1
				FOOD AND DRUG ADMINISTRATION
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CENTER FOR DRUG EVALUATION AND RESEARCH + + + + +
	NONPRESCRIPTION DRUGS ADVISORY COMMITTEE
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							MEETING ON
LABELING AND REMARKETING ISSUES THE TODAY SPONGE

(NDA 18-683)
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WEDNESDAY
JULY 12, 2000
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				The Committee met at 1:00 p.m. in the Versailles II Room of the Bethesda Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Louis Cantilena, Acting Chairman, presiding.
MEMBERS PRESENT:
LOUIS R. CANTILENA, JR. M.D., PH.D., Acting Chairman GEORGE A. BLEWITT, M.D., Non-voting Industry Liaison JAIME A. DAVIDSON, M.D., Consumer Representative EDWIN E. GILLIAM, PH.D., Member
MICHAEL GREENE, M.D., Voting Consultant

JULE A. JOHNSON, Pharm. D., Member
EDWARD P. KRENZELOK, Pharm. D., Member JODI LERNER, M.D., Voting Consultant RICHARD A. NEILL, M.D., Member

DONALD L. UDEN, Pharm. D., Member
HENRY W. WILLIAMS, JR., M.D., Member SANDRA TITUS, PH.D., Executive Secretary

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ALLENDALE PHARMACEUTICALS REPRESENTATIVES:
	GENE DETROYER
	R.J. STAAB, PH.D.
	ROBERTA GEIDNER ANTONIOTTI

ELIZABETH B. CONNELL, M.D. MARY DELANEY, M.S.
	FORREST GREENSLADE, PH.D.
PUBLIC SPEAKERS:
	AMY ALLINA
ELIZABETH ARNDORFER
LIZZA GONZALES
	ARMAND LIONE, PH.D.

DONNA RICHMOND
	WILLIAM SMITH
	R. WILLIAM SOLLER, PH.D.

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		I-N-D-E-X
Call to Order, Introductions. . . . . . . . . . . .4

Conflict of Interest Statement. . . . . . . . . . .6 Open Public Hearing .	. . . . . . . . . . . . . . .7
Welcome . . . . . . .	. . . . . . . . . . . . . . 38
Allendale Pharmaceuticals Presentations
Today Sponge: A Contraceptive Option. . . . . . . 42 for Women
Toxic Shock Syndrome and the Today Sponge . . . . 49
Relative Public Health Need for the . . . . . . . 55 Today Sponge
Communicating Effectiveness Data for the. . . . . 64 Today Sponge
Today Sponge. . . . .	. . . . . . . . . . . . . . 73
FDA Presentation
	Chronology. . .	. . . . . . . . . . . . . .106
	Safety. . . . .	. . . . . . . . . . . . . .112
	Labeling. . . .	. . . . . . . . . . . . . .121
Charge to Committee .	. . . . . . . . . . . . . .148
Committee Discussion.	. . . . . . . . . . . . . .151
Adjourn

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	1		    P-R-O-C-E-E-D-I-N-G-S
	2		                             (1:09 p.m.)

	3		DR. CANTILENA:  I would like to ask the
	4	committee members to return to their seats and we'd
	5	like to get started.  I would like to welcome you to
	6	the July 12th, 2000 meeting of the Nonprescription
	7	Drugs Advisory Committee.

	8		And before we get going, we'll start with
	9	the usual introductions.  My name is Lou Cantilena,
10	I'm head of clinical pharmacology at the Uniform
11	Services University right down the road here in
12	Bethesda.  I'll be acting chair for this afternoon's
13	meeting.  If I can ask all of the individuals here at
14	the table to please introduce themselves and say who
15	they are and their role today.  And we'll just start
16	over there with Dr. DeLap and go around the table.

17		DR. DELAP:  I'm Robert DeLap, Office
18	Director for the Office of Drug Evaluation V at the
19	FDA.
20		DR. GANLEY:  I'm Charley Ganley, Director
21	of Over The Counter Drugs.
22		DR. KATZ:  Linda Katz, Deputy Director for
23	Over The Counter Drugs.
24		DR. CHIN:  Ling Chin, Medical Officer of
25	Over The Counter Drugs.

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	1		DR. KARWOSKI:  Claudia Karwoski, Safety
	2	Evaluator with the Office of the Post-Marketing Drug
	3	Risk Assessment.
	4		MS. CHANG:  Gloria Chang, Pharmacist, the
	5	Division of OTC Drug Products.
	6		DR. NEILL:  Richard Neill, NDAC Member
	7	from the University of Pennsylvania.
	8		DR. GREENE:  I'm Dr. Michael Greene.  I'm
	9	the Director of Maternal Fetal Medicine, Massachusetts
10	General Hospital and I serve as the Chairman of the
11	Advisory Committee on Reproductive Drugs.
12		DR. TITUS:  I'm Sandy Titus.  I'm the
13	Executive Secretary for the Nonprescription Drugs
14	Advisory Committee.
15		DR. GILLIAM:  Edwin Gilliam, I'm a family
16	nurse practitioner from Tucson, Arizona.
17		DR. LERNER:  Hi, I'm Dr. Jodi Lerner.  I'm
18	an Associate Professor of OB/GYN at Columbia
19	Presbyterian in New York and on the Reproductive Drug
20	Side Advisory Committee.
21		DR. WILLIAMS:  Yes, I'm Henry Williams
22	from Howard University from Committee Health and
23	Family Practice and a member of the Advisory Committee
24	on Over The Counter Drugs.
25		DR. UDEN:  I'm Don Uden from the

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	1	University of Minnesota and a member of the
	2	Nonprescription Advisory Committee.
	3		DR. JOHNSON:  Julie Johnson from the
	4	University of Florida College of Pharmacy and a member
	5	of the Nonprescription Advisory Committee.
	6		DR. BLEWITT:  George Blewitt, Industry
	7	Representative to the Nonprescription Drugs Advisory
	8	Committee.
	9		DR. KRENZELOK:  Ed Krenzelok, Pittsburgh

10	Poison Center and the University of Pittsburgh Schools
11	of Pharmacy and Medicine and I'm on the NDAC.
12		DR. CANTILENA:  Okay.  Thank you everyone. 
13	What we'd now like to do is hear from Dr. Titus, who
14	will go over the conflict of interest statement.
15		DR. TITUS:  The following announcement
16	addresses the issue of conflict of interest with

17	regard to this meeting and as made a part of the
18	record to preclude it in the appearance of such at
19	this meeting.
20		Based on the submitted agenda for the
21	meeting and all financial interests reported by the
22	Committee participants, it is determined that all
23	interests and firms regulated by the Center for Drug
24	Evaluation and Research present no potential for an

25	appearance of a conflict of interest at this meeting.

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	1	            We would like to note for the record that
	2	Dr. George Blewitt is the non-voting industry
	3	representative and is on the committee to represent
	4	industry interests.  As such, he has not been screened

	5	for any conflict of interests.  In the event that the
	6	discussions involving any other products or firms not
	7	already on the agenda for which an FDA participant has
	8	a financial interest, the participants are aware of
	9	the need to exclude themselves from such involvement
10	and their exclusion will be noted for the record.
11	            With regard to all other participants we
12	ask in the interest of fairness that they address any
13	current or previous financial involvement with any
14	firm whose products they may wish to comment upon.
15	            DR. CANTILENA:  Okay.  Thank you Dr.
16	Titus.  What we'll now -- move to the open public
17	hearing section of the meeting and at first I'd like
18	to just announce there have been seven individuals who
19	have registered as speakers.  If there is anyone else
20	who would like to make public comment, please at this
21	time, if you can step outside and contact the staff
22	and sign in.  If not, if we don't hear from you in the
23	next, say fifteen minutes or so, we'll just close it
24	at seven speakers.
25	            And as a reminder to the speakers, the

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	1	allocated time is five minutes.  There's a light
	2	system here that we're using and with a timer, which

	3	is here.  But when you see the yellow light, you have
	4	one minute left.  And when you see the red light, you
	5	should be closing your comments at that time.
	6		So, again, if there's anyone else who
	7	would like to speak, please sign up outside of the
	8	room with the staff from FDA and if not, we will move
	9	ahead to the first speaker in the open public section,
10	which would be William Smith from SIECUS.
11		Mr. Smith.
12		MR. SMITH:  Thank you.  Good afternoon. 
13	My name is William Smith and I'm speaking on behalf of
14	the Sexuality Information and Education Counsel of the
15	United States or SEICUS, a 36-year-old national
16	nonprofit that has been a leading voice for sexuality
17	education and the right of all individuals to make
18	informed responsible sexual choices.
19		I'm here today to urge you to approve the
20	Today Sponge for reintroduction to the United States
21	market.  In advance, I want to thank you for the
22	opportunity to offer my comments today.
23		The unmet need for increased contraceptive
24	choices for women is glaringly obvious.  There are

25	more than three million unintended pregnancies every

			9
	1	year in the United States.  Yet, at present, there
	2	remains a dirth of contraceptive choices often forcing
	3	women to prioritize and choose between safety,
	4	efficacy and accessibility.  Different women have
	5	different needs and many of those needs are not fully
	6	recognized by the current selection of contraceptive
	7	options.
	8	            The contraceptive sponge offers women
	9	another choice that is in a word, unique.  No other
10	product on the market offers the same option for
11	sexually active women.  Further, the Today Sponge is

12	a product we believe is important one and that allows
13	women to exercise and maintain control over their own
14	reproductive health.
15	            In many instances, women cannot rely on
16	their partners to make responsible decisions about
17	contraception or more seriously are faced with
18	negative or violent reactions when they either use or
19	express a desire to use contraception.
20	            The Today Sponge allows women to be
21	discreet as it can remain the vagina for 24 hours.  It
22	can be used for multiple acts of intercourse and is
23	generally undetectable by either partner during
24	intercourse.
25	            In addition, in terms of promoting women's

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	1	health, the Today Sponge offers women an alternative
	2	to hormonal contraception such as birth control pills. 
	3	Many women cannot use or choose not to use methods
	4	such as birth control pills because they induce
	5	significant hormonal changes in the body, which can
	6	sometimes result in adverse side effects.  As you
	7	know, the only active ingredient in the sponge is the
	8	spermicide Nonoxynol-9, which has been available for
	9	40 years and has a proven safety record.
10	            Finally, the Today Sponge is comfortable,
11	convenient and accessible.  For these reasons, the
12	sponge was used by tens of thousands of women
13	nationwide until it was removed from the market in
14	1995 and continues to be used in other countries
15	including Canada at present.
16	            An issue at this time seems to be product

17	labeling and safety.  These issues are certainly of
18	great concern to SIECUS.  In this case, however, as I
19	mentioned, the safety of the product has already been
20	established.  The Today Sponge, if used as instructed,
21	delivers a dose of Nonoxynol-9 that remains effective
22	for multiple acts of intercourse without additional
23	dosing.  The studies that indicate harm in using N-9,
24	including the one released this morning in Durban,
25	seem to result from an over-dosage of N-9 by repeated

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	1	dosing over numerous acts of intercourse that in some
	2	cases, according to the actual study, reached nearly
	3	40 times in a single day.
	4	            So the question then is to what is -- what

	5	extent does the proposed labeling of the Today Sponge
	6	help to assure proper and safe usage.  It's
	7	unfortunate that at present, to my knowledge, there
	8	exists no uniform labeling requirements for products
	9	containing N-9.  Our own informal review of over-the-
10	counter contraceptives delivering N-9 including

11	inserts, foams, gels and films indicate a vast
12	disparity of guidelines for usage and safety warnings.
13	            Given this to be the case, it's our
14	judgment that the Today Sponge's labeling continues to
15	instruct consumers in safe usage of the sponge.  We're
16	also to understand that the outer carton of the --
17	carton of the product will contain a directive to use
18	condoms to prevent sexually transmitted disease.  Well
19	this directive eases some concerns over a consumer's
20	possible mistaken belief that the contraceptive sponge
21	also serves to prevent sexually transmitted disease,
22	we suggest the inclusion of a clear, unambiguous
23	statement to this effect.
24	            For example, the contraceptive product and
25	care which delivers N-9 via vaginal insert contains

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	1	the statement Athis product has not been shown to
	2	product against HIV Aids or other sexually transmitted
	3	diseases.@  This minor adjustment coupled with the
	4	FDA's previous approval of the sponge's labeling under
	5	the former manufacturer seems duly sufficient to
	6	assume that the proposed labeling is safe, accurate
	7	and ultimately geared toward helping insure proper use
	8	of the product.
	9		Please consider the potential role of the

10	Today Sponge in providing women with choices that will
11	improve their health and their lives.  We strongly
12	urge you to support the production and distribution of
13	this product.
14		And thank you very much for your time.
15		DR. CANTILENA:  Okay.  Thank you, Mr.
16	Smith.
17		Are there any questions from the committee
18	members for Mr. Smith?  Okay.  Thank you.
19		And if the speakers would actually like to
20	come up and use the podium, that's okay, it's easier
21	for you to see the warning lights.  So, if you would
22	do that, that would be great.
23		Our next speaker is, I believe, Amy Allina
24	from the National Women's Health Network.
25		MS. ALLINA:  Thank you.  My name is Amy

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	1	Allina.  I'm the program and policy director of the
	2	National Women's Health Network.  The Network is a
	3	nonprofit science-based consumer advocacy organization
	4	that does not accept any financial support from
	5	pharmaceutical or medical device companies.  We're
	6	supported by a national membership of 10,000
	7	individuals and about 300 organizations.
	8	            Those of you who have heard the network
	9	speak before about contraception might expect that we
10	would be here to advocate for the return of a woman
11	controlled barrier method of contraception that offers
12	an alternative to hormonal contraceptives and
13	accessibility of over-the-counter distribution, all of
14	which are characteristics of the sponge, the product
15	under discussion today.  And you're right, we are here
16	to advocate for that.
17	            As you heard from the previous speaker,
18	and as I believe you'll hear from other advocacy
19	groups today, the sponge was a popular product.  It
20	was used by thousands of women who were very satisfied
21	with it and who were disappointed when it disappeared
22	in 1995.  It's return to the U.S. market will benefit
23	women by expanding contraceptive choice in particular
24	the range of non-hormonal options.
25	            On the other hand, those of you who have

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	1	heard the network speak before might also be expecting
	2	that our skepticism and caution regarding drug and
	3	device side-effects would lead us to raise many
	4	questions about the safety of the sponge itself and
	5	also about the effects in the vagina of the Nonoxynol-
	6	9 that's part of the product.  And in a sense you're
	7	right as well.  The network has raised those questions
	8	and we've carefully considered the scientific data
	9	that goes toward answering them.
10	            In 1983, when the Today Sponge first came

11	on the U.S. market, we produced a position paper which
12	called for more research on a number of safety
13	questions, including the material used in the sponge
14	and the possible risk of Toxic Shock Syndrome.
15	            In the years following the approval of the
16	sponge, the network carefully monitored both clinical
17	studies and women's experience with the product and
18	some important points emerged from the research and
19	from the actual use experience.  A small percentage of
20	women reported allergic reactions while some women did
21	experience vaginal irritation when they used the
22	sponge, the vast majority of users were very satisfied
23	with the method.  There were a small number of toxic
24	shock cases reported in women using the sponge. 
25	Although the increase in TSS risk associated with the

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	1	sponge did not appear to be greater than the risk
	2	associated with other vaginal barrier methods.
	3	            Today as the threat that that the HIV Aids
	4	epidemic poses has become increasingly clear,
	5	questions have been raised about the safety of the
	6	Nonoxynol-9 that is in the sponge.  In particular,
	7	there's concern about one recent study mentioned by
	8	the previous speaker that was conducted by UNAIDS,
	9	which was a multi-center randomized double blind
10	placebo controlled trial of N-9 gel used by female sex
11	workers who were engaging in multiple acts of
12	intercourse daily.
13	            The preliminary analysis of this trial has
14	found an association between the use of N-9 and an
15	increased risk of becoming infected with HIV.  While
16	these results merit serious consideration, it is
17	important to remember that no studies involving the

18	sponge itself have produced any scientifically valid
19	evidence that the sponge, used as recommended, poses
20	a threat to women's health.
21	            Additionally, it's worth noting that the
22	sponge serves as a physical barrier as well as a
23	chemical one covering the cervix which is a prime
24	location for infection.
25	            The important question for this committee

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	1	is whether the information about the possible
	2	infection risk associated with the use of Nonoxynol-9
	3	in other forms and under specific conditions is
	4	relevant for users of the contraceptive sponge.  The

	5	network is strongly committed to the principle that
	6	women can be trusted with complete information and
	7	that informed consumers can make responsible and good
	8	healthcare decisions for themselves.
	9	            We've carefully reviewed the data from the
10	studies that have been conducted on Nonoxynol-9 and we
11	believe that if the preliminary results of the recent
12	trial are born out by further analysis, it would be
13	appropriate to include some information for women
14	about the possible risk in the label.  That
15	information could include something like the
16	following:  The sponge contains the spermicide
17	Nonoxynol-9 which can cause vaginal irritation in some
18	women.  The sponge has not been demonstrated to offer
19	protection against sexually transmitted infection and
20	some studies have indicated that under extreme
21	conditions with multiple daily acts of intercourse
22	Nonoxynol-9 may slightly increase the risk of HIV
23	infection.
24	            Additionally, we believe the label should
25	include information about the possible risk of toxic

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	1	shock and the symptoms associated with it so that
	2	women can -- will be aware of the need to seek medical
	3	attention should such symptoms develop.
	4		In conclusion, the network wants to convey

	5	two important messages.  First, that the return of the
	6	vaginal contraceptive sponge to the U.S. market will
	7	provide women with an important additional option for
	8	non-hormonal barrier contraception.  And second, that
	9	with adequate labeling about the emerging research on
10	Nonoxynol-9 and toxic shock, women can make informed
11	decisions about the possible risk associated with this
12	method and whether it's appropriate for them.
13		I'd be glad to answer any questions. 
14	Thank you.
15		DR. CANTILENA:  Okay.  Thank you very much
16	for your comments.
17		Any questions?  Go ahead then.
18		DR. GILLIAM:  Do you feel that there
19	should be information on the label about the efficacy
20	of the product?
21		MS. ALLINA:  Yes, I do.
22		DR. CANTILENA:  Okay.  Thank you.  Further
23	questions?
24		DR. UDEN:  Are we going to be able to see
25	the study that the past two speakers have referenced?

