even though transmission of sexually transmitted diseases was well
comprehended, I still would bold and cap "Plan B does not prevent HIV," again to essentially send the
subliminal message that barrier contraception should be continued.
Thank
you.
CHAIRMAN
CANTILENA: Okay. Thank you.
I
vote yes, and in terms of the label, I think perhaps something that's not been
suggested in terms of the possible mechanism of action could be that the FDA in
the advertising and the information sheets that are sent out to physicians'
offices and/or pharmacies, they be required to have possible mechanisms of
action there.
With
regard to the item on the outside, which says Plan B is not recommended for,
you know, regular contraception, I think something strong like "is not FDA
approved for that" could help, you know, enforce that.
And
I would agree with the comments about stating the information about vaginal
bleeding as well.
Dr.
Tinetti.
DR.
TINETTI: I vote yes, and for the
labeling, my only concern is we're adding too much, and it's well known that
the more we add to the labeling, the less message people get across. I think the key message as I hear it, again,
"as soon as possible." So that
clear the wording that is; number one, that this is only for after unprotected
intercourse, and number three, that it's not a protection again sexually
transmitted diseases I think are the three most important messages that need to
be on the label.
CHAIRMAN
CANTILENA: Dr. Hewitt.
DR.
HEWITT: I vote yes to the question. I think it has been clearly demonstrated that
the majority of patients are able to use the medication appropriately.
My
only comments about the current packaging would be I agree with the statement
of removing the issue related to breast feeding. I agree with the importance of emphasizing to
take the medication as soon as possible, and I think a statement educating
patients that the sooner they take it the more effective it is may be important
to include somehow.
And
I agree with removing the warning about the abnormal vaginal bleeding. I think from caring for patients as a
gynecologist, there is such a broad interpretation of abnormal bleeding. Patients where their period lasts six days
instead of four days that month might interpret that as abnormal bleeding. Some mid-cycle ovulatory bleeding might be
interpreted as abnormal.
And
then young, healthy, reproductive age women with the majority of the diagnoses
associated with abnormal bleeding, I can't imagine how taking one course of
Plan B would negatively impact their health, and I think that that might
preclude patients from taking it that otherwise would benefit from it.
CHAIRMAN
CANTILENA: Dr. Greene.
DR.
GREENE: I would respond yes to the
question, and the point that you made is the one that I was just going to make,
that although abnormal bleeding or undiagnosed bleeding could be a problem,
it's hard for me to imagine any problem that would preclude the use of this
medication or that this medication would exacerbate.
So
I believe that it should also be eliminated from the contraindications to use.
I
would like to point out one obvious thing with respect to the abdominal pain issue,
and that is that if you look through the actual use data, about 14 percent of
patients reported abdominal pain and another 14 percent reported nausea and
vomiting.
Let
me just point out the obvious, that if somebody has an ectopic gestation, it's
going to be four weeks; as the result of failure of this medication to prevent
pregnancy, it's going to be four weeks after she has taken the medication, not
48 hours later.
So
rather than trying to distinguish whether the abdominal pain is cramping up or
lower pelvic, we could just simply alert her that if she has pain weeks after
use of this medication, that it might be an ectopic gestation, not within 24 to
48 hours of use of the medication.
CHAIRMAN
CANTILENA: Dr. Clapp.
DR.
CLAPP: The answer to the question is
yes. I think the actual use study did
demonstrate the appropriate use.
But
I do note that the patients were in all of the circumstances studied pretty
much self-directed. I'm interested in
the patient who has not heard of emergency contraception, who wanders into the
pharmacy and is looking for a solution to a problem.
For
that reason I'm going to encourage the pharmaceutical company to think of
defining "emergency contraceptive" in layman's terms on the outside
of the package because perhaps people don't pick it up, turn it around and get
a good conception -- conception?
(Laughter.)
DR.
CLAPP: -- understanding of the use of
the medication.
So
I'm encouraging the consideration of putting on the outside what you say on the
back of the package. Emergency
contraception for use in case of birth control failure or unprotected sex in
small print underneath.
Secondly,
the mechanism of action I think best belongs on the inside of the package. The package is a lot to digest on its own,
but would become very cumbersome with that information on the outside.
But
giving patients the opportunity who want to think about it briefly because they
should think about it quick, within 24 hours preferably, perhaps a Web site or
a phone number could be included on the outside of the package to direct them
if they have questions before they purchase it.
But
I think that the important consideration to using the medication promptly can't
be understated. I'm concerned that the
mention of 72 hours gives people perhaps the thought that they have an option
of waiting until 72 hours to initiate the treatment, giving them a false sense
of security.
And
in people who are financially pressed, it could be, "Well, let me wait
another day and see if I can borrow the money," or see that 48 hours has
passed and then you just get there at 71 hours and start taking your
medication.
We
perhaps have given them a false sense of security or comfort with that. So I'm encouraging clarity with the "as
soon as possible" and with emphasis within 24 hours but up till 72 hours
so that there is a sense of urgency associated with it.
And
as far as the other two issues, I think vaginal bleeding certainly Dr. Hewitt
said it very perfectly. I think it
should be removed.
And
breast feeding, there's no necessity to include it on the package.
CHAIRMAN
CANTILENA: Dr. Snodgrass.
DR.
SNODGRASS: The answer to the question
would be yes, and my additions to the label would be many of what have already
been stated regarding mechanism of action in the package insert, for example;
24-hour use period or as soon as possible; and the elimination of the breast
feeding statement. I think those are all
important considerations.
Another
point that is not directly to the label per se at this point would be
consideration down the road post marketing of a label comprehension study in
those who are less than 18 years of age.
CHAIRMAN
CANTILENA: Dr. Lewis.
DR.
LEWIS: I also vote yes for the actual
use study demonstrating that consumers use the product as recommended. I agree with the comments about putting the
mechanism of action inside the package because I think it's a little
complicated for the front of the box.
I
also think removing the statement about vaginal bleeding is fine. As far as having menstrual changes there, you
might want to qualify that as short-term menstrual changes, and again, to
emphasize the timing perhaps with an additional statement that the drug is most
effective if used within 24 hours.
And
I also agree with bolding that this is a back-up method of contraception.
CHAIRMAN
CANTILENA: Dr. Blaschke.
DR.
BLASCHKE: Yes. I also vote yes on the question, and the two
things that I would emphasize is I do believe that the front of the package
probably could be improved to indicate that this is a post intercourse method
of contraception just to eliminate that problem.
And
I agree with what's been said by a number of others about emphasizing the
importance of early use with data or in some mechanism.
CHAIRMAN
CANTILENA: Dr. Wood.
DR.
WOOD: I also vote yes. I would caution, however, against studding
the outside of the packet like a Christmas tree with all sorts of issues. I'm particularly concerned about putting
things on the outside of the package which are unsupported by data.
I
haven't seen any data today to suggest that ectopic pregnancy is more common
with this drug than with other forms of contraception. It's not on the package for other forms of
contraception, and in fact, the data that we saw presented didn't suggest that
it was more common than it was with any other or with no contraception.
So
the idea that we just sort of say that beware of abdominal pain seems to me to
make relatively little sense.
Similarly
with vaginal bleeding, and we don't suggest that aspirin has a treatise on
prostaglandin synthase on the outside of the packet, and I would be against
putting the mechanism of action for this drug on the outside of the packet for
the same reasons that I would not suggest that we start legislating for
acetaminophen or aspirin or any other complex mechanism of action, particularly
when it's so speculative.
CHAIRMAN
CANTILENA: Dr. Berenson or -- excuse me
-- Dr. Emerson.
DR.
EMERSON: My answer would be yes. I agree with the desirability of having
quantitative data about the waning of the effect with time since unprotected
sex.
I
also agree with the idea of putting the mechanism of action inside rather than
complicating the box.
And
then the other question that I do have is if there is any time period at which
you shouldn't use this twice, I would think certainly 12 hours, unprotected sex
twice within 12 hours would be certainly one limit, but if there is any sort of
a limit, I would think that that should be included, that you know, either
through the idea that efficacy persists for 48 hours, that there would not be a
need to repeat this within 48 hours or if it posed problems medically for
repeating this within 48 hours or whatever, I think that some sort of limit
should be placed.
CHAIRMAN
CANTILENA: Dr. Berenson.
DR.
BERENSON: I would vote yes to the first
question, and regarding the package labeling, I would suggest that less
information rather than more be included on the outside of the package.
Personally
I'm at an age where I'm developing presbyopia.
So I guess that makes me not a great candidate to need to use Plan B.
(Laughter.)
DR.
BERENSON: But the type is quite small on
the back. While that is normal for many
packages that are sold over the counter, in this particular case the need for
the patient to be able to read the directions for use, I think, and use it
correctly is stronger due to the adverse effects that could result.
So
some particular recommendations I have how to get the print larger is to, first
and foremost, remove the statement of breast feeding as has been stated before;
ask a doctor before use. I'm not even
certain why that statement is on there because, as physicians, we would just
give the Plan B anyway to a breast feeding patient because a great many
patients each year get pregnant while they're breast feeding. So that certainly is no protection.
Second,
I'm not sure why every side effect, every possible side effect is listed on the
back of the package. It seems to me that
could also be in the package insert.
Third,
I don't know why the active ingredients have to be listed on the front of the
page and the back of the box.
So
there seem to be several opportunities that they could get things off and make
the print larger.
Finally,
for the same reasons, I would agree that the mechanism of action should be in
the package insert rather trying to put one more additional thing on the
outside of the box.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Davidoff.
DR.
DAVIDOFF: Yes on the question, and I'd
also weigh in on the issue of the wording about timing because I think it's not
just a question of urgency, but specificity.
And I think the data do support specifically, as a number of people have
pointed out, the rapidly decreasing efficacy over time.
So
I would urge not to wordsmith here, but something along the lines of putting a
specific indication of earliness.
"As soon as possible" is much too vague.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Montgomery Rice.
DR.
MONTGOMERY RICE: I would keep in vaginal
bleeding, but I would definitely move it to the warning section instead of the
side effect section, which it is now, and I would call it unexpected vaginal
bleeding because the patient should expect to bleed at a normal time or so on
the next cycle because I do think that is one of the indications of possible
ectopic.
And
so if it's in a warning, the patient may have some better information instead
of a side effect because it's more of a warning. And I think the mechanism goes on the inside
of the package insert, and my answer is yes.
CHAIRMAN
CANTILENA: How did you know we were
going to ask that?
DR.
MONTGOMERY RICE: I could tell by the
look on her face she was getting anxious.
CHAIRMAN
CANTILENA: Okay. Well, since you're on a roll, then why don't
we continue with that side of the table -- oh, I'm sorry. I have to read the tallies.
We
had 28 voting, 27 yes, one no, zero abstain.
Okay. Question 2, and we'll start with this side of
the room, Dr. Montgomery Rice. Question
2, and we'll start with this side of the room, Dr. Montgomery Rice, Question
No. 2 states: are the actual use study
data generalizable to the overall population of potential non-Rx users of Plan
B?
And
here it's a yes or no with your reasons.
Thank you.
DR.
MONTGOMERY RICE: I do think if you
review the data from the study that these are the people who would come in for
emergency contraceptive, but clearly, they had to know that emergency
contraception existed. And so I think
with the appropriate marketing, other people would be more educated and would
know that it potentially exists.
So
I would say, yes, the data is generalizable to the overall population.
DR.
DAVIDOFF: I would also say yes to the
question. Sampling is always a difficult
challenge, and no sampling is perfect unless you sample the universe, but I
think it's a reasonable approximation.
CHAIRMAN
CANTILENA: Okay. Dr. Berenson.
DR.
BERENSON: Yes, I think it was
generalizable.
CHAIRMAN
CANTILENA: Dr. Emerson.
DR.
EMERSON: Statistics means never having
to say you're certain. I would say, yes,
it's acceptably generalizable.
CHAIRMAN
CANTILENA: Dr. Wood.
DR.
WOOD: Yes.
CHAIRMAN
CANTILENA: Yes. Dr. Blaschke.
DR.
BLASCHKE: Yes.
CHAIRMAN
CANTILENA: Dr. Lewis.
DR.
LEWIS: Yes, but I think it really should
be translated at least into Spanish and possibly into other languages because
it was only done in people who speak English well enough to participate in the
study.
CHAIRMAN
CANTILENA: Dr. Snodgrass.
DR.
SNODGRASS: The answer is yes, and that
would, again, be based on the data that's presented.
CHAIRMAN
CANTILENA: Dr. Clapp.
DR.
CLAPP: Yes.
CHAIRMAN
CANTILENA: Dr. Greene.
DR.
GREENE: Yes.
CHAIRMAN
CANTILENA: Dr. Hewitt.
DR.
HEWITT: Yes.
CHAIRMAN
CANTILENA: Dr. Tinetti.
DR.
TINETTI: Yes. Probably a little bit of overstatement
because they're probably more informed than the other population, but I think
close enough.
CHAIRMAN
CANTILENA: Okay. So your answer is, yes, that it would be
generalizable.
DR.
TINETTI: I say yes.
CHAIRMAN
CANTILENA: Okay. Dr. Giudice.
DR.
GIUDICE: Yes.
CHAIRMAN
CANTILENA: Dr. Trussell.
DR.
TRUSSELL: Yes.
CHAIRMAN
CANTILENA: Dr. Tulman.
DR.
TULMAN: Yes.
CHAIRMAN
CANTILENA: Dr. Lockwood.
DR.
LOCKWOOD: Yes.
CHAIRMAN
CANTILENA: Dr. Benowitz.
DR.
BENOWITZ: I would say acceptable,
yes. I do share the concerns about a
family practice clinic being a little bit different. The fact that 74 percent of these women had
some college education is not the usual user, but there were enough in the
subgroups that I think we could extrapolate and say it's acceptably
generalizable.
CHAIRMAN
CANTILENA: Dr. Stanford.
DR.
STANFORD: Yes,
CHAIRMAN
CANTILENA: Any comments?
DR.
STANFORD: No.
CHAIRMAN
CANTILENA: Okay. Dr. Uden.
DR.
UDEN: Yes, with other language provisos.
CHAIRMAN
CANTILENA: Dr. Crockett.
DR.
CROCKETT: Yes. However, I have some other concerns. One is the illiterate population, that the
results may not be generalizable to them.
My
second concern is for off-label use potential, which was not addressed in the
AUS data at all.
And
thirdly, if we're going to generalize the data from the actual use trial, we
have to remember that there were a significant number of patients that did not
see this as a secondary form of birth control; that intimated that they may use
it as a primary method of birth control.
And so if we're going to generalize the good points, we need to
generalize that also.
CHAIRMAN
CANTILENA: Dr. Williams.
DR.
WILLIAMS: Yes, with the appropriate
training that's coming along with the CARE Program that is described by the
sponsor.
CHAIRMAN
CANTILENA: Okay. Dr. Patten.
DR.
PATTEN: Yes, with the proviso that the
overall population of potential users is a very diverse population and --
CHAIRMAN
CANTILENA: I'm sorry. Can you speak up?
DR.
PATTEN: Yes. With the proviso that the overall population
of potential users in the U.S. is very diverse in terms of language, and so
consideration needs to be given to that situation.
CHAIRMAN
CANTILENA: Okay. Dr. Macones.
DR.
MACONES: Yes.
CHAIRMAN
CANTILENA: Dr. Johnson.
DR.
JOHNSON: Yes, to the extent that's I
think reasonably possible.
CHAIRMAN
CANTILENA: Okay. Dr. Lipshultz.
DR.
LIPSHULTZ: Yes.
CHAIRMAN
CANTILENA: Dr. Lam.
DR.
LAM: Yes, if there's more educational
effort directed to other ethnic minority groups.
CHAIRMAN
CANTILENA: Dr. Hager.
DR.
HAGER: My answer is yes, although I
still am concerned about the younger
adolescent, the low numbers included in the AUS, and the literacy
information. This is a very high risk
group of young women who deserve our attention as much as those who would
attend family planning clinics and have college degrees.
And
so I'm concerned that there is not as much information both as to ability to
follow the directions, effectiveness and follow-up among that population. And so my answer is yes, but I think we need
more information from that group of patients.
CHAIRMAN
CANTILENA: Okay. Thank you, Dr. Hager.
Actually
my vote on this will be no for the reasons I think Dr. Hager just stated and
Dr. Crockett and Dr. Benowitz. There
were enough segments of the population studied which really did not do well,
and I think when we generalize this out I have concerns because the study was
really done in a somewhat artificial environment, and I understand the
limitations on an actual use.
But
I think we could have had it more actual and in an actual use. So I'm not convinced that as in terms of
information we have on hand, that it would be generalizable to the general
population.