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	1		DR. CANTILENA:  Charlie, any comment?
	2		DR. GANLEY:  No.
	3		DR. UDEN:  Okay.  Thank you.
	4		DR. CANTILENA:  Are you curious as to why

	5	you're not going to be able to see it?  Because I am. 
	6	Is that -- is it, you know, not in file or, you know,
	7	has it not been filed yet or what -- what's the issue?
	8		DR. GANLEY:  It's -- we don't have access
	9	to the data, I guess is the best way to put it and so
10	I think until we get access to data, I think we would
11	be silent on that.  And I think one of the speakers
12	will bring up other issues and -- regarding the safety
13	of N-9.
14		So, as I will address the committee later
15	I think the issue that was brought up in the citizens'
16	petitions that we had provided will be addressed by
17	the agency and so I'm not sure that that's the
18	appropriate discussion for this meeting and as the
19	meeting progresses you will get an idea what the focus
20	will be.
21		DR. CANTILENA:  Okay.  Thank you, Dr.
22	Ganley  and any further questions?  Yes, Ed?
23		DR. KRENZELOK:  Do you think the
24	instructions, as they're now on the package or were on
25	the package in 1995, are adequate for a whole cross

				19
	1	section of women to be able to use the product
	2	properly in terms of both insertion, removal and
	3	understand how to use it adequately?
	4		MS. ALLINA:  I am aware that there were
	5	some women who had problems with removal, but I
	6	believe that the instructions are -- are quite good
	7	and that women have been able to -- were able to get
	8	help when they needed it.  So I -- I would have to
	9	say, yes, if people have ideas for improving them, I'd

10	be interested to hear them but I -- my review was that
11	they were quite good.
12		DR. CANTILENA:  Okay.  Well, thank you
13	very  much for your comments and the responses to the
14	question.  Our next speaker is Donna Richmond who is
15	from the Association of the Reproductive Health
16	Professionals.
17		Ms. Richmond.
18		MS. RICHMOND:  Thank you and good
19	afternoon.  My name is Donna Richmond and I'm
20	representing the Association of Reproductive Health
21	Professionals or ARHP, which is an inter-disciplinary
22	association composed of professionals who provide
23	reproductive health services or education, conduct
24	reproductive health research or influence reproductive
25	health policy.

			20
	1	            ARHP founded in 1963 has a mission to
	2	educate healthcare professionals, public policy makers

	3	and the public.  The organization fosters research and
	4	advocacy to promote reproductive health.  ARHP, as a
	5	non-profit educational organization, firmly abides by
	6	national accreditation guidelines for industry support
	7	by producing credible and independent enduring
	8	materials for clinicians and consumers.  Our
	9	association in 1999 received 70 percent of our support
10	from industry, 20 percent from private foundations and
11	10 percent from member dues and donations.  And 2,000
12	Allendale Pharmaceuticals, Incorporated is one of 20
13	meeting supporters for our annual conference in
14	September.
15	            The statement is written to express our
16	support for Allendale's application to re-introduce
17	the Today Sponge to the consumer market.  We recognize
18	the important goal of improving reproductive health by
19	reducing the unacceptably high rate of unintended
20	pregnancy in the United States.  We also recognize
21	that every woman has a unique contraceptive needs or
22	has unique contraceptive needs.  To meet these needs,
23	we strongly encourage all efforts to make as many safe
24	and effective contraceptive methods available to
25	American women as possible.

				21
	1		The Today Sponge, prior to the 1995
	2	removal from store shelves, provided women with a
	3	valuable nonprescription option.  It is a self-
	4	administered, non-hormonal method that appeals to many
	5	women and has been missed by both consumers and a
	6	reproductive health professional community.  We
	7	strongly support the return of this product to the
	8	American market.  We feel that the approval of
	9	Allendale's application by the FDA will be a positive
10	step in expanding the number and variety of
11	contraceptive options available in the United States. 
12	Thank you.
13		DR. CANTILENA:  Okay.  Thank you, Ms.
14	Richmond.
15		Any questions from the committee members? 
16	Okay.  Thank you very much.
17		Our next speaker is Dr. Armand Lione from
18	the Associated Pharmacologists and Toxicologist.

19		DR. LIONE:  Members of the Advisory
20	Committee, it is a pleasure to be here today to
21	comment briefly on some of the shortcomings of the
22	labeling of the Today contraceptive sponge. 
23	Associated Pharmacologist and Toxicologist is the
24	organization that I'm president of.  It receives
25	funding only from the production of educational

			22
	1	materials that we receive some royalties from.  I'm
	2	also employed by the Reproductive Toxicology Center,
	3	which is here in Bethesda.  I co-authored the database
	4	REPROTOX.
	5	            As you know, the Today Sponge contains one
	6	gram of the detergent Nonoxynol-9, N-9, that serves as
	7	a chemical spermicide in this and other OTC
	8	contraceptives.  Whereas other OTC contraceptives
	9	involve acute exposures to N-9, that is comparable
10	contraceptive products containing much smaller amounts

11	of N-9, are introduced into the vagina and the N-9 is
12	allowed to dissipate.
13	            The Today Sponge exposes a woman to a
14	chronic source of N-9 for the entire 24 to 30 hours it
15	is in the vagina.  Because the sponge is a source of
16	chronic exposure to N-9, we believe it is more likely
17	than any other OTC contraceptive to cause vaginal

18	damage and to endanger a woman's health.  Available
19	research now shows that N-9 may alter the vaginal
20	environment to favor the survival of pathogenic
21	organisms and when used repeated N-9 may enhance the
22	formation of lesions in the vagina.
23	            As noted in the detailed references that
24	accompany this presentation, researchers have found
25	that women typically are unaware of the lesions

			23
	1	produced by high dose exposure to N-9.  There is now
	2	general agreement among researchers that damage done
	3	by high dosages of N-9 may increase the risk of
	4	various infections including Toxic Shock Syndrome and
	5	infections with the Aids virus.
	6	            The details of the increased risk of TSS
	7	are quite clear being based on studies done by members
	8	of the FDA and the Centers for Disease Control.  This
	9	should be stated clearly in the package label.  The

10	current label does not make clear the likelihood of
11	vaginal damage caused by the repeated use of the Today
12	Sponge.
13	            For example, the instructions only
14	recommend that the sponge not be used during
15	menstruation.  Indirectly, this suggest that the
16	sponge may be used throughout this 21 days of each
17	month when a woman is not menstruating.  In the
18	original data submitted for this product over 18 years
19	ago, five of fifteen women developed vaginal
20	irritation when they attempted to use the sponge for
21	seven consecutive days.
22	            In responding to the high level of
23	irritation observed in this study, an FDA spokeswoman
24	described the repeated use of the Today Sponge as a

25	strong challenge and the irritation that occurred as

				24
	1	predictable.
	2		The label for this product, therefore,
	3	should warn that repeated use of the Today Sponge is

	4	very likely to produce notable vaginal irritation and
	5	vaginal lesions.  Currently, the label only states
	6	that a small number of men and woman may be sensitive
	7	to the spermicide in this product and previous
	8	versions of the packaging describe the spermicide as
	9	gentle.
10		To summarize, additions to the label for
11	this product should warn the users that the sponge may
12	cause vaginal lesions without her awareness and these
13	lesions may increase the risk of various vaginal
14	infections including infections with the AIDS virus. 
15	The package labeling should not suggest that
16	irritation is a rare side-effect caused by the
17	detergent N-9.  Users must also be told the Today
18	Sponge is very likely to produce vaginal irritation if
19	worn for several consecutive days.
20		Thank you.
21		DR. CANTILENA:  Okay.  Thank you for your
22	comments.  Any questions for Dr. Lione?  Okay.
23		Then I wish to thank you and we'll move on
24	to our next public hearing speaker which is Lizza
25	Gonzales from the Alan Guttmacher Institute.

				25
	1		Ms. Gonzales.
	2		MS. GONZALES:  My name is Lizza Gonzales. 

	3	I'm reading this statement today on behalf of the Alan
	4	Guttmacher Institute and the National Black Women's
	5	Health Project about the importance of expanding
	6	contraceptive options for women in the United States
	7	and the role of the contraceptive sponge in pursuing
	8	that goal.  We appreciate the opportunity to provide
	9	you with our comments on this topic.
10		Even a cursory examination of the
11	reproductive health indicators reveals that there are
12	unmet contraceptive needs in this country and women
13	want more choices.  There are more than three million
14	unintended pregnancies every year in the United
15	States.  Ten percent of sexually active fertile women
16	do not use any contraceptive method even though they
17	do not intend to become pregnant.
18		In addition, the prevalence of sexually
19	transmitting diseases, STD is increasing --
20	increasingly rapid in some groups of women.  While
21	lack of access to services and education contributes
22	to unintended pregnancy in STD rates, dissatisfaction
23	with currently available contraceptive options is also
24	a significant factor in the equation.
25		Even women with access to family planning

			26
	1	services experience significant rates of unintended
	2	pregnancy and STDs.  More than half of the unintended
	3	pregnancies in this country occur in women who are

	4	using contraception.  Many of the women who are not
	5	using contraception have tried unsuccessfully to find
	6	a method that meets their needs.  The Today Sponge
	7	offers women the opportunity to reclaim a previously
	8	popular contraceptive technology.  Before its removal
	9	from the market in 1995, the sponge was used by tens
10	of thousands of women nationwide.  And today continues
11	to be known and well liked.
12	            When the sponge was taken off the market
13	in 1995, many women were dismayed at the loss of the
14	option.  The sponge possesses specific characteristics
15	which make it a desirable option for many at varying
16	stages in their lives.
17	            One very important characteristic of the
18	contraceptive sponge is its availability over-the-

19	counter.  Other than the female condom the sponge is
20	the only over-the-counter contraceptive option for
21	women.  Women appreciated the fact that it was
22	available without a prescription and could be
23	purchased at a corner drugstore without scheduling or
24	waiting for an appointment with a healthcare provider. 
25	This convenience and accessibility are a great benefit

				27
	1	to women consumers.
	2		Finally, the contraceptive sponge is a

	3	barrier contraceptive method which is important for
	4	those women who may be seeking an alternative to
	5	hormonal contraception.  We urge the FDA to approve
	6	the return of this product to the U.S.  And we thank
	7	you for your time.
	8		DR. CANTILENA:  Okay.  Thank you for your
	9	comments.  Are there questions for Ms. Gonzales? 
10	Okay.  Thank you very much.
11		Our next speaker is Ms. Elizabeth
12	Arndorfer from the National Abortion and Reproductive
13	Rights Organization.
14		MS. ARNDORFER:  Good afternoon.  Thank you
15	for holding this important meeting.  My name's
16	Elizabeth Arndorfer and I'm here representing NARAL,
17	the National Abortion and Reproductive Rights Action
18	League.  NARAL is a grass roots advocacy organization

19	with over 200,000 members and state affiliate network. 
20	NARAL is committed to insuring women's access to the
21	full range of reproductive options including
22	preventing unintended pregnancy, bearing healthy
23	children and access to legal abortion.
24		We believe that expanding women's

25	contraceptive options is crucial to preventing

			28
	1	unintended pregnancy and abortion and improving
	2	women's overall reproductive health.  For this reason,
	3	we support the return of Today Sponge to the market.

	4	            Thirty-three million women in the United
	5	States are in need of contraceptive options.  However,
	6	the options currently on the market do not fully
	7	address their needs.  Nearly 50 percent of all
	8	pregnancies are unintended and 54 percent of those
	9	unintended pregnancies end in abortion.  As a striking
10	demonstration of the inadequacy of existing
11	contraceptive options is the fact that over 50 percent
12	of unintended pregnancies, and that includes 58
13	percent of women who have abortions were using some
14	method of family planning in the month that they
15	conceived.
16	            Moreover, women are dissatisfied with the
17	methods that they're using.  The average woman will

18	stop using a contraceptive method nearly ten times in
19	her life.  It is clear that women want and need a
20	wider range of reproductive contraceptive options. 
21	The Today Sponge will provide that alternative.  It
22	has several very important advantages.
23	            First, as you've heard from other
24	speakers, it's over-the-counter.  For women who don't
25	have insurance this is particularly important.  It

			29
	1	allows them to have access to a contraceptive without
	2	having to make and go to a healthcare provider.  And
	3	even for women who are insured, it's important to have

	4	contraceptive options that are over-the-counter since
	5	many insurers don't cover contraceptive.
	6	            Second, as we've also heard, it's
	7	important because it's a non-hormonal method.  And for
	8	many women the medical conditions preclude them from
	9	using hormonal methods or just the fact that they wish
10	to avoid some of the side-effects associated with
11	that.  And finally, the contraceptive -- the Today
12	Sponge was a very popular method when it was on the
13	market and women used it.  And we know that one of the
14	most important is that women like their method so that
15	they use it consistently.
16	            While the sponge has important advantages,
17	it is not the right option for all women.  And for
18	this reason, we fully support that women have adequate
19	and full information that they need to weigh the risks
20	and benefits of the option and also the information
21	they need to use it properly.  Labeling that is
22	informative and easy to understand will allow women to
23	make an informed choice about whether the sponge is
24	appropriate for them.
25	            In sum, returning the Today Sponge to the

			30
	1	U.S. market will be an important step towards
	2	expanding women's contraceptive options especially

	3	because of its over-the-counter availability, the
	4	sponge has the potential to increase women's access to
	5	contraception and help them avoid unintended pregnancy
	6	and abortion.  We strongly encourage you to protect
	7	women's health by returning the sponge to the market.
	8	            Thank you very much.
	9	            DR. CANTILENA:  Exquisite timing. 

10	Exquisite timing.  Thank you, Ms. Arndorfer.  Any
11	questions from the committee?  Okay.  Thank you very
12	much.
13	            Our seventh and final speaker will be Dr.
14	William Soller from CHPA.
15	            DR. SOLLER:  Thank you.  Good afternoon. 
16	My name's Dr. Bill Soller.  I'm Senior Vice President
17	and Director of Science and Technology for the
18	Consumer Healthcare Products Association which we

19	appreciate CHPA.  CHPA is the 119-year-old trade
20	organization representing the producers of quality
21	nonprescription medicines and dietary supplements
22	including over 200 members across the manufacturing,
23	distributing supply research testing and advertising
24	sectors of the healthcare industry.  And several of
25	our members produce OTC spermicide products.

			31
	1	            We're here today to address the issue of
	2	efficacy labeling and, therefore, the issue of
	3	comparative effectiveness labeling of OTC spermicide

	4	products and plan to submit comments to the relevant
	5	docket and records.
	6	            As background, about two million women use
	7	spermicide containing vaginal contraceptives.  OTC
	8	spermicidal contraceptives serve an important role in
	9	meeting a women's choice of preferred contraception. 
10	Spermicides are chosen by women who wish a safe,

11	simple readily available contraceptive method that
12	offers many benefits including self choice and use
13	without partner involvement, easy availability for
14	immediate protection whenever needed irrespective of
15	the interval between use, non-hormonal contraceptive
16	control without affecting menses and a backup to the
17	barrier method such as the condom, cervical cap or
18	diaphragm.