So
the vote tally for Question No. 2 is 27 yes and one no.
Okay. I think what I'd like to do here to speed
things along a little bit is to do Question 3 by a show of hands, and then
depending on how the vote comes out, we will have to identify those individuals
voting, and of course, after the vote you are free to comment as well.
Number
3, based on the actual use study and literature review, is there evidence that non-Rx availability of Plan B leads to
substitution of emergency contraceptive for the regular use of other methods of
contraception.
Let
us word this correctly. Okay. We are going to compromise. Dr. Templeton-Somers is very persuasive, and
for her ability to record the minutes accurately, we'll just go around the
table. I think it will be easier for
her.
And,
again, it's a yes/no, and then your comments if you feel like you need to
comment, and we'll start over on this side.
Dr. Hager.
DR.
HAGER: No.
CHAIRMAN
CANTILENA: Dr. Lam.
DR.
LAM: No, based on some of the
contraceptive behavior studies presented this morning by the FDA.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Lipshultz.
DR.
LIPSHULTZ: No.
CHAIRMAN
CANTILENA: Dr. Johnson.
DR.
JOHNSON: No.
CHAIRMAN
CANTILENA: Dr. Macones.
DR.
MACONES: No.
CHAIRMAN
CANTILENA: Dr. Patten.
DR.
PATTEN: No.
CHAIRMAN
CANTILENA: Dr. Williams.
DR.
WILLIAMS: One way or another, no.
CHAIRMAN
CANTILENA: You don't have to speed. I'm going fast, but please don't feel rushed.
(Laughter.)
CHAIRMAN
CANTILENA: We have plenty of time. In fact, we're planning on ordering supper
in.
Dr.
Crockett.
DR.
CROCKETT: I'm going to say no. However, the AUS, the literature review
didn't lead us to think that. However,
the public testimony did, which I think is very important because those are
high literacy people speaking.
And
the other point I'd like to make is I don't think that the AUS and the
literature review will accurately reflect what the true over-the-counter use
would be, and I would suspect that the substitution of EC for regular use of
other methods might be higher than we're led to believe in these studies, which
also have, as I said before, an educational and an accountability component
built in which change behavior.
CHAIRMAN
CANTILENA: Okay. Dr. Uden.
DR.
UDEN: No.
CHAIRMAN
CANTILENA: Dr. Stanford.
DR.
STANFORD: No, but I also think that post
marketing surveillance is warranted because there are enough different
variables, and I will say no imbalance because there was one of the studies
that showed some possible substitution.
So
I think that post marketing surveillance is important.
CHAIRMAN
CANTILENA: Dr. Benowitz.
DR.
BENOWITZ: No.
CHAIRMAN
CANTILENA: Dr. Lockwood.
DR.
LOCKWOOD: No, but in view of the UCSF
study, I also agree that post marketing analysis would be very important.
CHAIRMAN
CANTILENA: Dr. Tulman.
DR.
TULMAN: No.
CHAIRMAN
CANTILENA: Dr. Trussell.
DR.
TRUSSELL: No, and in fact, the evidence
would suggest the opposite.
CHAIRMAN
CANTILENA: Dr. Giudice.
DR.
GIUDICE: No.
CHAIRMAN
CANTILENA: Dr. Tinetti.
DR.
TINETTI: No, but I agree with Dr.
Crockett's extra comments.
CHAIRMAN
CANTILENA: Dr. Hewitt.
DR.
HEWITT: No.
CHAIRMAN
CANTILENA: Dr. Greene.
DR.
GREENE: No.
CHAIRMAN
CANTILENA: Dr. Clapp.
DR.
CLAPP: No.
CHAIRMAN
CANTILENA: Dr. Snodgrass.
DR.
SNODGRASS: No.
CHAIRMAN
CANTILENA: Dr. Lewis.
DR.
LEWIS: No, but I also think post
marketing surveillance is a good idea mostly because you don't want to see
people stop using barrier contraception.
CHAIRMAN
CANTILENA: Dr. Blaschke.
DR.
BLASCHKE: No.
CHAIRMAN
CANTILENA: Dr. Wood.
DR.
WOOD: No.
CHAIRMAN
CANTILENA: Dr. Emerson.
DR.
EMERSON: No, but I just say that all of
this should be done carefully because just having failed contraception, it
might not be unusual for people to change their methods.
CHAIRMAN
CANTILENA: Dr. Berenson.
DR.
BERENSON: No.
CHAIRMAN
CANTILENA: Dr. Davidoff.
DR.
DAVIDOFF: No.
CHAIRMAN
CANTILENA: Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: No, but I agree partly
with Dr. Crockett. I think our speakers
definitely gave some indication that there may be some use or substitution, and
I think in the labeling in that package insert thing that has all of that
information that there should be something that lists all of the appropriate
available forms of contraception.
CHAIRMAN
CANTILENA: Okay. Thank you.
And
I also vote no, and I would second what was said by Dr. Tulman. There is the possibility for that with the
San Francisco study, but only a possibility, and the fact that this is an NDA,
Curt, and it's on a switch, then you'll automatically follow with a post
marketing surveillance, you know, because it's a switch product.
DR.
ROSEBRAUGH: That's something we'll talk
over with the sponsor.
CHAIRMAN
CANTILENA: Okay. I thought it was automatic if you --
DR.
ROSEBRAUGH: Oh, yeah. I'm sorry.
With NDA, right, there is post marketing surveillance. Sorry.
CHAIRMAN
CANTILENA: Okay. So the vote tally to Question 3 was 28 yes
and zero -- excuse me. Sorry. That will be two sodas you owe me,
Karen. One because it was unanimous and
two because -- okay. So the vote total
is zero yes and 28 no.
Okay. Question No. 4, do the data demonstrate that
Plan B is safe for use in the nonprescription setting?
And,
again, this will be yes or no with your reasons, and we'll start on this end
with Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: You know, you could
start in the middle sometime, but --
(Laughter.)
CHAIRMAN
CANTILENA: If you think I have a hard
time keeping track of one end or the other, it would be chaos in the
middle. Sorry.
(Laughter.)
DR.
MONTGOMERY RICE: I do believe the data
does support that Plan B is safe for use in a nonprescription setting.
CHAIRMAN
CANTILENA: Dr. Davidoff.
DR.
DAVIDOFF: Yes to the question, and
because of the effect on reducing unwanted pregnancies I would say that it's
safer than not using it.
CHAIRMAN
CANTILENA: Dr. Berenson.
DR.
BERENSON: Yes.
CHAIRMAN
CANTILENA: Dr. Emerson.
DR.
EMERSON: Yes.
CHAIRMAN
CANTILENA: Dr. Wood.
DR.
WOOD: Yes, I would say it's
extraordinarily safe.
CHAIRMAN
CANTILENA: Dr. Blaschke.
DR.
BLASCHKE: Yes.
CHAIRMAN
CANTILENA: Dr. Lewis.
DR.
LEWIS: Yes.
CHAIRMAN
CANTILENA: Dr. Snodgrass.
DR.
SNODGRASS: Yes.
CHAIRMAN
CANTILENA: Dr. Clapp.
DR.
CLAPP: Yes.
CHAIRMAN
CANTILENA: Dr. Green.
DR.
GREENE: Yes.
CHAIRMAN
CANTILENA: Dr. Hewitt.
DR.
HEWITT: Yes.
CHAIRMAN
CANTILENA: Dr. Tinetti.
DR.
TINETTI: Yes.
CHAIRMAN
CANTILENA: Dr. Giudice.
DR.
GIUDICE: Yes, with a wide safety margin.
CHAIRMAN
CANTILENA: Dr. Trussell.
DR.
TRUSSELL: Yes.
CHAIRMAN
CANTILENA: Dr. Tulman.
MS.
TULMAN: Yes, definitely.
CHAIRMAN
CANTILENA: Dr. Lockwood.
DR.
LOCKWOOD: Yes, with statistical
certainty.
(Laughter.)
CHAIRMAN
CANTILENA: Well, that's something we
haven't had a lot of today.
(Laughter.)
CHAIRMAN
CANTILENA: Thank you very much.
Dr.
Benowitz.
DR.
BENOWITZ: Yes, and I think because no
one else has done it, I think it should be on the record in light of some of
the comments. I would just say why. It's short-term use only, regular use of this
product for contraception in some studies; for planned contraception it has
been safe even at much higher doses.
There is a long track record of safety of progestin only oral
contraceptives, and the post marketing surveillance is totally clean. So I think it's very safe.
CHAIRMAN
CANTILENA: Thank you, Dr. Benowitz.
Dr.
Stanford.
DR.
STANFORD: Yes, safe for the women.
CHAIRMAN
CANTILENA: Okay. Dr. Uden.
DR.
UDEN: Yes.
CHAIRMAN
CANTILENA: Dr. Crockett.
DR.
CROCKETT: I would say yes. I'm sure that it's safe for maternal
use. I have not seen enough data to
determine if it has any long-term effects on fetuses that are conceived as
failures of this method of contraception.
So I would suggest that as a post marketing strategy that we collect
data on the babies that are born.
CHAIRMAN
CANTILENA: Dr. Williams.
DR.
WILLIAMS: Yes.
CHAIRMAN
CANTILENA: Dr. Patten.
DR.
PATTEN: Yes.
CHAIRMAN
CANTILENA: Dr. Macones.
DR.
MACONES: Yes.
CHAIRMAN
CANTILENA: Dr. Johnson.
DR.
JOHNSON: Yes. I've been on this committee, the
Nonprescription Committee, for almost four years, and I would task this to be
the safest produce that we have seen brought before us.
CHAIRMAN
CANTILENA: Dr. Lipshultz.
DR.
LIPSHULTZ: Yes.
CHAIRMAN
CANTILENA: Dr. Lam.
DR.
LAM: Yes.
CHAIRMAN
CANTILENA: Dr. Hager.
DR.
HAGER: Yes. I would like to see continued post marketing
evaluation of the pregnancies, the failures, and also more information on the
ectopic pregnancies because I think we can enhance our data bank by having that
information.
CHAIRMAN
CANTILENA: Okay, and I also vote yes,
and I would just second the comments of Dr. Benowitz and also actually Dr.
Hager.
The
vote on Question 4 was 28 yes and zero no.
Question
No. 5: are the plans for introduction of
Plan B into the non-Rx setting adequate with respect to consumer access and
safe use?
If
no, what other options would you recommend?
And
here I think what we're getting at is, you know, points of sale, how the drug
is sold, and so those are the kinds of things that you can comment on.
So
are the plans adequate with respect to consumer access and safe use? Dr. Hager.
DR.
HAGER: Well, I don't want to take a lot
of time, but we've talked about this quite a bit today, and my concern, once
again, is for adolescents. My concern is
the pricing, and I think the sponsor has kind of danced around this issue of we
intend to price this drug so that it is not used excessively, and when that is
done, in my opinion, there is the risk of pricing out a large group of women of
low socioeconomic status who are economically deprived.
And
so I have significant concern about that, and that leads me to vote that the
plans are not currently adequate.
CHAIRMAN
CANTILENA: Okay. I think for a point of clarification, if I'm
correct, the FDA does not control the pricing issue, but they can stipulate in
terms of the ages required for sale, and it's my -- is that true? I see some people going no.
DR.
HAGER: Well, excuse me for interrupting,
but I think that the FDA can alter the problem of pricing affecting
access. Is that not true?
DR.
KWEDER: No. We are not able to weigh in at all on pricing
other than to perhaps make sure that the company is aware of the comments that
we've made, but we have absolutely no authority on pricing.
DR.
HAGER: Okay. Then my comments are directed to the company,
I guess.
CHAIRMAN
CANTILENA: Okay. Can you talk about, Sandy, in terms of the
age? What are the ages as, you know,
proposed here in terms of, you know, legal sale? Are there any restrictions to age as
proposed?
DR.
KWEDER: For the most part we usually
label the drug for use in general as it has been studied. In some conditions, we put an age restriction
on it because there has been an age restriction in the trials. In some, that would be typical, for example,
in an antihypertensive that was studied in adults. You know, these are prescription products. We would limit the indication to adults
partly because the treatment of hypertension in children is a little bit
different.
This
is a product that currently does not have an age restriction in the prescription form. So in general, we would not have reason to
impose an age restriction for the product unless there were specific reasons to
do so.
Historically
for all oral contraceptives, we do not have an age restriction because most of
the studies are done in a wide range of ages, and we have considered women of
reproductive age are capable of reproduction as one group.
CHAIRMAN
CANTILENA: So when you say that you've
approved drugs according to the study population, in the actual use study here
is that what you would then use?
Because, you know, I think it was down to age 14; is that correct?
DR.
KWEDER: We would probably not put a specific
age limit on it, yes.
CHAIRMAN
CANTILENA: Okay.
DR.
KWEDER: But Steven wants to add.
DR.
GALSON: If members of the committee feel
that this drug should be restricted according to age, we'd like to know it, but
what Sandy said is valid.
CHAIRMAN
CANTILENA: Okay. Well, then, Dr. Hager, you know, you've heard
that they have no control or authority in terms of how much the drug will cost. Perhaps you'd like to comment on the ages
that it's available for.
DR.
KWEDER: Actually, let me also add to
that. When you're talking about a
product that's over the country, imposing a specific restriction on age is
somewhat difficult. There are not very
many products of that nature.
It's
much easier or it's a little easier for a prescription product because the
pharmacist is there. Imposing an age
specific restriction really puts the burden on the pharmacist or the store
carrying the product to check the age of the purchaser.
CHAIRMAN
CANTILENA: Right, but a lot of
pharmacies also sell cigarettes.
DR.
KWEDER: Exactly, exactly.
CHAIRMAN
CANTILENA: So it's not impossible.
DR.
KWEDER: Right. It's not impossible, but you know, in
considering that, we would weight the pros and cons of access, but yes, it is
not impossible. It's done for Nicorette
and nicotine replacement products because it is also in place for tobacco
products, but again, that's not something that we enforce. That's something that's voluntary on the part
of the pharmacy.
CHAIRMAN
CANTILENA: So then you would not have the
authority to then require that they check the age of whoever is buying this?
DR.
KWEDER: It's something that we would
discuss with the company.
CHAIRMAN
CANTILENA: Okay, and that is not the
same as the process in Canada, you know, behind the counter?
DR.
KWEDER: That's not the same.
CHAIRMAN
CANTILENA: Okay.
DR.
KWEDER: The Canadian system of behind
the counter is not a model that we specifically have, but we have many programs
where, for example, as the company is proposing here, something that might
achieve some of the same purposes by where the product is placed.
CHAIRMAN
CANTILENA: Well, Dr. Hager, now that
we've given you a lot more information, would you like to comment on the age
issue?
DR.
HAGER: I think we are being asked to
make a decision about the introduction of the product and age without adequate
information. I don't think that the
actual use study gives us adequate information for that younger adolescent
population, and for me, that is enough of a concern to say that the plans for
introduction of Plan B into the nontreatment setting need more evaluation if it
is going to be generalizably available to a nine year old regardless, a ten
year old regardless of, you know; there's no restriction.
And
so that's my opinion.
CHAIRMAN
CANTILENA: So then if I can --
DR.
WOOD: Just a moment. In the questions that I've got, I don't see
anything about age. Where did this come
in this question?
CHAIRMAN
CANTILENA: It's under access, customer
access, consumer access.
DR.
WOOD: It doesn't say anything about age
though. This question seems to be posed
in terms of age. The version I've got
doesn't mention age.
CHAIRMAN
CANTILENA: The original comment was
about the cost and uncertainty with the younger population. So then the question that I asked FDA was are
there any mechanisms available for them to control access, you know, based on
page, and I'm just asking if you choose to do so, you can comment about how you
feel about the age for sale, whether it's an option thing. It's not a yes or no.
You
don't have to comment on it. It's just
optional because he had to, you know, raise the issue.
Yes,
Dr. Berenson.
DR.
BERENSON: I would just like to make a
point that it is extremely rare that the nine or ten year old has menstrual
cycles, and so if we're going to talk about adolescents, let's talk about the
mean age of menarche in this country is 12, and I can't imagine where a nine
year old would get $40 to go buy Plan B over the counter and who would buy it
for this nine year old.
I
just think we need to distinguish between children and adolescents.
DR.
HAGER: Well, I'm sorry, but there are
young women that age who do start menstrual cycles, and although the numbers
aren't large, it is enough of a concern that if there is an 11 year old who is
having a menstrual period and becomes sexually active, then she chooses to
access this means of emergency contraception, and my only point is not the
number. It's that we don't have
information available on that younger age population. It just wasn't in the actual use study.
DR.
KWEDER: Can I? Lou, let me.