19	            Turning to FDA's on efficacy labeling and,
20	therefore, comparative efficacy labeling on all -- all
21	OTC contraceptive products, it is a matter of long
22	standing FDA policy that decisions about drug
23	availability or label statements including warnings or
24	other information should be, and I quote,
25	scientifically documented, clinically significant and

			32
	1	important to the safe and effective use of the product
	2	by the consumer.  And this is a very important three
	3	part hurdle that there is directly on the
	4	consideration of comparative effectiveness labeling.
	5	            First, regarding the initial hurdle of
	6	scientific documentation, any decision on OTC labeling
	7	requires an evaluation by FDA that the suggested
	8	labeling, here related to comparative effectiveness
	9	labeling of vaginal spermicide products, is supported
10	by high quality scientific evidence.
11	            This means that before such labeling is
12	recommended for all OTC spermicides which are
13	currently covered under the public OTC review rule
14	making process, FDA should ask for and be open to the
15	public review and comment to evaluate the quality of
16	the scientific documentation.  It also means that if

17	we're considering comparative effectiveness labeling,
18	that is new valid evidence emerges, that there's a

19	mechanism to expeditiously update that labeling in
20	order to help insure competitive fairness in the
21	market place.
22	            Second, OTC labeling as a matter of
23	regulatory policy contains only essential information
24	necessary to the safe and effective use of the product
25	by the consumers.  The two hurdles in the policy

			33
	1	clinical significance and the importance to the
	2	consumer bear on this aspect of the essentiality of
	3	information and labeling.  And the nature of the
	4	condition to be treated or preventive relates directly
	5	to these considerations.
	6	            In the case of prevention of pregnancy and
	7	the consequences of an unwanted pregnancy, the
	8	uniqueness of this condition and its consequences for
	9	the unborn, the mother, the father are unparalleled in
10	any self care category.  The life altering of an
11	unwanted pregnancy are potentially profound. 
12	Providing comparative effectiveness information to a
13	woman who is choosing a contraceptive method allows
14	her the best opportunity for self determination of
15	this unique situation.  So on this background,
16	questions to consider in developing efficacy labeling
17	for OTC spermicide products are the following:

18	            And that is, first, is the proposed
19	labeling consistent with FDA's long-standing policy
20	that label statements must be scientifically
21	documented, a clinical significant and important to
22	the safe and effective use of the product by the
23	consumer.
24	            Secondly, is there sufficiently a large
25	database that is adequately, scientifically documented

			34
	1	to permit reasonable comparisons of product
	2	effectiveness for all products with the specific
	3	indications under review.
	4	            And, third, does the label statement
	5	communicate comparative effectiveness and a consumer
	6	friendly and easy to understand way and in a -- in a
	7	form that is consistent with FDA's final rule on OTC
	8	label content and format.
	9	            Hence, CHPA would support a public review
10	and comment process on the issue of efficacy and
11	specifically comparative effectiveness labeling on all
12	OTC spermicides only because pregnancy is unique in
13	the self-care category and requires special
14	consideration.
15	            In the past, CHPA has supported
16	specialized labeling relating to pregnancy including,

17	for example, the OTC drug pregnancy nursing statement
18	on all OTC drug products and the recent voluntary
19	program for label statements pertaining to pregnancy
20	and nursing for dietary supplements which we recently
21	adopted and submitted as a citizen's petition to FDA.
22	            However, CHPA does not support comparative
23	effectiveness labeling for other OTC indications in
24	categories of drugs given that they do not rise to the
25	level of uniqueness of the potentially life altering

				35
	1	consequences of failed pregnancy prevention.  We
	2	believe public comment process would be important
	3	before extending comparative efficacy labeling to all
	4	spermicide products because this would provide the
	5	best opportunity for all stake holders to have
	6	adequate time to develop input on this important
	7	matter.
	8		The fact that the question on efficacy
	9	and, therefore, comparative efficacy labeling for all
10	OTC contraceptive products was not publically

11	available with due notice before this meeting
12	essentially makes this aspect of today's discussion in
13	public, but essentially not by or of the public as it
14	should be.
15		Thank you very much.
16		DR. CANTILENA:  Thank you, Dr. Soller. 
17	Any questions from the committee for Dr. Soller?
18		Yes, Ed.
19		DR. KRENZELOK:  You mentioned that the
20	label should be consumer friendly presumably that it
21	should be a readable label by a large segment of the
22	population.  Do you think this label for the Today
23	Sponge is consumer friendly that -- that people can
24	understand how to use it?
25		DR. SOLLER:  I'm not here to comment

				36
	1	specifically on that aspect and haven't reviewed that
	2	labeling.
	3		As I say, going into this meeting, we had

	4	anticipated that we would be monitoring this meeting,
	5	have not reviewed that label and then the specific
	6	question related to efficacy labeling came to our
	7	attention two days ago.  And as for that reason that
	8	we offer these comments essentially on process.
	9		DR. CANTILENA:  Dr. Ganley, did you have
10	a question?
11		DR. GANLEY:  No.
12		DR. CANTILENA:  Oh, sorry.  Thought you
13	were waiving at me.  Yes, actually, Dr. Soller, I just
14	have a quick question for you.  So the -- so your
15	comments are basically directed, if you will, at the
16	second question regarding efficacy information on the
17	carton.
18		DR. SOLLER:  The sub-question A.
19		DR. CANTILENA:  Sub-question A, right. 
20	Should it be required.  Okay.
21		DR. SOLLER:  As it relates to all.  Now as
22	you might relate that specifically to the sponge and
23	come to a determination specifically to the sponge,
24	that's one matter.  As you then extend that to use the
25	word all, then I think a very different matter comes

				37
	1	to play.  And what also comes to play is that basic
	2	label statement because you're now thinking about
	3	plying this widespread.  And that is scientifically

	4	documented, clinically significant important to the
	5	safe and effective use.
	6		I would remind you if you're dealing just
	7	with efficacy for the sponge, that label statement
	8	should apply as well in a non-comparative sense, the
	9	scientific documentation, clinical significance
10	importance to the consumer.
11		DR. CANTILENA:  Right.  But in terms of
12	process, you know, correct me if I'm wrong, but
13	because this -- this is a product that is under, you
14	know, the NDA, anything that has to do with its
15	specific label is really, you know, confined to this
16	product.  So your comments are, if I understand you
17	correctly, addressed to the issue of, if the committee
18	were to consider or recommend all.
19		DR. SOLLER:  That's correct.
20		DR. CANTILENA:  Okay.  Thank you very
21	much.  Any other questions for Dr. Soller?  If not,
22	thank you very much.
23		DR. SOLLER:  Thank you.
24		DR. CANTILENA:  Okay.  I think we're now
25	at the point according to the agenda, this is where

				38
	1	Dr. Ganley welcomes us so I would like to please call
	2	on Dr. Ganley to speak to the Committee.
	3		DR. GANLEY:  Do I have a timer?
	4		DR. CANTILENA:  No.
	5		DR. GANLEY:  No.  Okay.  The floor drops
	6	down, is that it?
	7		First, I just want to thank the members of
	8	the Advisory Committee for coming in for today's
	9	meeting on such short notice.  I would also like to

10	thank Dr. Cantilena for gracely acting as the rule of
11	chair in Dr. Brass's absence.  Dr. Cantilena is a past
12	member of the Nonprescription Prescription Drug
13	Advisory Committee and is starting another term with
14	today's meeting.  Dr. Brass will resume his role as
15	chair at tomorrow's meeting.
16		And I will deviate somewhat from what I
17	was going to talk about and I'm going to actually jump
18	ahead a little bit to try to focus the meeting a
19	little bit and see if this works here.  And a lot of
20	these slides were based on seeing the presentation of
21	FDA, so I'm sort of jumping ahead here mainly to focus
22	the discussion.
23		And the thing that I want to just discuss
24	right now is the regulatory status of Today's Sponge. 
25	Today's Sponge is an approved drug product.  It was

			39
	1	voluntarily withdrawn from the market in 1995.  With
	2	Allendale Pharmaceuticals taking over the new drug

	3	application and changing the manufacturing facility
	4	for the drug product, they are required under our
	5	regulations to submit a chemistry supplement providing
	6	information on the manufacturing process.
	7	            So, I just want to point out there are
	8	outstanding chemistry issues, particularly
	9	manufacturing that need to be resolved by Allendale
10	before they could market.
11	            I just want to also point out that this is
12	very important because good manufacturing practices
13	are essential to the designation of safe and effective
14	drugs.  Okay.
15	            The main focus of today's meeting is
16	really to focus on the labeling of the product.  And
17	I think a lot of our interest is stemmed by a rare but
18	serious adverse event that has been reported with the
19	use of the product.  And when Today's Sponge is re-
20	marketed, Toxic Shock Syndrome will likely be reported
21	with the use again.
22	            So it becomes very important that the
23	product is adequately labeled.  And that's not only

24	for consumers who have used this product in the past
25	so they can assess their risk, determine signs and

			40
	1	symptoms or take measures to decrease risk.  But also
	2	for consumers to understand whether they want to
	3	purchase the product.  Okay.  And there are a lot of

	4	consumers that will have access to the product that
	5	would not have been using it in 1995 because they were
	6	younger, particularly teenagers possibly.
	7	            And I think what you're going to hear
	8	today is some diverge in opinion on the part of the
	9	company and the FDA as the -- as what the appropriate
10	label should read.  And I just want to point out that
11	since 1991, the FDA has made efforts to improve the
12	OTC labeling so that it is more legible and readable. 
13	And this culminated in the OTC label ruling.  Again,
14	you will hear about this in the FDA presentation and
15	I'm sort of jumping ahead here.
16	            And we will also show that we are
17	suggesting that there are substantial changes proposed
18	in the labeling that justify us converting this to the
19	Drug Facts format at this time before re-marketing.
20	            So I'm going to end my comments here and
21	allow Dr. Cantilena to resume the meeting and I'll be
22	back later to provide some further comment.
23	            DR. CANTILENA:  Okay.  Thank you, Dr.
24	Ganley.  We now have scheduled the sponsor
25	presentation from Allendale Pharmaceuticals and we'll

			41
	1	start -- we've allocated 45 minutes.  So, I'd like to
	2	ask the sponsor if you can please try to stay in that
	3	time frame.
	4	            And the sponsor will be starting off with
	5	Dr. Stabb, who will introduce the other speakers.
	6	            DR. STABB:  Thank you very much.  I want
	7	to thank the FDA and the Advisory Committee for their
	8	time in reviewing this product today.
	9	            I am Dr. Bob Staab.  I'm from Allendale

10	Pharmaceuticals and I am Chief Scientific Officer and
11	Chairman of the company.  We do welcome the
12	opportunity to discuss the issues surrounding this
13	label.  We are very interested in getting the product
14	back onto the market.  We're getting pressured --
15	constantly getting questions constantly of what we
16	need to do in order to get it back on.
17	            There have been a lot of comments from the
18	agency with respect to the labeling.  And we think
19	that there's time and our group today will take that
20	time to point out some of the pros and cons of those
21	comments.  Because in the end, I do believe that the
22	agency and Allendale Pharmaceuticals and probably just
23	about everybody here is most interested in having a

24	clear understanding and to make sure the consumer has
25	a clear understanding of the pros and cons of the

			42
	1	product.
	2	            So we did bring some people here today,

	3	people who have been very, very experienced in the
	4	areas of contraception, OB/GYN, Toxic Shock Syndrome
	5	and so forth.  You'll be hearing from them, and the
	6	first person we'll be hearing from will be Dr.
	7	Connell, Professor Meritus, the OB/GYN Emory
	8	University School of Medicine and she has had a lot
	9	experience with Nonoxynol-9 and with the sponge.  She
10	has actually sat on an advisory panel for the
11	development of the OTC monograph for Nonoxynol-9.  I
12	look forward to hearing her comments.
13	            Dr. Connell.
14	            DR. CONNELL:  Thank you very much.  It's
15	a pleasure to be back.  This is deja vu all over

16	again.  I realized yesterday I've been coming here for
17	30 years.  I don't know what that means but in any
18	event I have always had a major interest in
19	contraception and particularly this type of product. 
20	And this goes back to the days when women, many
21	centuries ago, realized there's a relationship between
22	the ejaculate and babies and at that point began to
23	put wonderful things into their vaginas.
24	            As you can see here, the Egyptians went to
25	the oceans for sponges and cut them up.  Cleopatra

			43
	1	became well recognized for developing pessaries
	2	against pregnancy and gonorrhea.  Casanova made a gold
	3	ball.  He reported using the same one for 15 years.
	4	            And then -- it's a wonderful, it's a very

	5	colorful history as you go through all the plant and
	6	animal pessaries that were developed over the years. 
	7	It makes fascinating reading.  This continued on --
	8	next, into the more modern era.  We had all kinds of
	9	liquids and chemicals and little pledgets of various
10	types with strings on them.  And we -- a number of

11	years ago had the collagen sponge.  It was kind of a
12	dreadful, very rough unpleasant thing that never made
13	it to the market.  But it did culminate ultimately in
14	the Today Sponge that we're talking about now.
15	            Now we spent, as you heard, a number of us
16	about, well most of the 1970s looking at over-the-
17	counter products and our bottom line which is
18	ultimately showed in the Federal Register we found
19	Nonoxynol-9 to be safe and effective.  A number of us
20	came to the FDA in `82, at that point, the sponge was
21	approved in March of `83.  It was then, of course,
22	sold as you know to Whitehall, American Home Products.
23	            And I think the important thing, in
24	addition to what's already been said, is that when it
25	went off the market, there was a tremendous amount of

			44
	1	concern and  I think a lot of that still persists that
	2	since it was taken off the market it was dangerous. 
	3	And I think we still have this to be concerned about. 

	4	People not realizing it was still FDA approved and it
	5	was not removed because it was dangerous.
	6	            And next, we move on through what actually
	7	went on in the development of the sponge.  Seven years
	8	of trials, a lot of work that went on looking at very
	9	aspects of labeling and packaging, many, many hours
10	looking at these things, looking at consumer data. 
11	During this time the 800 number was set up and it was
12	extremely useful in terms of getting help as to what
13	to do and when to do it and how to get through to
14	consumers in an effective fashion.
15	            Removal problems at that time were
16	recognized to be a major difficulty.  And the removal
17	tab was changed to a different, from the braided
18	polyester to a woven loop, simply because women were
19	able to find it more easily and has helped a lot.  And
20	parenthetically, the VLI experience was that when
21	women couldn't get them out, if they got to the 800
22	number, the vast majority of women, with the support
23	of some wonderful people on the 800 number, were able
24	to get their sponge out.  This was a very, very useful
25	thing that occurred during all those years.

			45
	1	            Next, please.
	2	            During all of the studies, it was quite
	3	apparent that the sponge worked in three ways, a slow
	4	release of Nonoxynol-9 and a reasonably low but
	5	effective level, the blockage of the cervical os by
	6	the sponge and in the laboratory it was found that
	7	eight ejaculates in three days could be put in the
	8	milieu of the sponge and leave no viable sperm.  So
	9	there is a lot of very good clinical and laboratory
10	data.
11	            Now you heard a lot about the advantages. 

12	There are many of them.  I just pulled four I thought
13	were probably the most important from a consumer point
14	of view.   We already know many people, many women are
15	not happy to get into the healthcare system.  Not only
16	are they not happy, they're not able to and in today's
17	situation very often.  And so it was always wonderful
18	to have a good option available over-the-counter. 
19	Many women like the fact that it is available.
20	            Historically, it was going to be the two-
21	day sponge.  But the FDA said, no, thirty hour limit. 
22	And that's, of course, still in the labeling.  But
23	women didn't have to go back like they did with the

24	diaphragm and keep adding spermicide each time they
25	had sexual intercourse.  Very easy to put in.  Not

			46
	1	messy.  And a lot of women and a lot of men find the
	2	other vaginal products very messy, unaesthetic and

	3	unattractive.  And the nice thing about it is that
	4	unlike the condoms, unlike the female condom, the

	5	sponge can be put in in advance and this has certain
	6	cosmetic aesthetic advances.
	7	            Next.
	8	            Now, clearly there are disadvantages.  One
	9	of the more important ones being the fact that it
10	really is less effective than IUDs and all the
11	hormonal methods.  Quite clearly it does have to be
12	used each time somebody has sexual intercourse which
13	is a real turn-off to some women and some men.  We
14	recognize and we saw this with our extensive review of
15	N-9 in the `70s.
16	            There is local irritation, male and female
17	in a small percentage of individuals.  And then the
18	issue of toxic shock which we looked at but Mary
19	Delaney will talk about in much more detail so I want
20	to skip over that.  Removal problems, I think will
21	continue to be an issue.  Clearly the labeling is
22	particularly important and as I already mentioned in
23	the VLI days, the use of the 800 was extremely
24	helpful.
25	            I would like to just sort of look at what

			47
	1	I think are some of the more important general
	2	considerations without getting into the details of the
	3	chemistry.  And I think the efficacy data that has

	4	just been talked about is very critical.  I think
	5	those of us who spent a lot of time at the FDA looking
	6	at labeling and efficacy issue and trying to look at
	7	evidence-based medicine have always had problems
	8	because there are such variability in the various
	9	studies, in the various study populations over the
10	years.  It has produced a lot of problems in terms of
11	how best to present efficacy data to the consumers so
12	it's easily understood.  We recognized years ago there
13	were no comparative trials and I doubt will there ever
14	be good comparative trials of the various barrier
15	methods.
16	            It's technically probably not an easy
17	thing to do and it may never be done.  Therefore, it's
18	incumbent honest, I think, to develop language which
19	will point out to women the importance of the efficacy
20	data but give them a sense of the bottom line of the
21	efficacy data, not overwhelm them with large numbers
22	of numbers that are basically incomprehensible.  So I
23	think the issue that was raised a little earlier about
24	efficacy is very, very relevant.  And Forrest
25	Greenslade will talk about that in greater detail.

			48
	1	            Looking at the labeling, it's, as I said,
	2	something that a number of us have worked on over the

	3	years.  I think the written and the particularly the
	4	graphics are extremely important particularly with a
	5	product like this.  And another consideration always,
	6	is how would you pick up a problem if one developed
	7	that you perhaps are not aware of or perhaps you are
	8	not aware of the extent of the problem.
	9	            And if you review the current side-effect
10	reporting, it seems to be that this is adequate for
11	this particular reporting system would pick up

12	anything of great significance.  So I think that
13	there's really not a major problem there in that area.
14	            And finally, I think if you look at the
15	issues of women, pregnancy, babies, all the things
16	you've already heard about that when you look at the
17	sponge in context, there is a decidedly favorable risk
18	benefit ratio, clearly, and we saw this very markedly
19	among the teens particularly.  It was a method of
20	choice for many of the reasons that you've already
21	heard, personal reasons, for medical reasons.  And I
22	think all of us were disturbed when it went off the
23	market.  This was an extremely valuable contraceptive
24	option that was missed.  It is missed.  It's still

25	misunderstood.  And I have no doubt that it would be

				49
	1	very profitable for women, particularly, if the sponge
	2	were to go back on the market.  And, therefore, I
	3	would certainly encourage the re-institution of the
	4	use of the sponge.
	5		Thank you.
	6		I neglected my duty here.  The next
	7	speaker is Mary Delaney from Brigham and Women's
	8	Hospital at Harvard and she will address TSS. 
	9		Sorry about that.
10		MS. DELANEY:  Thank you and good

11	afternoon.  What I would like to address this
12	afternoon is Toxic Shock Syndrome and the Today
13	contraceptive sponge.
14		Toxic Shock Syndrome was first described
15	in 1978 by Todd.  And it received national attention
16	in 1980 when unexplained febrile illness associated
17	with shock, multi-organ dysfunction and high death

18	rates were reported in healthy young women.  TSS is a
19	systemic disease characterized by the rapid onset of
20	fever, vomiting, diarrhea, muscle pain, rash,
21	hypotension, multiple organ system dysfunction and
22	late desquamation.  The incidents of TSS has declined
23	dramatically.  From six to twelve per 100,000 cases in
24	1980 to approximately less than one per 100,000 cases
25	today.

			50
	1	            TSS is characterized by the time of onset. 
	2	There's menstrual TSS and non-menstrual TSS. 
	3	Menstrual TSS occurs as a result of vaginal
	4	colonization with Staphyloccocus aureus during

	5	menstruation and is associated with tampon use.
	6	            While non-menstrual TSS results as a
	7	complication of Staphylococcal infections of the skin,
	8	soft tissue of the respiratory tract, following
	9	obstetric and gynecologic procedures, following

10	influenza or without a known focus of infection.
11	            The causative agent in TSS is toxin

12	produced by the bacterium Staphyloccocus aureus called
13	Toxic Shock Syndrome Toxin - 1, abbreviated TSST-1. 
14	Staph aureus is a normal member of the human micro
15	flora and is commonly isolated from the mucosal
16	services, skin and feces.  To develop TSS, an
17	individual must be colonized with the toxigenic strain
18	of Staph aureus, conditions must ideal for toxins
19	production by the bacterium and there must be an
20	absence or insufficient level of neutralizing antibody
21	to the toxin.  These factors make TSS a rare disease. 
22	It has been reported that approximately ten to fifteen
23	percent of women carry Staph aureus vaginally and that
24	approximately one-third of these strains produce TSST-
25	1.

			51
	1	            In a recent study just conducted in our
	2	laboratory, we examined the colonization rates of over
	3	3,000 healthy women to determine the colonization
	4	rates in the nares, vagina and anus.  We found that

	5	overall 26 percent of all women were colonized with
	6	Staph  aureus.  Nine percent were vaginal carriers,
	7	eight were anal carriers and 18 percent were nasal
	8	carriers.  We further analyze these isolates to
	9	determine if they could produce the toxin TSST-1.  And
10	as you can see from the graph, there's a substantial
11	decrease in the number.  There's only one percent of
12	all Staph aureus strains capable of producing TSST-1.
13	            In addition, we looked at serum antibody
14	levels in these women and we found that 98 percent of

15	all women had protective antibody levels to the toxin. 
16	There was only one subject that had vaginal -- that

17	had a vaginal micro flora with producing TSST-1 that
18	did not have the protected antibody levels.
19	            In 1989, Schwartz published a case
20	controlled study using TSS surveillance records from
21	five states from January, 1986 to June, 1987 to
22	determine the rate of a non-menstrual TSS associated
23	with all barrier contraceptives.  It's important to
24	note that 49 percent of all TSS cases were non-
25	menstrual.  And most of these cases were associated

			52
	1	with surgical or cutaneous wounds or occurred within
	2	three days post-partum.  Those made up 53 percent of

	3	the cases.  Of the remaining cases, only 13 percent
	4	were associated with barrier contraceptives including
	5	the sponge.  At five percent, the diaphragm, seven
	6	percent and the cervical cap, one percent.
	7	            Schwartz went on to report that the
	8	relative risk of non-menstrual TSS attributed to all
	9	barrier contraceptives was 2.4 cases per 100,000 users
10	per year.  And the death rate was 01.8 deaths per
11	100,000 women per year.  Although this risk may be
12	elevated, the number of cases assists still small and
13	that can be seen in the next overhead.
14	            In a recent publication by Hajjeh at the
15	Centers for Disease Control on the surveillance update
16	of TSS from 1979 to 1996, the years were divided into
17	three based on the epidemic years, the active
18	surveillance years and the present time.  And as you
19	can see from the overhead, the cases of menstrual TSS
20	decrease over the time period and that there's an
21	increase in the non-menstrual cases.  But what's
22	important to see is that the non-menstrual cases
23	related to barrier contraceptives have not changed
24	over the years.
25	            More specifically, when the Today Sponge

			53
	1	was introduced in 1983, the cases still remained low. 
	2	And again when it was removed from the market in 1995,

	3	there is not a significant difference among the rates.
	4	            Data obtained from the Today Sponge
	5	sponsors and the FDA adverse event reporting system
	6	describing the incidence of TSS cases reported to the
	7	sponge so that the incidents remains low and that
	8	there are no reported deaths from TSS attributable to
	9	sponge use.  And this data is found in Ling Chin's OTC
10	medical officer's review and Claudia Karwoski
11	memorandum.
12	            Furthermore, some of the reported cases of 
13	TSS had predisposing and extenuating circumstances,
14	including the wearing of the sponge for longer than
15	the recommended 30 hours, using the sponge while
16	postpartum or while menstruating.
17	            In addition to the epidemia logic reports,
18	there are various in vitro studies that report on the
19	sponge and Nonoxynol-9 on the growth and production of
20	TSST-1.  All three of these reports indicate that
21	Staph aureus is inhibited by the sponge and Nonoxynol-
22	9.
23	            In summary, TSS is a rare disease cased by
24	a toxin, TSST-1, produced by the bacterium Staph
25	aureus.  Staphyloccocus aureus is not introduced into

			54
	1	the vagina by the sponge but rather it is a normal
	2	component of the vagina micro flora.  For disease to

	3	occur, the woman must be colonized with a strain of
	4	toxin producing staph aureus and she must lack
	5	protected antibody.  These are two facts which make
	6	the disease rare.  Tampons and barrier contraceptives
	7	have been shown to have an association with the
	8	occurrence of TSS, although they are not the causative
	9	agents in the disease.  The sponge does not pose a

10	risk any greater than that associated with tampons.
11	            In fact, the cases of non-menstrual TSS
12	associated with barrier contraceptives are far fewer
13	than menstrual tampon related TSS, two percent versus
14	50 percent.  And several of the reported cases of TSS
15	while using barrier contraceptives have resulted from
16	misuse of the product.
17	            However small the risk of developing TSS

18	while using the sponge, it is essential to provide the
19	necessary information to the consumer regarding the
20	possibility of developing TSS, consequences associated
21	with TSS, as well as ways to decrease the small but
22	present risk while using the sponge.
23	            The information contained on the carton

24	itself, as well as in the user instruction booklet,
25	adequately informs and advises the consumer of the

			55
	1	risks of developing TSS, the severity of TSS, symptoms
	2	associated with the disease process, safeguards to

	3	reduce the risk of developing TSS and guidelines to
	4	follow if TSS-like symptoms occur.  This information
	5	is clearly marked as a warning on the carton and in
	6	the enclosed booklet.
	7	            What I have up here is the currently
	8	improved -- approved 1991 label as well as a proposed
	9	revised 2000 label.  And the arrows point to where

10	these pertinent statements are found regarding TSS. 
11	The information contained on the product label
12	adequately informs the consumer for safe and effective
13	use of this product.
14	            I'd like to introduce the next speaker. 
15	It's Roberta Geidner Antoniotti.  She's -- she will
16	present the relative public health need for the Today
17	Sponge.
18	            MS. ANTONIOTTI:  Good afternoon.  Thank

19	you very much for this opportunity to come and really
20	talk about the public health need for improved
21	contraception with the vaginal sponge being one
22	additional option that we could look at for that.
23	            I represent Planned Parenthood of
24	Maryland, which serves 16,000 patients a year in 22
25	counties in the State of Maryland.  We are one of 132

			56
	1	affiliates for Planned Parenthood Federation of
	2	America and our seven health centers are part of a

	3	network of over 850 health centers serving over 4
	4	million men and women a year with different forms of
	5	reproductive health services.
	6	            One of the things I do want to make clear
	7	is that my presentation here and my participation in
	8	this as a representative of Planned Parenthood
	9	Federation is not an endorsement of Allendale
10	Pharmaceuticals or of this particular product that

11	they may be able to bring to the market.  But we do
12	strongly commend them for looking for ways to bring
13	additional options to women and our effort to reduce
14	the high rate of unintended pregnancy. 
15	            As one of the oldest and largest
16	reproductive health providers in the country, Planned
17	Parenthood Federation of America has a strong interest
18	in insuring women have easy access to safe, effective
19	and affordable contraception.
20	            One of the key problems that we face in
21	assisting men and women prevent unintended pregnancy
22	is the lack of innovation and approved technology in
23	contraceptive research and methods.  And one of the
24	documents that has come out in 1995, that's documented
25	very well, is the Institute of Medicine research on

			57
	1	unintended pregnancy and its affect on the well being
	2	of families and children in our United States.
	3	            I think you can see here, as many of the

	4	speakers previously documented, we have an epidemic
	5	rate of unintended pregnancy in the United States
	6	where close to half of all pregnancies are unintended
	7	and close to 10 percent of that half are totally
	8	unwanted children.  We have the highest rate of any
	9	unintended pregnancy of any industrialized country in
10	the world.  In fact, the rate of unintended pregnancy
11	in this country in 1983 was even higher than our

12	planned pregnancies.  And if you look at our rates
13	compared to Canada or Great Britain, we are at least
14	double and in some cases close to six times higher
15	than other industrialized countries.
16	            Unintended pregnancy remains a serious
17	problem in the United States.  Although the birth

18	control has been available for 40 years and other
19	innovations and contraception have been introduced in
20	the past several decades, most pregnancies, as I've
21	stated, are still unintended.
22	            The last major introduction of a new
23	contraceptive was Depo-Provera in the early 1990s. 
24	American women need safe and accessible birth control
25	and they need more options that are affordable for

			58
	1	those without health insurance or for those with
	2	health insurance that do not provide coverage for

	3	contraceptives that still plages women across the
	4	country.
	5	            In terms of Planned Parenthood, we serve
	6	almost two million women every year for contraception. 
	7	And that is one of the relationships that we may have
	8	with Allendale in the future if this product is
	9	approved.  It is possible because we do serve two
10	million women, as we do with many other pharmaceutical
11	companies, we will have a conversation with them about
12	how to increase access to the products that they can
13	provide to reduce unintended pregnancy.
14	            Of the women that -- of that two million,
15	12.6 percent of them preferred non-prescriptive
16	barrier methods.  There are important benefits to
17	contraception that can be obtained without a
18	prescription.  While birth control methods such as the
19	pill and Norplant or Depo-Provera involve one or more
20	visits to a healthcare provider.  The vaginal sponge
21	appealed to women with busy schedules and
22	accessibility issues because it could be bought over-
23	the-counter at a local pharmacy sometimes 24 hours a

24	day, seven days a week, where that's the only source
25	of care that they have.

			59
	1	            In a recent study published in Family
	2	Planning Perspectives, 19 percent of Missouri women
	3	surveyed reported that it was hard to get time off of
	4	work or out of school to go to a clinic.  While 25
	5	percent said that they would more likely to use birth
	6	control pills if they were available without a
	7	prescription.  With easy access to contraception, the
	8	key to preventing unintended pregnancy, over-the-
	9	counter products makes sense.
10	            In Maryland, where Planned Parenthood of
11	Maryland serves women and men with reproductive

12	healthcare, there's over 1,273,000 women of child
13	bearing age between the ages of 13 and 44.  We serve
14	this population through the seven health centers that
15	we have available.
16	            According to a 1995 assessment of
17	contraceptive needs and services, that was part of the
18	Allen Guttmacher Institute study of contraceptive
19	needs and services across the country, of the 664,000
20	women who need contraceptive supplies and services
21	because they're at risk of an unintended pregnancy,
22	more than a third of them are at or below 200 percent
23	of poverty, close to a quarter of a million -- a
24	little over a quarter of a million women.
25	            And these women, whether they're black,

			60
	1	white, Hispanic, Korean, whatever race, culture,
	2	ethnicity, they need publically funded and support
	3	health services.  This is the group who could benefit
	4	most by the reintroduction of the vaginal sponge
	5	product, a safe, affordable birth control method which
	6	should be permitted from our perspective over-the-
	7	counter.
	8	            Many of the women in this demographic will
	9	not use contraception if they do not have access to a
10	viable over-the-counter method because of the
11	difficulty in accessing the public health system as
12	Dr. Connell so adequately described.
13	            In Maryland alone, it is estimated that
14	only 46 percent of the women in need of publically
15	funded services are being served through the private
16	and public healthcare system and that leaves a little
17	over a 150,000 women at risk of an unintended
18	pregnancy.  And you can see by county and by our major
19	city in Maryland how this impacts women across the
20	state, whether they're rural women, urban women,
21	suburban women, it affects them everywhere across our
22	state and across the country.
23	            Another valuable benefit of the non-
24	prescriptive products like the vaginal sponge is its

25	affordability.  As I said, may low income women cannot

			61
	1	afford to pay for prescription contraceptives such as
	2	the pill or a diaphragm, yet they can remain protected
	3	from unintended pregnancy by purchasing the vaginal
	4	sponge, a more affordable alternative.
	5	            For millions of uninsured Americans, over-
	6	the-counter medicine is the only means of healthcare
	7	that's available to them and this includes
	8	contraception.  Our hope would be that we would get
	9	contraceptive coverage passed at a federal level.  I'm
10	going to give my one little political statement here,