Can I just say one of the things that we do, the model that we usually
use for over the counter is we would say something like -- on the insert we
would say "under age X see a doctor."
That would be the most common method that we would use on a product
that's generally over the counter.
CHAIRMAN
CANTILENA: Okay. Dr. Lam.
DR.
LAM: The answer to the question is yes,
and I would recommend the sponsor to think about doing long-term study to look
at the long-term effect especially after multiple uses, and also would
recommend the sponsor to work with pharmacy to make sure that they're not
locked up, especially with CVS Pharmacy in the State of New Jersey.
(Laughter.)
CHAIRMAN
CANTILENA: We will call the governor of
New Jersey right after this meeting.
Dr.
Lipshultz.
DR.
LIPSHULTZ: I wish I had the luxury of
starting over there because I think this is a very difficult question to answer
in that there are plans that may be adequate if they work, but they're just
plans, and I think some of the words that are used, like
"responsible," "reasonable," "easy access by the
consumer to a pharmacist," I mean, I'm not sure these can really be
done. This is kind of a unique drug.
If
we had behind the counter, or whatever they have in Canada, system, I think it
would be ideal to put it there so they were forced to talk to somebody.
So
do I think that it's -- are the plans adequate?
No, I don't think they're adequate because I don't think they're tested.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Johnson.
DR.
JOHNSON: I think their plans are
adequate and reasonable. I think that it
should not be pursued as behind the counter.
I think there would be less barrier than there is currently, but still
substantial barriers in such an access mechanism.
I
think that the intention to limit sale to stores that contain a pharmacy is a
good one, and I would question -- the only thing that I would have concern or
question is as the program is described, the primary educational focus for
health care professionals is with OB-GYNs, and I would suggest that your
primary focus should be on pharmacists for two reasons.
One
is that they're going to be the primary
health care professional who will be interfacing with the consumers who
are wishing to purchase this product.
And
secondly, as a pharmacist, I can almost guarantee you that their current
knowledge of this product is much lower than the current knowledge of the
average OB-GYN.
And
then finally, in terms of age, I'm not an OB-GYN, but I can't imagine that I
would prefer a ten or 11 year old to be pregnant over some hypothetical risk
that there might be with a ten or 11 year old taking this product.
So
I guess I would feel pretty strongly about not having any age restrictions.
CHAIRMAN
CANTILENA: Okay. Dr. Macones.
DR.
MACONES: My answer is yes to the
question. My only comment would be
regarding the hotline that the company is proposing. I think that's going to be a very, very
widely used hotline, and I'd really like to see the scripts for the answers to
some of the questions that people are going to be calling with commonly be
worked out well in advance of this product, you know, potentially going over
the counter.
In
addition, there was a mention that the hot line could be used for some post
marketing surveillance, and I'd also like to see a plan for exactly how that
could be accomplished, but I think it is a unique opportunity.
CHAIRMAN
CANTILENA: Dr. Patten.
DR.
PATTEN: My answer is yes, and I see safe
use being linked to changes in the label and the insert that have been
suggested around the table, and if those suggestions are responded to, then,
yes, safe use.
And
I would concur that there should be no age restrictions.
CHAIRMAN
CANTILENA: Dr. Williams.
DR.
WILLIAMS: My answer is yes. My concerns, of course, the professional and
the health care professionals' educational programs that were initiated in the
sponsor's presentation, and I'm hoping that that would augment what is given to
the media for presentations.
CHAIRMAN
CANTILENA: Dr. Crockett.
DR.
CROCKETT: I would say no for these
reasons. We heard about other countries
that have similar programs and 71 others of the countries have some kind of
pharmacist dispensing as a behind-the-counter component, giving education and
support to these women. There are only
two countries where that's not done and it's truly over the counter, and I saw
no data that would duplicate what we could expect to see in the true
over-the-counter use here in the United States.
It's
my opinion that this class of drug does not belong over the counter.
I
have other concerns. We heard some very
impassioned testimony this morning about how hard it was for women to obtain
this drug because they were afraid to contact people or didn't want to tell
what had happened to them. That's one
way to look at it, that is, to look at it as a barrier.
But
the way I prefer to look at it as a physician and a caring, compassionate
physician to my patients is that if you remove the ability or the necessity for
that patient to come in and talk to me or just to talk to me, you're removing
my ability to support them, to be an advocate for them, especially in cases of
rape or incest; to help them get support and to help them to determine the
necessity of the medication that they're taking.
I
have concerns that although I believe that this company is well intentioned in
decreasing intentional abortion rates, and I wholeheartedly support that, I
have a concern that there will be an exploitation of young women's fear of
becoming pregnant, and that there will be a tendency for this medication to be
used over the counter much more and to sell much more than is really needed,
and to consider exposing this large of a population to that kind of open use I
think is a bad idea.
And
I have a question to end my comments, and that is one of the public speakers
mentioned a pediatric act concerning testing of pediatric use, and I would like
for somebody from the FDA to explain that a little bit more and to clarify how
that would apply to this drug in particular.
DR.
KWEDER: This is a pediatric rule for
lack of using the longer term, requires that all products be considered and
studied in pediatrics when the population is relevant, when there is a relevant
population to be studied.
As
I mentioned earlier, historically for oral contraceptives, we have not
considered teenagers or adolescents a different population that needs
independent study. So we have not
previously required specific testing or studies in the adolescent population.
CHAIRMAN
CANTILENA: So, Sandy, you would then not
apply that rule, you know, for this application?
DR.
KWEDER: No, no. We would not be applying the pediatric rule
to this application.
That
is not to say that we can't ask, that we can't work with the sponsor in any
subpopulation of, you know, the general population of users to collect
additional data on patterns of use or, you know, whatever may be a topic of interest,
but we would probably not apply specifically the pediatric rule to require
separate studies in that population.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Uden.
DR.
UDEN: I guess I have to abstain because
I can't vote yes or no for this because I don't have enough information. We have an actual use trial which was in
clinics and with very literate people. I
have no clue what their plan is for people who are not as literate as what has
been studied.
We've
had come before this committee four sponsors who have said they're going to put
together a post marketing support system like the CARE system. I've never seen any data that companies have
actually done that and that those have been successful.
I'm
sure they're going to do it. They're
going to give it a try, but will it be successful? I have no idea.
And
then I don't know the impact of having these products sold in grocery stores
and gas stations. What's that going to
be without them being sold in pharmacies?
CHAIRMAN
CANTILENA: Dr. Stanford.
DR.
STANFORD: Based on what I currently
know, I think I have to say no. I base
that primarily on the current company Web site, and if some of these changes
that we've talked about are made to the package insert and are also reflected
in the Web site adequately for informed consent about number one -- my two
biggest issues, number one, informed consent for mechanism of action and,
number two, the best, accurate effectiveness information.
Then
maybe if that all gets filtered out into the hotline and the health care
presentations and everything, then I think I could maybe say yes, but at this
point I have to say no.
CHAIRMAN
CANTILENA: Dr. Benowitz.
DR.
BENOWITZ: I think as far as we've heard
I would vote yes. I do think that the
issue of making counseling available is an important one since we don't have
behind-the-counter available and since there are some drawbacks.
What
I would like to see is some proactive point of sale signage or something that
says "counseling is available, and if you want counseling, see the
pharmacist."'
I
really think pharmacists need to be more involved in medications than they
are. I think this drug should only be
sold in pharmacies or where a pharmacist is available, and I think pharmacists
should be educated about this.
I
also think that if someone doesn't want to talk to the pharmacist, they should
be encouraged to either call the hotline or the Web site rather than just
optional because it is an opportunity to educate someone, to make sure they're
using the product correctly, to deal with sexual abuse issues and all of the
things we've heard about before.
CHAIRMAN
CANTILENA: Dr. Lockwood.
DR.
LOCKWOOD: Let me just make a couple of
points. The first one is that New Haven
is the most inaccessible city to air traffic in the United States, and if
anybody can do anything about that in the federal government, I'd be very
appreciative.
But
I --
(Laughter.)
CHAIRMAN
CANTILENA: This is the wrong advisory
committee for that.
DR.
LOCKWOOD: I say that because I'm going
to have to run to the airport to catch the last flight to hartford in about two
minutes. So I wanted to sort of make my
comments about five and I'll make my comments about six, although I'm not sure
my vote will count.
I
vote yes, and I think that eh company has done an extraordinarily good job of
carefully considering the nuances of this issue, and I support their rationale
for locating the product, and I think that their CARE Program is well thought
out as well.
I'd
also emphasize the need for clear -- no one is going to talk to the pharmacist
-- but that there's a clear method for them to access the Web site and/or an
anonymous phone number.
And
if I could just comment about six, I do recommend a switch in this product to
over the counter, absolutely. I think
the evidence for efficacy and safety are overwhelming. However, I strongly feel the labeling that I
already described ought to be incorporated into it.
Thank
you.
CHAIRMAN
CANTILENA: Dr. Tulman.
MS.
TULMAN: As I'm looking at Question 5, I
really see it as two questions, and I would vote yes to both. I think there's the issue of consumer access
and the issue of safe use, and I think in safe use, the company, the sponsor
has more than adequately demonstrated that the public can use it in the
nonprescription setting.
When
it comes to consumer access, I would urge it not be a behind-the-counter, but
be an on-the-shelf access. I think the
notion of having counseling going on in a pharmacy with respect to my colleague
sitting next to me, I also live in the State of New Jersey, and in my local
pharmacy, there are at any one given moment about 30 people waiting for their
prescription, and the least thing I would want is a pharmacist and I to hold a
conversation about my sex life in front of my 30 neighbors standing behind me
very impatient waiting for their prescriptions.
(Applause.)
MS.
TULMAN: So, therefore, I'm not sure that
pharmacies are actually the place to do health counseling.
I
do applause the company for trying to bring access of this product to the
consumer.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Trussell.
DR.
TRUSSELL: Yes.
CHAIRMAN
CANTILENA: Dr. Giudice.
DR.
GIUDICE: I vote yes, although I have a
few comments. One has to do with the age
and whether or not we should consider an age restriction. I actually vote not to specify an age
restriction.
However,
in the CARE Program, in the sponsor briefing document on page 85, the campaign
is quoted to appeal to women age 17 to 44, and therefore, I'm just wondering
what happens to young women who are less than 17 years old, and I encourage the
sponsor to work with the FDA to address that issue.
Secondly,
with regard to WEB access here we're making a huge assumption here, and that is
primarily for individuals who are more literate and also more affluent, and I
would encourage the sponsor again to work with the FDA to enable women who have
lower literacy and who are in lower socioeconomic groups to have more
understandable information, and in addition, also to consider translation into
other languages.
Thank
you.
CHAIRMAN
CANTILENA: thank you.
I
guess my vote is somewhere between Dr. Lipshultz and Dr. Uden, which would put
me formally as a no, but for the following reasons. We're actually going out into uncharted
areas. The plan is good, but the
effectiveness of the plan is unknown.
With
regard to the comment about the age, the application of pediatric rule, it
seems to me like the population that we have extremely little information on
are the adolescents, and I think this would be an appropriate use of the rule,
and a study could be done to assess their behaviors and the information that
these individuals will need to use the product correctly.
So
I think that that's, I think, a hole in the information that's currently
available, and for those reasons I think the plan as currently on the books is
not adequate.
Dr.
Tinetti.
DR.
TINETTI: I would vote that's actually a
split vote. It's really two parts. I think it's yes for safe use. I'm concerned that there's not enough work
towards getting access off the information for the people who could most
benefit from this, and I vote to not have any age restriction.
I
guess it's a yes overall, but there was really two parts of the question.
CHAIRMAN
CANTILENA: Dr. Hewitt?
DR.
HEWITT: I vote yes, and I would like to
make some comments about the age restriction.
I'm currently a pediatric analyst and gynecologist, and I will try to
keep my comments brief, but I do think there are some things in the literature
that we can use to help us make a decision about the age.
When
we think about teenagers, we need to think about are they different medically,
physiologically, and then also are they different behaviorally?
And
I do think we have some evidence that we can apply. In terms of the medical physical difference
with teenagers, I think we have lots of information in the medical literature
that shows that a progestin would be completely safe for them to use and
there's no evidence it would have any impact on their pubital growth or
development, and I see no reason that medically a young, adolescent woman would
not use Plan B safely.
In
terms of behavioral characteristics of adolescent women, we have lots of
information about their use of contraception, and most of that information says
that they are poor contraceptors, and because of inherent aspects of adolescent
development, they are not good at planning ahead. They don't always understand the consequences
of their actions, and for these reasons, they become poor contraceptors, and
they need access to emergency contraception.
I
think it's very important that they do not have to ask a pharmacist to open up
a cabinet or to hand them physically the emergency contraception. I think it's important that it's out in the
open; it's easy for them to identify.
Oftentimes
we have condoms in our clinic, and we know from use that if we put a condom in
a bag and we sit it on the table and say, "Here's condoms if you want to
take them," they will take them.
They won't ask for them, but we know if it's there, they're much more
likely to use them.
I
also think that there's also lots of information currently about teenagers
using the Internet, and there's been studies that are showing that more and
more teenagers are going to the Internet to get information about their health
care. So I like the idea of a pharmacist
being available, but I don't want that to be a burden or an obstacle to them
obtaining emergency contraception, and I think it's important that they have
multiple avenues to go to and not to underestimate the power of the Internet
for adolescents receiving their health care.
And
also I think the 24-hour toll free number staffed by a health care
provider is very important.
So
I apologize for the length of my comments.
CHAIRMAN
CANTILENA: Dr. Greene.
DR.
GREENE: I would answer the question ye,
and I would suggest with respect to the age requirement that when adolescent
women agree to proof of age to a pharmacist before they have intercourse, then
that would be the time that they should prove their age before obtaining the
product.
CHAIRMAN
CANTILENA: Dr. Clapp.
DR.
CLAPP: Dr. Hewitt and Dr. Greene have
said it all, but I will say yes. The
privacy issue, I think is important to consider at the pharmacy, and I think
the pharmaceutical company said that they would like this product within the
line of sight of the pharmacist, and I think that condoms are no longer in the
line of sight of the pharmacist because people are uncomfortable about picking
up condoms.
I
think for the same reason, these products don't belong in the view of those who
are at the pharmacy desk. They should
have more privacy for the access of these products.
Secondly,
in terms of age certainly, if you are a sexually active ten year old or 11 year
old, it's certainly a bad situation, and I've had patients who are ten and 11
and pregnant, and I think their families and they would have far preferred this
option than pregnancy, and it would have been safer. We know that the morbidity and mortality
associated with teen pregnancies is quite high.
So
there's no question that this is a safer option than the alternative, and
that's a term pregnancy.
As
a physician, I don't want to have an inflated sense of self-importance, and I
don't think that I should act as the gate keeper or barrier to women, teenagers
or whatever age accessing medical care for themselves, and this is a
circumstance that I think that we need to promote independence of the women and
even teenagers accessing something that can prevent or make a determination of
their future that they want to determine.
The
pricing issue is very interesting, and I think in my experience the government
has stepped in for some people who are in certain income brackets and covered over-the-counter pharmaceutical
products. If you are a patient who had
Medicaid and a pediatric patient, over-the-counter products are paid for by
Medicaid, and I hope that the powers that be can see that this would be one
over-the-counter product that could be accessible by federal government
supplements.
Thank
you.
CHAIRMAN
CANTILENA: Dr. Snodgrass.
DR.
SNODGRASS: Yes, my answer overall is
yes. The only caveat is the issue of
consumer access, and I think it's crucial for reasons that have already been
stated that this not be behind the counter, but needs to be on the shelf or
true OTC.
I
deal with probably the third or fourth most busy poison center in the United
States. Seventy percent are in the
pediatric age group. Safety is not an
issue here compared to the things I deal with.
So it's certainly not an issue about safety.
The
only reason for perhaps or at least a major reason for post marketing that I
would suggest, post marketing studies in less than 18 years old has to do more
with label comprehension and education.
CHAIRMAN
CANTILENA: Dr. Lewis.
DR.
LEWIS: I also vote yes, and I agree with
the comments of Dr. Giudice. I'd like to
see some plans to enhance access and understandability of the product, the use
of the product, and so on, for adolescents and for those who don't speak
English as their first language.
CHAIRMAN
CANTILENA: Dr. Blaschke.
DR.
BLASCHKE: My answer is yes. I think the company has a well thought
through plan, a care plan and further monitoring plan. It hasn't been tested. It can't be tested, obviously before the
product goes over the counter, but I think the plan itself is well thought out.
CHAIRMAN
CANTILENA: Dr. Wood.
DR.