11	so that all insurance companies have to provide this
12	as an option as they provide Viagra to men, we should
13	be providing contraception to women.
14	            And, in fact, even women with health
15	insurance aren't always guaranteed access to
16	contraceptive care.  Maryland, I'm proud to say, was
17	the first state in the country that did pass a law

18	requiring equity and prescriptive coverage.
19	            The issue of privacy as well is another
20	issue that needs to be considered when it comes to
21	purchasing contraception.  While obtaining a
22	prescription for birth control pills or getting
23	fitting for a diaphragm involves visiting a healthcare
24	provider and getting the necessary tests, many women
25	need the privacy and anonymity of purchasing a product

			62
	1	like the vaginal sponge if it is made available over-
	2	the-counter.  It's easier to use and longer lasting in
	3	providing protection against pregnancy than other
	4	over-the-counter methods available such as spermicides
	5	and condoms.
	6	            We would also promote the use of condom
	7	with the vaginal sponge in order to provide full
	8	protection against sexually transmitted infections and
	9	HIV.
10	            Although the goal of Planned Parenthood
11	Federation of America and other reproductive
12	healthcare providers that we've heard from earlier is
13	to increase access to all types of contraception, we
14	understand that the unique properties of the vaginal
15	sponge fills a void that has remained empty since it
16	was taken off the market five years ago.
17	            When it was discontinued in 1995, it was

18	one of the most popular contraceptive choices that did
19	not require a doctor's visit with one quarter of a
20	billion sold over 12 years nationwide.  In addition to
21	its ease and affordability, women who do not engage in
22	regular intercourse found the vaginal sponge to be an
23	ideal method of contraception.
24	            A survey conducted by the CDC, National

25	Center for Health Statistics, shows that births from

			63
	1	unintended pregnancy are increasing among never
	2	married women.  We saw that they're increasing among
	3	married women as well, it's increasing among never

	4	married women.  A lot of the myths that unintended
	5	pregnancy only affects certain categories of women is
	6	totally inaccurate and I think Best Intentions has
	7	very well done -- done a very good job to dispel some
	8	of those myths.
	9	            Many of the women, though, who fall in a
10	never married category who has occasional sex could
11	use this particular method where they don't want to
12	use a method like the pill and a Norplant, Depo-
13	Provera or IUD which are more expensive and not
14	necessary when you have an occasional act of
15	intercourse.
16	            According to research by James Trussell,
17	the vaginal sponge has been proven to as effective as

18	a diaphragm and the cervical cap for women who have no
19	previous births.  The effectiveness of any method, of
20	course, often is more determined by the human factor
21	in appropriately and consistently using the method.
22	            From the anecdotal information that I was
23	able to obtain from our medical director and associate
24	medical director, the problems that they saw in the

25	early 90s -- late 80s and early 90s with the sponge

				64
	1	with removal,  more often than not, was the practice
	2	of the woman and not the labeling, the instructions to
	3	the woman, it was a matter of her own awareness and

	4	her own ability to follow the directions that were
	5	provided to her.
	6		And as far as we're concerned, the use of
	7	any contraceptive method is always much more effective
	8	than no method at all at preventing unintended
	9	pregnancy.  We feel that the vaginal sponge in the 12
10	years that it was on the market was -- has proven
11	itself to be a valuable and popular method of over-
12	the-counter contraception.  When it was taken off the
13	market, it meant the removal of another opportunity
14	for women to choose for themselves how best to prevent
15	an unwanted pregnancy.
16		If we are to diminish the epidemic of
17	unintended pregnancy in the United States, we must
18	provide women and men with more options, not less.  At
19	Planned Parenthood we feel strongly that women should
20	be able to benefit from its ease of use, accessibility
21	and affordability.  And we ask you to reinstate the
22	vaginal sponge as an over-the-counter product.
23		I'd like to introduce Dr. Forrest

24	Greenslade, who will be our next presenter.
25		DR. GREENSLADE:  Good afternoon.  I'm

			65
	1	really pleased to have the opportunity to speak with
	2	you today.  My name is Forrest Greenslade and for well
	3	over forty years, I've worked on the development and
	4	introduction of reproductive health technologies.
	5	            While working at Ortho Pharmaceuticals, I
	6	served on the OTC panel for vaginal contraceptives
	7	that Dr. Connell chaired.  When working with the
	8	Population Council, I  guided the introduction
	9	globally of Norplant and the Copper T380 IUD.  And for
10	the last almost decade I've served as President of
11	Ipas, an international not for profit women
12	organization that confronts the issue of maternal
13	mortality.
14	            The reintroduction of the Today Sponge is
15	really important.  Unwanted pregnancy, as you've
16	heard, is a really serious issue for many women.  No

17	contraceptive is ideal for all women and as a matter
18	of fact, no contraceptive is ideal for any one woman

19	throughout her reproductive life.  Women need choices. 
20	And the Today Sponge fills that niche for many, many
21	women.  Women also need information by which to make
22	those choices and I'm sure that Allendale
23	Pharmaceuticals and the FDA want exactly what I want,
24	labeling, that is accurate and both consumer friendly.
25	            Let me put the first overhead up.  This is

			66
	1	blow up of the 1991 approved labeling.  And there's
	2	lots and lots of information here.  And people who

	3	like lots and lots of information will enjoy this
	4	labeling.  You can see that there was a large study,
	5	it was done in the U.S., done internationally, a large
	6	database of 1,800 patients.  You can see that there's
	7	method effectiveness and use effectiveness and they're
	8	defined and you also can see that somewhere between
	9	9.2 and 11 percent method effectiveness and 13 to 15.5
10	percent use effectiveness was obtained.  Lots and lots
11	of data, not very consumer friendly.
12	            I like actually what the FDA is proposing
13	in the proposed labeling -- the 2000 labeling.  It's
14	very straightforward.  It says in clinical studies
15	with the Today Sponge, about one in ten women, that 11
16	to -- 9 to 11 percent became pregnant using this
17	product correctly all the time.  It also says the
18	possibility of getting pregnant increased to about one
19	in seven women, that 13 to 16 percent, when the
20	product was not used correctly.
21	            Not yet, not yet.
22	            Now, there's one problem with this.  And
23	that's time frame.  Was that one out of ten chance of
24	getting pregnant with the first intercourse?  No.  It
25	was a one out of ten chance during an entire year of

			67
	1	the first use of it.  Was that one in seven with that
	2	first intercourse?  No.  It was during the first year.
	3	            And to put this in perspective, think

	4	about it, 2.5 acts of intercourse per week is the
	5	average times 52 weeks times those hundred women, it
	6	took about 13,000 acts of intercourse to produce those
	7	ten pregnancies.  This needs to have that kind of
	8	perspective.  And what I suggest is simply adding
	9	language like, during the first year or within a year
10	or something like that.   This would make this very
11	accurate, give good perspective and be very, very
12	consumer friendly.
13	            Now, on a subsequent paragraph in the
14	proposed labeling, it says, no birth control product
15	can prevent pregnancy all the time and refers to a
16	table.  And it's the table that's in the package, it's
17	the table that comes from contraceptive technology. 
18	And to be quite honest, this is not very consumer
19	friendly at all.  And as a matter of fact, there's
20	some very troubling aspects to it.
21	            Now, remember, the FDA's proposed labeling
22	says, one out of ten women can be expected to be
23	pregnant within a year.  But look at this labeling. 
24	Therefore, the vaginal sponge for previous births, it
25	says up to 40 percent.  What is a woman to believe. 

			68
	1	Is it one out of ten or is it 40 percent.  I needed to
	2	take a pencil and a calculator  to figure in what does
	3	that come out to be, like one out of 22 women.  What
	4	is the woman to interpret from this?  What else is she
	5	to interpret?
	6	            Is she to interpret, for instance, that
	7	withdrawal or natural family planning is more
	8	effective than the Today Sponge, or is she to believe
	9	that a spermicide, a gel, foam, suppository or film is
10	more effective than the Today Sponge?  It's very hard

11	for someone just to take a look at that, especially
12	someone who's not really attuned to looking at tables
13	and really figure out what is it that she's to
14	interpret among all of those.
15	            I'm actually concerned with the way in
16	which these data were collected.  I'm going to just
17	read from you a sentence, the description of how these
18	data came about.  One would look at these data and
19	say, oh, these were observed in a clinical trial.  I
20	guess that would be my first interpretation.  But this
21	is not the case.  Let me just read this one sentence.
22	            In the sponge/diaphragm trial, the
23	proportion becoming pregnant in the first year of

24	typical use for parous users of the diaphragm, 12.4
25	percent was marginally lower than for nulliparous

			69
	1	users.  In the cap diaphragm trial, proportion
	2	becoming pregnant among parous users, 29.0 percent is
	3	almost double that among  nulliparous users, 14.8

	4	percent.  Faced with this estimation, we set the
	5	estimates for nulliparous users of the cervical cap
	6	and sponge equal to the estimate for all users of the
	7	diaphragm based on the NFSG survey, 20 percent.
	8	            Now, listen to this, we doubled the
	9	estimates for nulliparous users for the cervical cap
10	and sponge to obtain the estimates for parous use. 
11	That 40 percent is not an observed data -- piece of
12	data in a clinical trial.  It is an estimate based on
13	a bunch of assumptions.  Now, the writer's of this
14	book did a very good job.  And we all try to do this
15	to try to interpret the data.  But when compared to
16	clinical trials conducted under FDA mandated good

17	clinical practices, this 40 percent should not have
18	the weight of the one in ten that you propose in the
19	2000 labeling.
20	            Now, we've wrestled with this idea for
21	years and years and years -- the other way, that's
22	okay, that's a good way too.  That's fine.
23	            For years we've all tried to figure how
24	does one compare studies done in various countries
25	under different conditions with totally different

			70
	1	kinds of contraception.  And here's a table that was -
	2	- a graphic that was generated by Parker Mauldin at
	3	the Population Council several years ago.  And it's --
	4	it's pretty straightforward, isn't it?  If you look

	5	at, on the bottom periodic abstinence, spermicides,
	6	diaphragm, et cetera, you can see that there's wide
	7	range of effectiveness information that comes from
	8	studies under use conditions.  A wide range ranging
	9	from somewhere between 10 and 30 percent.  In the next
10	range, condoms, orals, et cetera  and then in the
11	final lowest range things like injectables, surgical
12	sterilization, Norplant.
13	            What is very clear from this is that with
14	those kinds of ranges to present to a potential
15	consumer, the finite difference between 40 percent and
16	20 percent as being real, as being something that they
17	should really make a judgment about their --
18	controlling their own fertility is -- is really not a
19	rational thing to do.  Let me suggest something that
20	is much more in line with the user friendly approach
21	that the FDA has proposed in the previous labeling.
22	            Over the years when people have asked me,
23	well, Forrest, what are the relative effectiveness of
24	different ones.  I've come up with a relatively simple
25	straightforward approach.  I say, if women don't use

			71
	1	any contraceptive method, more than eight out of ten
	2	of them will become pregnant within a year.  With
	3	natural family planning or periodic abstinence, it's

	4	about one to three out of ten will become pregnant. 
	5	It works.
	6	            Female barrier methods, probably one to
	7	two out of ten will become pregnant.  And this
	8	includes things like the sponge, diaphragm, cervical
	9	cap, female condom, foams, jellies, creams and films. 
10	The male condom about three to fifteen out of a
11	hundred will become pregnant.  The pill, either
12	combined or many, about one to five out of a hundred. 
13	Provider-base methods such as the copper IUD,
14	Norplant, injectables, tubal ligation or vasectomy,
15	about one to five out of a thousand. 
16	            Now, these are basic relative odds that I
17	think anyone can understand.  These are consistent
18	with our understanding over years and years of
19	clinical research, both on method and user
20	effectiveness.
21	            And I suggest to you that these are
22	totally consistent with a rationale interpretation of
23	the table that comes from contraceptive technology. 
24	And I think that these are consumer friendly and say
25	in simple straightforward terms what a woman can

			72
	1	anticipate when she picks up a product and says, will
	2	this serve my needs for effectiveness or will it not. 
	3	She can say, well, all of these are going to give me

	4	some level of protection.  Obviously, the provider-
	5	based methods will give me a higher level of
	6	protection.  The ones that I have to take, such as an
	7	oral, are a little bit less than that.  And all of the
	8	barrier methods are a little less than that.  But all
	9	contraction gives me a better chance to control my own
10	fertility.
11	            Now, obviously comparing effectiveness is
12	only one of the things that a woman has to decide when
13	she's trying to make a rationale choice because every
14	contraceptive technology has its own set of
15	advantages.  But issues like reversibility, side-
16	effects, frequency of administration and those special
17	considerations for use are all important.  There's no
18	time for dealing with that today but in the handout

19	that I left for you, I've given you my insight as to
20	what those relative things are.
21	            For me, the bottom line is this, the more
22	choices that a woman has, the higher probability that
23	she will find the one that meets her needs at her
24	particular time in her reproductive life.  I'm
25	delighted that she soon will have again the Today

				73
	1	contraceptive sponge.  And what's most important is
	2	for us to find a way to communicate to her whether or
	3	not this is the best choice that meets her needs at
	4	that time.
	5		I'd like to pass the baton on to Dr.
	6	Staab, who will summarize.
	7		Thanks for your attention.
	8		DR. STAAB:  Yes, we can go right -- okay. 
	9	Just as an introduction, some people don't know
10	Allendale, so I think it's worthwhile mentioning who

11	Allendale is.  We're a small start-up company.  We
12	have some -- a small number of people work in
13	marketing, manufacturing and finance.  And I happen to
14	be a toxicologist, I'm a board certified toxicologist. 
15	We currently have no products on the market.  No
16	income.  However, we're accumulating debt is what
17	we're doing as our activity.
18		Just to give a small amount of evidence,

19	as to how small we are, the gentlemen who's flipping
20	the slides is the President and CEO of Allendale
21	Pharmaceuticals, Gene Detroyer.  Next slide, please.
22		We come here, even though we're small,
23	with  some relevant experiences though.  I had worked
24	for Tambrands, the maker of Tampax tampons in the mid
25	80s during the Toxic Shock Syndrome heyday, if you

			74
	1	will, when there was big issues.  Working on TSS and
	2	consumer labeling.  I've also worked for Schmid

	3	Laboratories, London International with condoms,
	4	Nonoxynol-9 and the labeling of those products.  I
	5	don't come to the Today Sponge for the fist time.  As
	6	a matter of fact, even when I was at Tambrands, I ran
	7	into Forrest who helped us to do an assessment as to
	8	whether or not Tambrands should acquire the Today
	9	Sponge when it was being sold by VLI.  We did an
10	extensive review at that time.  So this is not a new
11	product for me or for the people that I am associated
12	with.
13	            Next slide, please, Gene.
14	            And the people that we came to speak here
15	today are not seeing contraception and the issues
16	related to consumer products labeling for the first
17	time.  Besides the people who have already spoken, we
18	had Dr. Onderdonk from Harvard write some background
19	information made available to the FDA and to the
20	panel.  And also Dr. Mike Burnhill, V.P. of Medical
21	Affairs for Planned Parenthood Federation of America,
22	got it right.
23	            Unfortunately, those two gentlemen had

24	previous commitments out of country, they are both not
25	here, although both had express an interest in being

			75
	1	and both are very supportive of the return of the
	2	product and an interest in keeping a label which
	3	communicates properly, simply and clearly.  Again, a
	4	common goal.
	5	            What I did, and I'm going to try and go
	6	through this quickly because I think you're getting an
	7	idea from where we're coming from, we're trying not to
	8	clutter up a label.  We trying to communicate.  We
	9	trying to do it simply and we're trying to get the key
10	information in the right place.  The medical officer

11	who wrote the recommendations for what's needed in a
12	label put these things down as something which would
13	be needed on the outside of the label, something like
14	Toxic Shock Syndrome to address it, allergy to
15	Nonoxynol-9, post-partum advice, TSS and menstrual use
16	should be contra indicated, miscarriage and abortion,
17	see a doctor if a vaginal infection exists or occurs
18	in use.
19	            Indeed, those things are in the label now,
20	maybe not the exact same words but its pretty good and
21	that's the kind of advice that the FDA and American
22	Home Products had in the 1991 label that was on the
23	market in 1995.
24	            Gene, next one.
25	            Also, they asked on the insert, which is

			76
	1	the insert which comes inside the box with this
	2	particular OTC product, if you had TSS, avoid the use

	3	of the product.  That's there.  Dropping down to the
	4	bottom of this slide, see the doctor if infection
	5	exists or if signs of infection exists.  That
	6	information is there.  And do not use if pregnant or
	7	if there are signs of pregnancy.  Those things were
	8	there.
	9	            The two dots, number one and two on this
10	particular slide are not on the label.  One suggestion
11	was explain the post-partum uterus to the consumer in
12	the labeling so that they could understand whether or
13	not the sponge would adequately fit and be used and so
14	forth.  Quite frankly, we think -- I think that that
15	information is probably best being B- being a
16	discussion between the health care provider, physician
17	and the potential user of the sponge, nurse
18	practitioners and physicians and so forth.  These are
19	people in this case particular who have given birth. 
20	More than likely they have someone that they're
21	talking to with respect to their health care.
22	            And the next one is use a condom to avoid
23	STDs as something that was not on the label, we would
24	not take exception to putting that onto the label. 