WOOD: I also vote yes, and would
advocate strongly against introducing subtle barriers to access, such as
raising flags about age and raising issues about behind the counter use. Suggesting that the drug should be only
available in the line of sight of the pharmacist seems to me to introduce a
privacy concern that I find quite offensive.
I
also think that the company should consider advocating its use and patients to
have the drug available at home prior to an emergency contraceptive accident so
that they don't have to go out and look for it on a snowy weekend or whatever
it is.
I
think the issue of behind the counter is false
one. The evidence that that has
worked in any country is nonexistent, and it has only been suggested, I think,
to introduce a barrier to access, which I think would be a disaster.
CHAIRMAN
CANTILENA: Dr. Emerson.
DR.
EMERSON: My answer would be yes, and I
also would be very strongly against the idea that there would be any behind the
counter or things. I think that it being
readily available on the shelf is very important.
CHAIRMAN
CANTILENA: Dr. Berenson.
DR.
BERENSON: My answer is yes. I think it is very important that the method
if placed over the counter is it's accessible to all women at risk of
unintended pregnancy. Any placement of
the drug behind the counter or in line of sight of the pharmacist is just
creating barriers to its use, and ultimately it's just going to result in
unintended pregnancies.
I
also do adolescent gynecology for the last 15 years, and I just had some points
I wanted to bring up as a result of this experience. First, I would like to say that the
adolescent female is very embarrassed about her sexuality. She's embarrassed to go to the pharmacy and
get Tampex. So it would even be helpful
if we could make sure that -- this is being said facetiously -- that there is a
woman at the checkout counter because it is difficult for he to go by tampons
much less emergency contraception and check out from a young male.
The
second thing is that although I encourage all of my patients before they are
sexually active to actually wait until they meet their Prince Charming or if
they decide not to do that, to certainly get on reliable contraception by
coming to see me before they start having sex.
It
is the are adolescent that ever comes to see me before she has sex the first
time. That's because she never planned
to have it in the first place. It just
happens, usually on a Saturday night when I'm not available.
The
only patients I've had as a rule that come and get contraception from me in
advance are the ones that are brought in by their mothers who almost
universally have been young teenage mothers themselves, and they feel the
experience was so difficult for them that they will place a young 12 or 13 year
old that doesn't even have a boyfriend yet on reliable contraception.
So
for all of these issues, I feel that we need to decrease barriers.
CHAIRMAN
CANTILENA: Dr. Davidoff.
DR.
DAVIDOFF: Yes on the question. I would, however, mention that all drugs, prescription or over-the-counter,
can be and are misused sometimes. I
think the issue of the possible potential overuse of the drug like with almost
all drugs is a real one, but I would see the tradeoff being that the current
under use of the drug is vastly less desirable than potentially some over use.
I
do think though that there is a potential misuse question that hasn't been
addressed, and I'd suggest that the company may want to keep an eye out for
this because I can see perhaps rarely, but unpleasantly that the drug might be
misused by partners as some of the documentation that has been sent to the
committee has suggested, and that that's worth keeping a close eye on.
CHAIRMAN
CANTILENA: Dr. Montgomery Rice.
DR.
MONTGOMERY RICE: I think the plan is
adequate, but clearly not as good as it could be. I am disappointed that based on the incidence
of unintended pregnancy in the lower socioeconomic age group that the company
did not consider that and consider the limitation of access based on
socioeconomic status.
I
think that making it available at a discount to clinics is not enough because
clearly remember what we're trying to do is remove the barrier of the patient
having to go to a health care provider or a health care setting to get the
prescription, to get the medication.
So
I think that the company can do more, and I fully expect for them to do more if
it is approved.
CHAIRMAN
CANTILENA: Okay. Thank you.
So
in response to Question No. 5 we had 22 yes, five no, and one abstain.
Can
I now ask who on the committee has to leave in short order so that we get your
votes in before you go? Are you going to
leave, Dr. Young. I'm just kidding.
DR.
BEITZ: I have a qualifier I would like
to ask your help on that would be of help to us in FDA as we move to review the
input from the committee and take an action on the application.
We've
heard a lot of recommendations addressing labeling change and what we would
like your help on is as you address Question 6 to take the way that the
"if yes" and "if no" for the things that might be suggested
for labeling changes, it would be very helpful from the standpoint of our
review if further studies are recommended, say, for example, another labeling
comprehension study, if that is needed; if a study is needed, should that be
done pre or post approval? Would that be
a condition of approval? Could it be
done in Phase 4 or would it need to be done, would the information be critical
enough to know prior to approval?
CHAIRMAN
CANTILENA: Okay. So if the answer is no, then you want that
specified.
DR.
BEITZ: Yes.
CHAIRMAN
CANTILENA: Okay. Phase 4 or prior to approval.
Okay. Dr. Tinetti, Question No. 6.
DR.
TINETTI: Okay. I vote yes to switch from prescription to
nonprescription status, and with the caveats of the labeling that we discussed
and to eliminate any barriers to access and to encourage as broad access,
particularly to vulnerable populations, as possible.
CHAIRMAN
CANTILENA: And are there any things that
you would specifically want for Phase 4 after approval?
DR.
TINETTI: I would like to -- if we could
have any effect on -- if there are live births, if there's any long-term
evidence for any adverse effect, but that might be a practical, one thing I'd
like to see.
CHAIRMAN
CANTILENA: Okay. Anyone else leaving early? Dr. Uden.
DR.
UDEN: Do you want to go to Dr. Lam?
CHAIRMAN
CANTILENA: Dr. Lam, are you leaving on
the same flight?
Use
your microphone, please.
DR.
LAM: Okay. My answer to Question No. 6 is yes, and I
would actually not encourage to include mechanism of action in the label
because when a distressed, young woman comes into the pharmacy very
apprehensive about the possibility of an unwanted pregnancy, the last thing she
wants is to read some scientific jargon on mechanism of action.
CHAIRMAN
CANTILENA: Dr. Uden.
DR.
UDEN: I vote yes, and we've had a lot of
label conversation, and I'm sure you'll find some richness out of that.
CHAIRMAN
CANTILENA: How about any specifics for
Phase 4 studies post approval?
DR.
UDEN: No, I have to think about that a
little more. No specifics.
CHAIRMAN
CANTILENA: Okay. Does anyone else have to run to the
airport? You could lie to me and leave
early, but that's okay.
(Laughter.)
CHAIRMAN
CANTILENA: Dr. Montgomery Rice, why
don't we start with you for Question No. 6?
DR.
MONTGOMERY RICE: Yes, I do believe we
should switch. Plan B should be switched
from prescription to nonprescription status, and I would recommend additional
post marketing studies. So that would be
Phase 4 studies after approval, and those would, of course, look at long-term
safety issues and actually addressing the question of whether or not people are
using it as a primary form of contraception.
CHAIRMAN
CANTILENA: Dr. Davidoff.
DR.
DAVIDOFF: Yes on the question. Just underscore the importance on the
labeling of the timing, the early timing of use .
CHAIRMAN
CANTILENA: Dr. Berenson.
DR.
BERENSON: Yes, and just with the
labeling issues that we brought up earlier.
CHAIRMAN
CANTILENA: Okay. So there's nothing specific for Phase 4 from
either Dr. Davidoff or Dr. Berenson, correct?
DR.
BERENSON: No.
CHAIRMAN
CANTILENA: Dr. Emerson.
DR.
EMERSON: Yes, with no specific Phase 4.
CHAIRMAN
CANTILENA: Dr. Wood.
DR.
WOOD: Yes, and with the maximum access
possible. I would suggest if we're going
to do any Phase 4 studies that we examine what the residual barriers to use are
in order that we can work on removing them.
CHAIRMAN
CANTILENA: Dr. Blaschke.
DR.
BLASCHKE: Yes on the question, and I
think the monitoring plan that has already been proposed is an adequate Phase 4
plan.
CHAIRMAN
CANTILENA: Dr. Lewis.
DR.
LEWIS: Yes, and on the labeling changes,
I think that's already been adequately addressed by our comments with respect
to number one. Post marketing studies,
the main thing I would like to see examined is effect on contraceptive
practices. I think there were so many
long-term studies looking at safety of levonorgestrel that that doesn't need to
be emphasized, although, of course, it should never be ignored, but those are
my comments.
CHAIRMAN
CANTILENA: Dr. Snodgrass.
DR.
SNODGRASS: Yes, and no specific
long-term Phase 4.
CHAIRMAN
CANTILENA: Dr. Clapp.