25	It's a -- it's probably a good recommendation today

			77
	1	considering the mortality and morbidity associated
	2	with sexual transmitted disease acquisition.
	3	            Going again, wash hands, 30 hour maximum

	4	retention time, don't use -- don't douche following
	5	use, difficulty  removal.  If you have difficulty
	6	removal, read the instructions.  We have the 800 and
	7	also call your doctor.  Those are things that were on
	8	the current label.  We say let's retain them.  I think
	9	that there's good information.  With respect to that
10	800 we've heard over and over again from Dr. Connell
11	and from people that I've spoken to American Home
12	Products in the Consumer Affairs Department where they
13	took these -- they're very capable of communicating
14	removal issues with the consumers when they have these
15	difficulties.  It's a very effective way of getting in
16	touch with your consumer if they're having a problem. 
17	So we are supporting them as well.
18	            Again, under insert information, we're
19	asked to talk about the local effects of irritation
20	and so forth which is in the current label.  And we're
21	ask to, if they're signs of infection, fever and so
22	forth, see your doctor.  That's in the current label.
23	            The one issue where, quite frankly, I'm

24	struggling a little is how do handle -- should we be
25	putting questions about or information about and

			78
	1	education about sexually transmitted diseases, what do
	2	you do if you're using multiple partners as sexual and
	3	if you have a new partner and so forth.  I guess I

	4	personally feel that if you tell the people that if
	5	they want protection from sexually transmitted
	6	diseases, to use a condom, you've addressed that
	7	issue.
	8	            Now, I don't know how much public health
	9	we could -- public health expounding that we can do in
10	a  label that would be effective.  I think there are
11	very effective communications that are available today
12	through clinics and through the public to get that
13	information across.  This is an NDA product and since
14	it's NDA product we do send in annual reports.  And
15	that 800 number that I spoke about before that was so
16	very effective in communicating with the consumers is
17	also effective to getting adverse events and reports. 
18	The consumer is never afraid to pick up the phone and
19	to call 800 -- a 1-800 number.  We believe that we do
20	get good information about the use of this product. 
21	We don't believe there were any major increases in
22	TSS, for example.  And I think Mary was very clear in
23	saying that there was not an increase in TSS.
24	            Go ahead.
25	            So, our post-market surveillance, we feel

			79
	1	pretty comfortable in staying with the 800 number. 
	2	And lastly, efficacy I'm going to stand by what
	3	Forrest had said.  I'm running out of time and I'm
	4	getting bad glares here.  But if somehow we can
	5	communicate the hybrid between what the FDA is asking
	6	for the one in ten failure or one in seven failure
	7	rate for imperfect use along with the time frame so
	8	that people know that we're talking about 1500 acts of
	9	intercourse that wind up getting a failure rate
10	instead of ten people have intercourse once and you

11	wind up with a pregnancy.  I think that we've come
12	together where we should be.
13	            The major issue that we have is if we wind
14	up trying to put all of the usable information onto
15	the outside of this package, it is going to be
16	unreadable and it is not going to be tool for the
17	consumer to learn about the use of the product.  We've
18	got minimize the amount of information that is on the
19	outside of that package.
20	            For example, we don't need full directions
21	for use on the outside of the package.  I think you
22	should state this is a product that has to be
23	moistened and inserted vaginally, see instructions on
24	the inside.  But if we can come together to find the
25	right key information, mention TSS and so forth, I

				80
	1	think we have a way to move forward. 
	2		I do thank you very much.  I know that I -
	3	- I'd be willing take any questions that you folks
	4	might have and I know the panel will as well.
	5		Thank you.
	6		DR. CANTILENA:  Okay.  Thank you very 
	7	much, Dr. Staab.  And, if you wouldn't mind actually
	8	staying at the podium and perhaps you could triage the
	9	questions as they come up --

10		DR. STAAB:  Sure.
11		DR. CANTILENA:  -- to members of your
12	team.  I'd actually like to open up this to questions
13	from the entire panel for the sponsor at this time.
14		Dr. Greene, would you like to start?
15		DR. GREENE:  I just -- just point of
16	clarification, when Ms. Delaney presented her data on
17	Toxic Shock Syndrome toxin, she said at one point, I
18	believe, that one percent of strains of Staph aureus
19	produced TSST-1, except it looked like you graph was
20	more like one percent of the people carrying Stap
21	aureus.
22		DR. DELANEY:  That was one percent of the
23	total nine percent of women that were carrying Staph
24	aureus.  Of those nine percent, one percent carried
25	the TSST-1 producing Staph aureus.

						81
	1		DR. GREENE:  Okay.
	2		DR. DELANEY:  That's going at the rarity
	3	of the disease essentially is what the point I was
	4	trying to get across.
	5		DR. GREENE:  Okay.  So of the nine women
	6	in a hundred, one of those nine?
	7		DR. DELANEY:  Correct.
	8		DR. GREENE:  Got it.  Okay.  And the other
	9	--
10		DR. DELANEY:  One of those nine percent. 

11	I mean there was not just nine, there were, I believe,
12	a percentage.
13		DR. GREENE:  Right.  Okay.  And the other
14	question I had was you mentioned a figure of the
15	incidents of anti-TSST-1 antibody, and it wasn't clear
16	to me whether the percentage that you mentioned, I
17	think you said 98 percent. 
18		DR. DELANEY:  98 percent.  Yes.
19		DR. GREENE:  It wasn't clear to me whether
20	that was of all women studied or of the women who
21	carried Staph aureus or of the women who carried Staph
22	aureus with the toxin?
23		DR. DELANEY:  That was of all women
24	studied.
25		DR. GREENE:  Thank you.

				82
	1		DR. CANTILENA:  Other questions?  Dr.
	2	Gilliam, did you have a question?
	3		DR. GILLIAM:  Just a comment, I guess, to
	4	Dr. Stabb.  I appreciate the comments that you've
	5	made, the only, I guess, problem I have with them is
	6	you're saying, you know, you're wanting this product
	7	to be over-the-counter and yet you're saying there are
	8	issues that they should talk with their healthcare
	9	provider about.  And recognizing that a lot of women
10	who possibly might use this aren't going to get
11	healthcare from a healthcare provider.
12		And so that's my concern regarding some of
13	the comments that you've made.
14		DR. STAAB:  Actually, I didn't quite
15	understand your question.  You were going back and
16	forth from the microphone.
17		DR. GILLIAM:  You were just, in your

18	comments you were saying that, I forget the exact
19	references you were saying, but you were saying that
20	there were certain items that the user should talk
21	with their healthcare provider about.  And yet this is
22	a product that you're recommending for over-the-
23	counter use and that many of the many might not go to
24	their healthcare provider to discuss these issues. 

25	And that's the point I'm trying to make.

				83
	1		DR. STAAB:  Currently, the FDA approved
	2	label does call for getting back to your healthcare
	3	provider with a whole series of questions.  That's not
	4	unusual.  The specific ones, I believe, where I was

	5	focusing, was a woman who had just a birth, just had
	6	abortion, she was -- she has been speaking to a
	7	healthcare provider who she can go back to.  And that
	8	was point that I was making there.  Rather than --
	9	rather than having a large amount of additional text
10	in an insert, which I think we have to realistically
11	recognize, there's just so much that consumers are

12	going to read.
13		I'd say, or the contraction of the uterus
14	and so forth following birth, she's just had a birth,
15	she can talk to her physician about it.  I think those
16	issues are more appropriate to go back to the
17	physician rather than trying to do an all encompassing
18	explanation of the female physiology hoping that we're
19	going to cover that particular person.
20		DR. GILLIAM:  Okay.  Thank you.
21		DR. CANTILENA:  Yes, Dr. Lerner?
22		DR. LERNER:  Everybody keeps referring to
23	the problems with removal.  Do you have any data over
24	the course of the 12 years that it was on the market,
25	what percent of women had trouble removing, what

			84
	1	percent were then sort of fixed by the telephone call,
	2	and then how many of those really needed to go see
	3	their physician?  Because I think that's -- has very

	4	important clinical implications if ten percent of the
	5	women called but, you know, 197 percent of those
	6	couldn't be talked through it by your 800 number and
	7	then had to go to their physicians.  Do you have any
	8	data on that?
	9	            DR. STAAB:  Well, you're talking about

10	several, and I don't have the numbers in front of me,
11	you're talking about several thousand complaints with
12	a quarter billion units sold.  So the percentages are
13	extremely low and of those that went to see a
14	physician, it is having -- it is relatively low as a
15	complaint but having said that, it is the number one
16	consumer complaint with the Today Sponge, first time 
17	users, a lot like a diaphragm, someone who's inserting
18	a diaphragm do have a certain amount of difficulty
19	with this but the 800 number has been able to minimize
20	the number of people.  Once you get to the 800 number
21	it's already a complaint.  So even if you help them
22	with it, they're recorded as a consumer who made a
23	complaint on the issue.
24	            DR. LERNER:  Just as a follow-up, I think
25	it would be interesting, I don't know that I saw it in

			85
	1	any of the background material, just the registry of
	2	the complaints and, you know, I think that would just
	3	be interesting information to have available.
	4	            DR. STAAB:  That information -- that

	5	information is available, is recorded.  And we do
	6	report on that by the way on an annual basis.  That's
	7	what I was saying.  When we have the -- the reason
	8	that we know that it is the number one complaint
	9	because we do record that through our 800 numbers or
10	if people happen to write and we put that information
11	in a tabulated format for review by the agency each
12	year.

13	            DR. LERNER:  I suppose in some ways I have
14	a vested interest in that as a very clinically
15	oriented OB/GYN, I want to make sure that if I have,
16	you know, a thousands patients using, I'm not going to
17	have 500 walk-ins per week.  And I think that we as

18	the, you know, healthcare providers are going to be
19	very interested in finding out that your numbers that
20	occur.
21	            DR. STAAB:  I thought maybe Dr. Connell,
22	who's got a lot of OB/GYN experience as opposed to
23	this poor lonely toxicologist might have a comment
24	about this.  Thank you.
25	            DR. CONNELL:  I think it was difficult as

			86
	1	you might imagine to come up with an absolute figure. 
	2	What we have is basically what has just been stated,
	3	that of all the complaints, and, you know, this is not

	4	evidence-based medicine really.  Of all the ones, and
	5	I used to keep track of what the calls were to the 800
	6	number back in the VLI days, and certainly this was
	7	the number one problem, as you reasonably knew you
	8	could talk most women through the removal process.
	9	            But I don't recall that anybody has ever
10	been to deal with the two million women and come up
11	with a figure of the various complications, then a
12	subset of removal problems.  It's one of those things
13	you'd like to be able to quantify, but I don't think
14	it's true.  I think you have to be a little bit global
15	in terms of the side-effects and the percentage of
16	those that are removal related.
17	            So I -- it's a good question but I'm not
18	sure the data are out that that you can do anything
19	other than say, side-effects are not common but of the
20	ones that have been problems in the past, removal
21	problems rank right up front.  That's the reason that
22	the loop was changed because in the very beginning
23	this polyester thing, women couldn't feel it.  And if
24	you can't feel it, you know, this was a real problem. 
25	But once it was changed to a braided loop, then again

				87
	1	the problems got less because they could find it and
	2	it was much easier to take it out.
	3		So numbers would be lovely but I don't

	4	think you're going find an accurate number with the
	5	scientific credibility that you might like.  I think
	6	we still have to go sort of globally.
	7		DR. CANTILENA:  Okay.  Dr. Uden?
	8		DR. UDEN:  Dr. Staab, if you could clarify
	9	some confusion for me.  Dr. Greenslade presented quite
10	of bit of good information in terms of labeling,
11	suggest that wording changes in terms of time per
12	year.  He didn't finish his presentation and he also
13	had quite a few additional charts back there that
14	were, I think are very interesting and can be a lot of
15	information.  In your comments, you wanted to be
16	brief.  The labeling to be as brief as it can be. 
17	What is your stand on Dr. Greenslade's suggestions in
18	terms of those additional tables that are there?  What
19	do you want included?  What didn't you want included
20	with that?
21		DR. STAAB:  I think Forrest will address
22	that.
23		You're referring to the tables in his
24	handout as opposed to the contraceptives.  Okay.
25		DR. GREENSLADE:  I was not suggesting that

			88
	1	the last set of tables that I handed out should be in
	2	labeling.  What I handed them out for was to simply to
	3	provide background that in addition to making a
	4	decision upon comparative effectiveness, women have a
	5	lot of other things to think about.  And it is
	6	virtually impossible to provide all of the different
	7	pieces of information about all of the different
	8	methods in one place.  But I thought for you on the
	9	panel, it would be useful just to have that insight as
10	perspective to look at the comparative effectiveness

11	numbers.  And they are basically my interpretation of
12	a lot of reading over a lot of years about a lot of
13	technologies.
14	            DR. CANTILENA:  Dr. Johnson?
15	            DR. JOHNSON:  I have two questions.  One
16	is for Ms. Delaney, so she can move to the podium
17	while I'm asking my first question.  And my first
18	question may be really belongs with the FDA.  In our
19	packet, we have this, I think, proposed label and it
20	has to do with the efficacy.  And it just says, no
21	birth control product can prevent pregnancy all the
22	time.  See table of pregnancy rate.  So, I'm a little
23	confused because that doesn't tell you anything about
24	the efficacy except that it's not a hundred percent. 
25	            And, again, maybe this question really

			89
	1	goes to the FDA, this issue of one out of ten over a
	2	period of a year, are you proposing that goes in the
	3	package insert inside or on the outside box?
	4	            DR. STAAB:  All right.  Historically, the
	5	efficacy data has been in the insert with the product. 
	6	We take no great exception to putting a single
	7	statement about the efficacy for the Today Sponge as
	8	part of Drug Facts labeling as long as some of the
	9	other information is compressed so that, I mean as it
10	is now, we'd have to go one and three quarters way
11	around the box with Drug Facts Labeling.
12	            We're just saying there's a certain amount
13	of critical information that we should have on the
14	outside of the box.  The reference that you're
15	referring to refers to the table that Forrest had
16	spoken about that was developed for technical people

17	in contraceptive technology which was fraught with
18	difficulties -- with some technical difficulties and
19	certainly readability.  If you talk about sixth grade
20	reading level or something, that table -- a consumer
21	will not walk away from that table and understand what
22	they need to know about relative rates of
23	contraception.
24	            For my perspective, if there was a
25	simplistic statement, verbal or numerical similar to

					90
	1	what, what I'll call the combined Forrest Greenslade
	2	and FDA comment, where the various methods are
	3	compared and that was scientifically accurate backed

	4	up.  And we would take no exception to putting that
	5	into the insert.
	6		DR. JOHNSON:  Okay.  My question for Ms.
	7	Delaney is just about toxic shock in general.  In the
	8	materials that we received, I think, from your
	9	laboratory are some data, I believe from the CDC, with
10	definite and probable cases of toxic shock with a peak
11	in 1980 of 892, down to 4 in 11 in `96 and `97.
12		My first question, is this the number of
13	cases total in  the U.S. or is this per --
14		MS. DELANEY:  I'm not -- which -- I'm
15	confused as what to your --
16		DR. JOHNSON:  This was, I believe, part of
17	Dr. Onderdonk's materials.
18		MS. DELANEY:  Oh, okay.
19		DR. JOHNSON:  Right.  And -- so one of  my
20	questions is are these absolute numbers?
21		DR. STAAB:  I can tell you the source of
22	that.  I'm sorry.
23		MS. DELANEY:  Okay.
24		DR. STAAB:  I made that available to Andy
25	Onderdonk, that is from the Center of Disease Control,

					91
	1	an `87 summary of the total number of reported cases
	2	of Toxic Shock Syndrome.
	3		DR. JOHNSON:  Okay.
	4		DR. STAAB:  A total number reported in the
	5	U.S. to the Center for Disease Control.
	6		DR. JOHNSON:  So there were four reported
	7	to the CDC in 1996, for example?
	8		DR. STAAB:  I don't have the table.
	9		DR. JOHNSON:  Well, that's what, I mean

10	that's what the table says.  So, my question, which
11	hopefully you can answer, is what is the explanation
12	for this very, very dramatic drop in the incidents of
13	TSS over 15 years or so.
14		MS. DELANEY:  Are you referring to the
15	menstrual.  The drop in the menstrual TSS.
16		DR. JOHNSON:  Well, either one.  If you
17	look at menstrual or total, they've both dropped from,
18	you know, near the 1,000 mark to down to like ten.
19		MS. DELANEY:  The menstrual TSS cases have
20	dropped because of the removing of the Rely Tampon
21	from the market, consumer has been advised to
22	alternate between pads and tampons, to use the tampons
23	that are most, the less absorbent that conforms to
24	their needs.
25		The cases of non-menstrual TSS cases, the

					92
	1	increase they believe because a majority are due to
	2	cutaneous wounds, surgical wounds, they think it's
	3	because of the new healthcare rules where people are
	4	not hospitalized as long.  A lot of the outpatient
	5	surgeries, they think that that's why those cases are
	6	increasing.
	7		DR. JOHNSON:  Yes, I guess from this table
	8	I don't see an increase.  I mean, it looks like -- it
	9	looks like everything is decreasing whether you look
10	at total.
11		MS. DELANEY:  I think the total cases are

12	decreasing but the percentage of menstrual -- what my
13	data was showing that the menstrual and non-menstrual
14	are now becoming close to 50 percent each as opposed
15	to before where it was 80 percent and 20 percent.
16		DR. JOHNSON:  Okay. So, I guess your
17	answer is that they main reason that it's -- the TSS
18	has dropped nationwide is because of more appropriate
19	use of tampons.
20		MS. DELANEY:  Exactly.
21		DR. CANTILENA:  Okay.  Dr. Davidson?
22		DR. DAVIDSON:  You know, most of us here
23	have lived, you know, in the U.S., there's a
24	percentage that are not, you know, full literate, 47
25	percent or so may not understand clearly what the

				93
	1	label is.  Did you do any field testing on your label
	2	to see the comprehension from the general public?

	3		DR. STAAB:  Since we had acquired the
	4	label, we were going to retain the label that had been
	5	approved by the FDA.  We did not do any additional
	6	comprehension or readability on that label.  Okay.
	7		DR. CANTILENA:  Other questions?  Yes, Dr.
	8	Krenzelok?
	9		DR. KRENZELOK:  If you'll bear with me, I
10	have a few questions and a couple of comments.  I'll
11	address the last one in just a moment.
12		You're going to have an 800 number or
13	there was an 800.  And it would appear that removal
14	problems can be a 24 hour a day, seven day a week
15	problem.  It's not a nine to five problem.  Will you
16	have this 800 line available for women, 24 hours a
17	day, seven days a week so that you can attend to those
18	needs no matter what time zone they're in or what
19	their particular predicament might be?
20		DR. STAAB:  We are setting up an 800 -- we
21	have the 800 number is place right now.  We are
22	setting up with a beeper system.  It is not set up
23	right now, but yes, it is our intention to answer
24	questions, urgent questions, to have a triage system
25	within the phone system so that if they're worried

					94
	1	because they bought three sponges and there's only two
	2	in the box, we don't want to handle that at three
	3	o'clock in the morning.  But urgent questions we would
	4	have an opportunity to beep the healthcare
	5	professional.
	6		DR. KRENZELOK:  Now, you also mentioned
	7	that you didn't want to make the package basically a
	8	compendium of every piece of information.
	9		DR. STAAB:  Right.
10		DR. KRENZELOK:  And, as I recall, the
11	product, it comes in a small box.
12		DR. STAAB:  Gene, do you have one you can
13	hold up?  Just, it's outside, sorry.
14		DR. KRENZELOK:  But it is, I recall --
15	there's one, I see.  Okay.  So, there's a box.
16		DR. STAAB:  There's a three pack.
17		DR. KRENZELOK:  Now, we're you intending

18	to have one package insert in there or would you have
19	a  package insert with each sponge?  Because the
20	package inserts would certainly have an opportunity to
21	get lost as people put these in their purse, in a
22	briefcase, in a suitcase.  Would that be an intention
23	of yours?
24		DR. STAAB:  It would not be out intention
25	to put an insert with each unit, rather one per

				95
	1	carton.  That's been historically the way that's been
	2	handled.
	3		DR. KRENZELOK:  Well, given the use
	4	pattern of this particular type of product, it seems

	5	to me that might be a reasonable thing to do.  Now,
	6	Dr. Greenslade talked about a variety of ways to
	7	present the data in terms of pregnancy and I agree
	8	this should be very consumer friendly.  Peoples should
	9	look at that and say, these are my odds of getting
10	pregnant.
11		One of the things you might want to
12	consider changing would be in each of those things you
13	had a different denominator, so it was --
14		DR. STAAB:  One out of ten.
15		DR. KRENZELOK:Yes.  One out of ten, one
16	out of a hundred, five out of a thousand, and it might
17	be good to bring those all to common denominator so
18	that people can really understand them.
19		DR. STAAB:  Forrest will comment on that
20	but that's a good comment.
21		DR. GREENSLADE:  Yes, I wrestled back and
22	forth with that for many years.  If you make it a
23	common denominator, say a hundred, then you're talking
24	about a tenth of a woman sometimes.  And that's kind
25	of confusing when you talk to people and say, well,

			96
	1	what does this mean.  If you set it up to a thousand
	2	women or 10,000 women, then the -- then the numbers

	3	are looking kind of large.  And one of the things I
	4	wouldn't want to do is frighten people from
	5	considering a very effective safe option that she
	6	could choose.
	7	            And so I agree, this is a way that you
	8	kind of flip a coin and say, what communicates the
	9	best for most women.  And whether you set it all at

10	one denominator and wrestle with the numerators or the
11	reverse is probably something that we have to talk,
12	you know, in focus group with real potential consumers
13	and get a sense what communicates best to them.
14	            This was the compromise that I came up
15	with talking to a few people over the years.  But I'm
16	not an expert in focus group interviewing.  It's a
17	very good point.
18	            DR. KRENZELOK:  Thank you.  As it relates
19	to probably the issue of literacy, I think was Ms.
20	Antoniotti, discussed unintended pregnancies.  And I
21	was wondering if there's any kind of data that have
22	been collected showing a relationship between
23	unintended pregnancies and low literacy women, for

24	example?  To see if -- what I'm getting to here in
25	just a moment is something to do with the label in

				97
	1	terms of literacy but I'm looking the population that
	2	uses these is literacy an issue?
	3		DR. STAAB:  There -- there may very well

	4	be some information.  Do you have something you could
	5	add on that, Roberta?
	6		MS. ANTONIOTTI:  Part of the -- part of
	7	the information that the Institute of Medicine looked
	8	at in terms of the Best Intentions research was
	9	literacy levels, cultural norms, just experience with
10	reproductive health issues in terms of background.
11		So, part of the things that we look at in
12	our clinical practice in dealing with a lot of low
13	income men and women who are disadvantaged in terms of
14	educational opportunities as well as a number of
15	immigrants.  I agree with Dr. Davidson that some of
16	the issues in terms of language barriers and literacy
17	levels, that's why we liked in the label the whole
18	graphic display because at least from that perspective
19	any woman can have an understanding or she has a
20	minimal knowledge of her body, how to use the product.
21		But I think Best Intentions is probably
22	one of the best resources to take a look at how
23	literacy impacts a woman's ability to get access to
24	healthcare.
25		DR. KRENZELOK:  Thank you.

			98
	1	            DR. STAAB:  I was just going to say, I
	2	think you're see with tampons, the industry that I've
	3	worked and with the sponges, a liberal use of those
	4	graphics for that very reason.
	5	            DR. GREENSLADE:  Dr. Trussell and his
	6	colleagues published a relatively recent paper where
	7	they used survey data and stratified it according to
	8	a whole bunch of different strata and one that they
	9	did was socioeconomic level.  And across all methods,

10	the lowest the socioeconomic level, the higher was the
11	pregnancy rate or the higher was the failure rate.  So
12	I suspect there's some sequelae point that you're
13	making that people of lower socioeconomic status have
14	a lessor access to the information and to the way of
15	assimilating the information.  So finding ways of
16	getting it to a simple communicative level is very,
17	very important.
18	            DR. KRENZELOK:  Thank you.  Along those
19	lines of communication, I don't purport to be a
20	readability or label expert by any means.  But I took
21	the liberty yesterday of just typing in parts of the
22	label to Microsoft Word 2000 and running a Flesch
23	Readability Score on it.  And for those of you who are
24	unfamiliar with Flesch, as I was until yesterday --
25	            DR. GREENSLADE:  So you are a world

			99
	1	expert.
	2	            DR. KRENZELOK:  Exactly.  I'll acknowledge

	3	that immediately.  But they have two different scores. 
	4	So all you have to do is you do basically spelling and
	5	grammar and then look at the options and it gives you
	6	this readability score.  So they have a readability
	7	score basically and it's based on a 100 point scale. 
	8	And the higher the number, the more easily
	9	comprehendible the label is or the paragraph or
10	whatever it is you're looking at is.  And it said that
11	most standard documents aim for a score of
12	approximately 60 to 70.
13	            Then they have something called the Flesh
14	Kincaid Grade Level Score, where they have a very
15	complex formula, basically it says that a score of
16	eight means that and eighth grader can read this.  And
17	it says again that most standard documents aim for a

18	score of approximately seven to eight.  So, if you
19	bear with me for just a minute, I took two parts of
20	the label, of the prosed 2000 label.
21	            DR. STAAB:  Of the current label?
22	            DR. KRENZELOK:  Of the 2000 proposed label
23	in our package.  Yes, the 2000 one.  And there was one
24	where it descried toxic shock which I thought was

25	important for people to understand.  And it said,

				100
	1	Toxic Shock Syndrome, some cases of Toxic Shock
	2	Syndrome, TSS, have been reported in women using
	3	barrier contraceptives including the sponge.  TSS is
	4	a rare but serious disease that may cause death. 
	5	Warning signs of TSS include fever, nausea, vomiting,
	6	diarrhea, muscle pain, dizziness, faintness or a
	7	sunburn-like rash on the face or body.
	8		If you have any of these signs, remove the
	9	sponge and get medical help right away.  Now the

10	reading ease score on that was 58.1 percent.  So it
11	was a little bit less than what the ideal document
12	should be.  The grade level was 9.4.  Now that's in
13	contrast to the very first part of the instructions
14	were -- it illustrates how to insert the sponge but
15	also describes how to insert the sponge.
16		And it says, Today vaginal contraceptive
17	sponge is inserted through the vaginal opening and
18	placed in the deepest part of the vagina just below
19	the cervix.  The cervix is the bottom end of the
20	uterus.  It has a small opening through which sperm
21	must travel to reach and fertilize the egg.  The
22	reading ease on that was 52 percent but the grade

23	level was	11.9.  So we're talking about a high school
24	senior being able to comprehend that.
25		So, again, those are two very isolated

			101
	1	aspects of the proposed label but it seems to me that
	2	we have a population that, as I've heard, is at least

	3	20 percent low literacy or illiterate.  And it seems
	4	like that's a group that perhaps the label should be
	5	downgraded to address more advantageously.
	6	            DR. STAAB:  I think it calls for a
	7	simplification also.  The more we get into medical

	8	explanations of various issues, the more it's going to
	9	make it more complex rather than simplified.  We go
10	around the world, we see some very simple labels that
11	don't get into all of the communications here.  And I
12	think it's hard to take that comment without putting
13	in the graphics that associate it.  I'm sure the
14	graphics aren't able to be reviewed through the
15	software problem you're referring to.
16	            So it's a difficult area when you work
17	with women's healthcare from the tampon experience and
18	from the contraceptive experience, communication is
19	not an easy area.  And when you change something,
20	which is one of the reason I really wanted to keep a
21	label that people were somewhat -- at least the users
22	were somewhat familiar with.
23	            When you change something, you really have
24	a risk of mis-communicating in some other place in the
25	label or in that particular area.

			102
	1	            But it is not an area that we can ignore
	2	and it isn't an area that we shouldn't consider making
	3	it as readable and simple as we can.  I -- I
	4	completely support your comment.  Make it readable.

	5	            DR. CANTILENA:  Okay.  I just -- I just
	6	have one question, if I may.  When you refer to your
	7	surveillance system and your 800 number, who is
	8	actually going to be answering the 800.  What are
	9	their qualifications and how does that information
10	then get handed off, if you will, to the people who
11	are going to be tracking the adverse events?

12	            DR. STAAB:  Okay.  Good question. 
13	Currently, we've got one LPN who's worked for about 15
14	years in an OB/GYN office and we also have a nurse
15	practitioner, I believe she has a Masters who's
16	currently working at a University and at an OB/GYN
17	clinic at a local hospital.
18	            Neither of those people are contract with
19	us but those of the people that we are interested in
20	right in bring on board to start this program.  They
21	would not only take that information but they would
22	more than likely, at this point, being a small company
23	would also probably record the information that would
24	be the basis of the annual report down the road for

25	all these events.

			103
	1	            For right now, it would be an LPN and a
	2	Masters in Nursing with a license, I guess license
	3	practical nurse would be her title.  No, I'm sorry, a
	4	nurse practitioner.
	5	            DR. CANTILENA:  Okay.  So, if it's the
	6	weekend when the LPN is on, I guess, are you
	7	comfortable with, you know, medical triage?  When if
	8	somebody calls in then they've had a hard, they've
	9	been unable to remove the sponge for five days,
10	they've tried and failed and now they may have some

11	symptoms.  As the sponsor, as the manufacturer, are
12	you comfortable with that level of expertise handling,
13	you know, triage and are there, you know, systems that
14	you plan on having to help that individual?
15	            DR. STAAB:  That's a good question.  There
16	are -- there's a guidance document that was put
17	together by American Home Products originally for what 
18	they -- we call the help line, the consumer help line. 
19	The guidance document is pretty clear as to where you
20	start and where you stop as far as giving advice goes. 
21	And there is a point where it says, see your
22	physician, get to a clinic, get to an emergency room
23	or something of that nature.
24	            The people that we're choosing are -- are
25	very mature and capable of following that information

				104
	1	and quite frankly they have a very good understanding
	2	of the women's healthcare issues.  So, I would say,

	3	yes, we are confident.  But I will also say with a
	4	caveat that we're going to learn over the next months
	5	and years about what else we need.  And we're open to
	6	fore find that is, as we need to.
	7		DR. LERNER:  Just a piece of advice.  I
	8	think they should be bilingual in Spanish as well.
	9		DR. STAAB:  The original -- what should be
10	bilingual?
11		DR. LERNER:  The help line people.  The
12	800 help line.
13		DR. STAAB:  We should have access to it. 
14	Okay.  Currently, what American Home Products had done
15	is they have access to the instructions in Spanish. 
16	If someone would need it, they would make them
17	available to them.  It was not put bilingually in each
18	package.  Okay.
19		As far as the help line goes, we haven't
20	addressed that issue.  But I think it makes sense. 
21	It's a reasonable request and I think that especially
22	today and especially considering some of the inner
23	city questions that might come up, I think it's a
24	reasonable request.
25		You bet.  Absolutely.  Absolutely.

				105
	1		DR. CANTILENA:  Yes, Dr. Gilliam?
	2		DR. GILLIAM:  I guess just to follow up on

	3	that.  Are you going to do any different packaging for 
	4	different areas of the country where you do have a
	5	more -- a higher Hispanic population?  The Southwest,
	6	that kind of thing?
	7		MR. DETROYER:  The way today's -- the way
	8	the distribution system is set up in the United States
	9	today with supermarkets, drug chains and mass

10	merchants, it is very difficult to control where
11	product goes.
12		Right now our plan is English product,
13	let's say going into Walmart, who spreads it all over
14	the country.  You don't have any control that this can
15	be Spanish product here and this can be English
16	product here.
17		But like American Home Products we will

18	provide Spanish literature, if it's necessary, for a
19	client and certainly for the clinic side of the
20	business that's very easy to provide.
21		DR. CANTILENA:  Okay.  Any further
22	questions?  Very good.  I guess without strong
23	objection will move to a 15 minute break and promptly
24	return in	15.
25		    (GROUP TAKES RECESS)

				106
	1		DR. CANTILENA:  It may not sound like it
	2	but I think we're ready.  We're now at the portion of

	3	the agenda where we're going to hear the presentation
	4	from the Food and Drug Administration.  And I believe
	5	in fairness Dr. Titus has allotted 45 minutes for the
	6	-- for the FDA.
	7		First presenter is Dr. Chin.
	8		DR. CHIN:  Good afternoon.  We have now
	9	come to the eagerly awaited FDA presentation for the
10	afternoon which will be presented by myself, Claudia
11	Karwoski, who will take about post-marketing adverse
12	events and Gloria Chang, who will address the label
13	changes that have been recommended.
14		Sorry.
15		I will provide a review of the
16	administrative record for the Today vaginal
17	contraceptive sponge over the last 20 years.
18		First, I will briefly run through some
19	administrative milestones for the NDA, some
20	information about the sponge itself and then focus on
21	labeling issues that brought about much discussion
22	between the agency and various sponsors over time.
23		The FDA for the Today Sponge was first
24	submitted in September of 1991 by VLI.  It was

25	withdrawn in December because of inadequate U.S.