DR.
CLAPP: Yes, and no Phase 4 that I can
think of.
CHAIRMAN
CANTILENA: Dr. Greene.
DR.
GREENE: I would answer yes to the
question. I agree that the safety of
levonorgestrel including for a fetus exposed is well demonstrated. I'm not concerned about that. I think the agency has received plenty of
guidance from the committee to this point about potential changes to the label.
CHAIRMAN
CANTILENA: Dr. Hewitt.
DR.
HEWITT: Yes, and no other comments on Phase 4.
CHAIRMAN
CANTILENA: Dr. Giudice.
DR.
GIUDICE: I vote yes, and one comment on
labeling, and that is to support mechanism of action at point of service so
that women can be informed when they purchase the product, not after they open
it and look at the package insert into whether or not they feel comfortable
with using this type of medication for the various potential mechanisms of
actions that we've described.
And
in terms of post marketing, I think that looking at potential changes in
contraceptive practices and also continued surveillance on incidence of
sexually transmitted infections would be important.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Trussell.
DR.
TRUSSELL: Yes, Plan B should be switched
from prescription to over-the-counter status.
No recommendations for Phase 4 studies.
CHAIRMAN
CANTILENA: Dr. Tulman.
MS.
TULMAN: Yes, and no recommendations for
Phase 4.
CHAIRMAN
CANTILENA: Dr. Benowitz.
DR.
BENOWITZ: Yes, and a couple of
suggestions. One I agree with or I think
someone said this, that there should be some surveillance particularly about
adolescent use patterns, adolescent comprehension, safety issues with
adolescents. It's something that had
been of concern to a number of people, and we may as well get the information
to reassure people about it.
I
wouldn't hole up approval on any age basis, but I think we should get the information.
And
then I still think because we do this for all drugs or most drugs, we should
have definitive data on drug interactions, especially if this product is used
and may be used as primary contraception by some people, and if it turns out
that if they're taking an anticonvulsant or rifampin and it doesn't work, we
should know that, and I think that's a study which could also be done Phase 4.
CHAIRMAN
CANTILENA: Dr. Stanford.
DR.
STANFORD: I still have concerns about
the labeling. We've talked about many of
them, but I guess because I'm not convinced enough that the labeling is
addressing the actual best effectiveness data and adequately addressing
informed consent, I'm going to formally vote no.
I
would say if those issues were adequately addressed, then I could vote yes, but
I'll record a no.
CHAIRMAN
CANTILENA: Dr. Crockett.
DR.
CROCKETT: I'm going to say no also, but
with some caveats. It's not that I don't
support the use of the drug and decreasing the barriers to its use because I do
believe it does decrease the intentional abortion rate, and I do believe that
it is a health care advancement for women to have access to it.
I
disagree that no barrier use is a good thing, and as an OB-GYN I'm going to go
down kicking and screaming before I allow somebody to break that relationship
between myself and my patients because I value the education component so much
in that relationship I have with my patients.
If
this is to be marketed as an over-the-counter drug, I do have some suggestions. I would like to see a better designed actual
use trial that more accurately reflects what's going to happen over the
counter, i.e., people would be able to get
more than one pack at a time, as was restricted in the actual use study
without reenrollment.
I
would like to see more data on teen use, in particular, and people with low or
no literacy levels.
And
I would like for some data to be gathered on how many times it's used in a
nonindicated manner if that's possible.
Also,
if this does go to a pure over-the-counter status, I think we would be doing a
disservice to our patients to not include a larger section on education of
alternate methods of contraception, including a very strong statement from the
company about abstinence and use of
condoms to prevent STDs, and this could be a necessary and required portion of
the labeling; and that it should be very clear that Plan B is only to be used
actually after abstinence and condoms or another primary form of birth control
are not used.
And
last but not least, I agree with the issues raised about labeling and the truth
in labeling mechanism of action. I think
as a young woman in this country of childbearing age that truth in labeling is
very important, and I think if you don't print on the label that this may
affect a fertilized egg in an unfavorable way that you're removing my choice
and my ability to make the decision about how I am affecting my body and my
pregnancy.
And
so I would very strongly agree that that needs to be on the outside of the
package.
And
thank you.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Williams.
DR.
WILLIAMS: Yes, and ditto.
CHAIRMAN
CANTILENA: Ditto with who? Which one?
With Dr. Crockett?
DR.
WILLIAMS: Yes.
CHAIRMAN
CANTILENA: Okay, but she voted no.
DR.
WILLIAMS: But yes for --
CHAIRMAN
CANTILENA: With the same concerns.
DR.
WILLIAMS: Yes.
CHAIRMAN
CANTILENA: The same concerns as Dr.
Crockett. But that's a yes vote,
correct?
DR.
WILLIAMS: That's a yes vote.
CHAIRMAN
CANTILENA: Okay. Thank you.
Dr.
Patten.
DR.
PATTEN: I vote yes, and this is taking
into consideration suggestions for modifications to labeling. We've had many discussions about that and
also paying attention to the access issues.
CHAIRMAN
CANTILENA: Yes, Dr. Macones.
DR.
MACONES: I would vote yes, and I would
agree with some post marketing studies to look at contraceptive use with this,
and I also would agree with Dr. Giudice that including mechanism somewhere in
this product label I think would be very important to women.
CHAIRMAN
CANTILENA: Dr. Johnson.
DR.
JOHNSON: I vote yes for a switch to
OTC. I also think that post marketing
studies to look at other contraceptive use would be important so that if they
change, then educational strategies can be undertaken.
I
think it's important at least that there's a Spanish language available, but
that would, I think, then also need to be tested in some form in terms of the
comprehension of that label.
CHAIRMAN
CANTILENA: Thank you.
Dr.
Lipshultz.
DR.
LIPSHULTZ: Yeah, I vote yes. In terms of labeling, the only thing is that
I would hope that the front would change somewhat so that there was something
in addition to emergency contraception because I think that may not be clearly
understood.
And
I would hope that at some point there is some way to make it less expensive for
people who don't have the money to buy it, either with a rebate policy or
something like that.
CHAIRMAN
CANTILENA: Okay, and are there any
specific suggestions for Phase 4?
DR.
LIPSHULTZ: No. I think I agree with Phase 4 suggestions.
CHAIRMAN
CANTILENA: Okay. Dr. Hager.
DR.
HAGER: I am opposed, vote no, and I
agree with the, if it is approved, for the post marketing strategies that have
already been voiced.
CHAIRMAN
CANTILENA: Okay, and the Chair votes
actually no on this for the following reasons.
The label comprehensive study was, I think, an overall failure. It was approved for the actual use, and there
was, I think, an improved track record in the actual use.
However,
my concern with the actual use is it doesn't accurately reflect what will
likely be the most common setting for this product based on what we've
heard. So the actual use was not as
close as possible to what we think will actually happen with the drug.
However,
I do applaud the sponsor. I do applaud
the effort. There is, you know, a need,
clearly. I think we can do a lot to
improve the communication to the lowering the literacy, which was I think
horrible in a word.
And
the issues of access, I understand the FDA has handcuffs on in terms of how
much the company charges, but I think that's something that I think you've
heard from all of us. We have a concern
for that.
So
let me read the tally, the final tally.
There were 27 votes on Question 6 and 23 yes, four no, zero abstained.
Okay. Are there any other issues that the FDA would
like to hear about?
(Applause.)
CHAIRMAN
CANTILENA: You're all applauding that
you can go now, but until we go, are there any other issues, Curt?
DR.
ROSEBRAUGH: I thought they were
applauding me. I'm sorry. I didn't know it was because they were going
to leave.
CHAIRMAN
CANTILENA: I know that usually happens
every time you speak in public.
DR.
ROSEBRAUGH: It's usually when I'm
leaving though.
CHAIRMAN
CANTILENA: Not today.
DR.
ROSEBRAUGH: I don't think there's any
other issues. I would like to take this
opportunity though to thank all of the committee. I know that this was a challenging drug for
you all to discuss today. It was a was a
very rich conversation, and I think your dialogue will be very helpful with
us.
Thank
you.
CHAIRMAN
CANTILENA: Yes, and I would also like to
thank all of the committee members from both committees. You handled this extremely well, very
courteous. Extremely helpful, and I
would like to thank the sponsor for an outstanding job and being very
responsive.
And
the meeting is hereby adjourned.
(Whereupon,
at 5:17 p.m., the meeting was concluded.)