			107
	1	experience.  It was resubmitted and finally approved
	2	in April of 1983 and was marketed by VLI from 1983 to
	3	1987.  The NDA was transferred to Whitehall in
	4	December of 1987 and Whitehall marketed the product

	5	until 1993 when it suspended, then ceased production
	6	due to manufacturing issues.
	7	            In January of 1995, Whitehall voluntarily
	8	withdrew the sponge from the market.  And I just want
	9	to take a second here to emphasize that the NDA is

10	currently an approved NDA and was never withdrawn. 
11	The product, itself, was voluntarily withdrawn from
12	the marketplace by the sponsor.
13	            And, finally, in March of 1999, the
14	transfer of the NDA went from Whitehall to Allendale
15	Pharmaceuticals.

16	            The Today Sponge was first approved by the
17	Division of Metabolic and Endocrine Drug Products in
18	1983.  (Inaudible), FDA administrative side and the
19	Division of Reproductive and Urologic Drug Products
20	was newly formed in June of 1996 and assumed
21	administrative responsibility for the sponge NDA.
22	            With the Division of OTC Drug Products
23	taking over administrative responsibilities for all
24	OTC drugs, the  NDA was finally transferred over to us
25	in November of 1997.

				108
	1		Just one slide on sponge characteristics. 
	2	The sponge is round and very soft, made of 70 percent

	3	polyurethane and 30 percent Nonoxynol-9.  The sponge
	4	contains a total of a thousand milligrams of N-9.  A
	5	loop was added for easier retrieval and later on a
	6	polyester skrim was inserted to reinforce the loop
	7	because of tearing at the time of removal.
	8		In terms of how much N-9 is released. 
	9	Spermicide release studies were done and concluded
10	that an overall mean of 124 milligrams of N-9 eluted
11	from the sponge with wear time up to 48 hours.
12		I'm sorry.

13		Okay.  The rest of these slides are going
14	to cover the key discussions about information that
15	should be provided in the labeling between the agency
16	and the sponsors throughout the development of the
17	Today Sponge.  Some of these reflect internal
18	discussions.  Others were written communications
19	between the agency and the sponsor.  Because of the
20	passage of time, it was difficult to construct exactly
21	when certain labeling changes were fully implemented.
22		At first approval in April of 1983, the
23	following labeling stipulations were conveyed in the
24	approval letter to the sponsor.  Effectiveness was

25	summarized as 12 months pregnancy rates per hundred

				109
	1	women.  Rates were provided for different methods, the
	2	sponge, the diaphragm and the foam suppository with
	3	some differences noted between U.S. and international
	4	studies.
	5		Effectiveness for the sponge at that time
	6	was considered to be in the same range as other
	7	vaginal birth control methods such as the diaphragm.
	8		These two statements were also to be
	9	included in the labeling, that there was no evidence

10	of significant health risk associated with the use of
11	the product and that used during menstrual period was
12	not recommended.
13		Whitehall followed up with a labeling
14	supplement and FDA responded with the following
15	recommendations in December of 1983.
16		Pregnancy rates were now stated as rates
17	per hundred women for the sponge only.  And a

18	distinction was made between method and use
19	effectiveness.  Simply stated method effectiveness
20	meant that consumers following instructions exactly
21	and use the sponge each time that it's needed.  Use
22	effectiveness meant that consumers may fail to use
23	correctly or to not use the sponge every time. 

24	Exiting labeling bears these pregnancy rates.
25		Other recommendations were that there

			110
	1	should be a statement that the sponge was not as
	2	effective as the pill or the IUD.  There should not be
	3	a reference of similarity to the diaphragm.  And it
	4	should not be used during menses.
	5	            Within the first year of approval, the
	6	agency was reviewing adverse events that were
	7	received, especially the reports of more severe
	8	illnesses and a latch cases of TSS, Toxic Shock
	9	Syndrome.
10	            The conclusions reached at a joint meeting
11	with the sponsor and investigators from CDC and FDA
12	staff were that severe illnesses may possibly be
13	associated with removal problems and fragmentation of
14	the sponge and post-partum use of the sponge. 
15	Additional warning were considered at that time that
16	the sponge should not be used post-partum and to
17	consult a physician for removal if there's
18	fragmentation.
19	            As a result of a further meeting with the
20	sponsor in 1984, FDA issued this letter of -- this
21	letter with  modifications to the labeling so that it
22	should say, that -- to limit sponge use to 30 hours,
23	to delete the phrase about no significant health risk

24	and to state the association of TSS and sponge use in
25	non-menstruating women.

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	1	            Other labeling developments.  In an annual
	2	report in 1987, VLI wanted to modify the instructions
	3	to wet and squeeze the sponge before use.  And FDA

	4	found that acceptable but to quantify it a little
	5	further to wet thoroughly and squeeze gently.
	6	            Other labeling discussed were submitted
	7	and approved in August of 1990.  Receipt of the final
	8	product label, the FPL, occurred in August of 1991,
	9	which was accepted.  This final product label is the
10	one that has been in use ever since.
11	            So, the Today Sponge has not been marketed
12	since it was voluntarily withdrawn by Whitehall in
13	1995.  It is not currently available except for the
14	diminishing stock pile -- except for the diminishing
15	supply stock piled by Elaine in ASeinfeld@.  Okay,
16	I'll restrain myself to then -- for now.  Let's go
17	back.
18	            The re-marketing of the Today Sponge was
19	initiated in March of 1999 with a transfer of
20	ownership of the NDA to Allendale.  This re-marketing
21	required that Allendale submit a chemistry supplement
22	because of a new manufacturing sight.  As part of this
23	process, OTC undertook a review of the safety update
24	as well as the existing labeling, which brings us next
25	to a review of the post-marketing adverse events by

				112
	1	Claudia Karwoski.
	2		Thank you for your attention.
	3		DR. KARWOSKI:  Good afternoon.  My name is
	4	Claudia Karwoski and I'm from the Division of Drug
	5	Risk Evaluation in the office of Post Marketing Drug
	6	Risk Assessment.
	7		The objectives of my presentation are to
	8	provide an overview of the post-marketing adverse
	9	events reported with the Today Sponge.  To review the

10	post-marketing safety issues that have previously been
11	identified, such as Toxic Shock Syndrome and sponge
12	removal difficulty and to describe all serious cases,
13	to identify any unexpected safety issues that have not
14	previously been identified.
15		I'll begin my presentation with a
16	description of the FDA Reporting System and Toxic
17	Shock Syndrome.  I'll then provide an overview of the
18	adverse events reported with the sponge.  I'll
19	describe the TSS cases associated with the sponge and
20	then describe cases involving sponge removal
21	difficulty.  I'll then briefly describe any unexpected
22	potentially serious cases and lastly I'll end with my
23	conclusions.
24		Adverse event reports are submitted to the
25	FDA by healthcare professionals or consumers either

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	1	directly through the MedWatch program or indirectly
	2	through the manufacturer.  The data from these reports
	3	are entered into a computerized data base.  The
	4	agencies first data base was created in 1969 and it

	5	was called the Spontaneous Reporting System.  It was
	6	replaced in 1997 by the Adverse Event Reporting System
	7	or AERS.
	8	            The advantages of Spontaneous Reporting
	9	System such as SRS and AERS are that they are
10	relatively simple and inexpensive.  They enable us to
11	detect rare events early in the marketing of a
12	product.  They also have inherent limitations.  They
13	are passive and voluntary and rely on the healthcare
14	provider or consumer not only report the event but to
15	provide adequate clinical data to determine the
16	relationship between the adverse event and the
17	product.  Because its voluntary it is associated with
18	substantial and to reporting.  And we cannot use this
19	Spontaneous Reporting System to determine incident
20	rates of the particular events.
21	            We also encountered limitation specific to
22	this review.  All of the adverse event reports for the
23	sponge were entered into SRS, our old database, and
24	were coded using very broad terminology.  We had no
25	specific terms for TSS for sponge removal difficulties

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	1	so it was challenging retrieving these cases.  Each
	2	report only has four surgical terms as opposed to
	3	unlimited terms that are currently available in AERS. 
	4	And the criteria for flagging serious cases varied
	5	over time.
	6	            We also noted in our review that the
	7	documentation, follow-up and completeness of many of
	8	these reports seem to decline over the years.
	9	            The TSS case definition requires five
10	clinical criteria:  fever, hypotension, rash,

11	desquamation and abnormalities in three or more
12	organs.  Those organs include gastrointestinal tract,
13	renal, hepatic, hematologic, central nervous system,
14	the mucus membranes or there may be muscular
15	involvement.
16	            The Center for Disease Control considers
17	a definite case of TSS as one that fulfills all five 
18	criteria.  And a probable case fulfilling four of the
19	five criteria.  We also consider possible TSS cases as
20	those that fulfilled three of the five criteria and
21	those that only reported TSS regardless of the
22	criteria reported.
23	            As was previously described by Mary
24	Delaney, there are two types of Toxic Shock Syndrome. 
25	It's considered menstrual if the symptoms occur during

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	1	menses or even a few days after the end of menses. 
	2	Non-menstrual TSS includes all other causes including
	3	use of barrier contraceptives such as the diaphragm
	4	and sponge, surgical and cutaneous infections and has
	5	occurred in post-partum, post-abortions patients.
	6	            The overall incidents of non-menstrual TSS 
	7	is low and has remained relatively stable over the
	8	past decade.  Our database contains 5,930 reports with
	9	over 13,000 adverse events reported in association
10	with the sponge.  Each report may and often does

11	contain more than one event.  The time period for
12	these reports is from approval in 1983 to 1997.  The
13	patients range from 12 to 55 years of age and the
14	majority of the reports occurred in female patients. 
15	The report of serious outcomes include 168 patients
16	that required hospitalization, ten that reported a
17	life threatening event and two that reported
18	disability.  There were no deaths or congenital
19	anomalies reported.
20	            This graph shows the top ten adverse event
21	terms reported with the Today Sponge.  The red bars
22	represent the total count of each event and the green
23	bars represent those with a serious outcome reported. 
24	The term with the highest frequency is cervical
25	disorder with a count of 1,072.  This is followed by

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	1	vaginitis, unintended pregnancy, migration of implant,
	2	vaginal discharge, application sight reaction,
	3	pruritus, infection, menometorrhagia and unevaluable
	4	reaction.  The infection reports show a larger

	5	proportion with a serious outcome.  As will be
	6	discussed later, the cervical disorder and migration
	7	of implant appeared to be primarily reports involving
	8	sponge removal difficulty.
	9	            To identify cases of TSS, we searched our
10	database for all cases from 1983 to `97 with the
11	following adverse event terms:  infection, bacterial
12	infection, sepsis, acute circulatory failure and
13	hypotension.  We selected for review cases that met at
14	least three of the CDC criteria or those that reported
15	TSS.  These numbers may vary a little bit differently
16	than the information that was handed out about a month
17	ago.
18	            One hundred fifty-two cases of 305 that we
19	review met at least three criteria or reported TSS. 
20	The ages range from 16 to 42 years of age with a
21	median and mean age of 25 and 26 years.  One hundred
22	eighteen patients required hospitalization.  Twenty-
23	three reported the event as life threatening or the
24	patients were admitted to the ICU.  Twenty-three

25	patients did not require hospitalization but were

			117
	1	treated as outpatients with antibiotics.  And the
	2	outcome in 11 cases was not reported.
	3	            The time to onset of symptoms after the

	4	use of the sponge range from one to four days.  The
	5	total time in the vagina range from 1.5 hours to six
	6	days.  Twelve patients reported a vaginal time of
	7	greater than 30 hours.  TSS risk factors or possible
	8	risk factors were identified in approximately 20
	9	percent of the cases.  Seventeen reported symptoms
10	within three days of the beginning or end of menses
11	and six may have been using the sponge while
12	menstruating.  Sixteen were post-partum ranging from
13	four to sixteen weeks with six under six weeks post-

14	partum.  Twenty-three reported difficulty removing the
15	sponge and 12 required medical assistance to remove
16	the product.
17	            So of all the 152 cases, 25 met five
18	criteria and are considered definite, 27 met four
19	criteria and are considered probable and 100 met three
20	criteria or reported TSS and are considered possible
21	cases.
22	            This graph show the TSS cases by the year
23	of occurrence.  The red bars represent the total
24	number of TSS cases and the green bars represent the
25	probable or definite TSS cases.  1984 had the highest

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	1	number of TSS cases reported in association with the
	2	sponge.  There were 27.  It also had the highest
	3	proportion of cases that were considered probable or
	4	definite and this 74 percent.
	5	            From 1985 to 1994, the numbers of reported
	6	cases range from 17, I'm sorry, from 17 to 16 per year
	7	with an average of 12 cases per year.  The proportion
	8	of probable or definite cases during those years was
	9	38 percent or less.  This may represent either that

10	the reports lack the document symptoms because many of
11	the earlier cases were submitted along with the CDC
12	report form or they provided medical records in
13	addition to the report form.  It may also, however,
14	represent increased knowledge recognition of toxic
15	shock.
16	            I'm next going to talk about sponge
17	removal difficulty.  Most coded -- most were coded in
18	our database as cervical disorder and migration of
19	implant.  And this represented a little over 1,800
20	reports.  We chose a random sample of 10 percent of
21	these reports for review.  Of the 188 cases that we
22	reviewed, 187 reported inability or difficulty in
23	removing the sponge.  There was one report of
24	cervicitis.
25	            Of those cases that reported difficulty in

			119
	1	removing the sponge, 116 required assistance from a
	2	healthcare provider to remove this sponge.  Most of
	3	these, however, were earlier on and occurred -- seemed
	4	to occur between 1984 and 1991.  There were 12
	5	patients that were able to remove the sponge after
	6	instructions were provided by the 1-800 number.  The
	7	outcome of 59, however, were not reported.  The sponge
	8	insertion time was reported in 108 cases and range
	9	from 30 minutes to six days.  Thirty-five cases
10	reported an insertion time of greater than 30 hours. 
11	Some common events that may have been related to
12	sponge removal difficulties include infection, vaginal
13	bleeding, vaginitis, urinary tract infection and pain.
14	            Our review of the random sample of these
15	cases indicate that sponge removal difficulty
16	represents at least 13 percent of all of the adverse

17	events reported with the sponge.  In 62 percent of the
18	cases reviewed, medical assistance was required to
19	remove this sponge.  The outcome was unknown in almost
20	one-third of the cases reviewed which may suggest that
21	more aggressive follow-up by the sponsor is warranted.
22	            In 19 percent of all cases reviewed,
23	sponge removal difficulty resulted in vaginal exposure
24	of greater than the recommended 30 hours.  We reviewed
25	all reports that were flagged as serious to determine

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	1	if there were any adverse events that are unexpected
	2	or not previously known to be a safety issue.  The FDA
	3	defined serious as cases resulting in death,
	4	hospitalization, disability, those reported as life
	5	threatening or those resulting as a congenital
	6	anomaly.
	7	            We identified a total of 169 reports with
	8	a serious outcome.  One hundred eighteen of these were
	9	the TSS cases, 51 represented other serious events, 36
10	of the 51 were non-TSS infectious adverse events and
11	15 were non-infectious events.
12	            Of the non-TSS infectious events, the only
13	event that appeared to be unusual were two reports of
14	peritonitis.  The -- These provided various sketchy
15	information and both cases were reported by the same
16	physician.  The miscellaneous cases include
17	undiagnosed infections or reports of symptoms that may
18	have been suggestive of an infection.  The other
19	events did not appear to be unusual or large in number
20	for whom the product might be used for.
21	            Of the non-infectious events, there were
22	two sponge removal difficulty cases that were not
23	picked up during our random search.  In one case, the

24	patient underwent an exploratory laparotomy to have
25	the sponge removed.  There were two reports of

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	1	systemic allergic reactions requiring ER treatment and
	2	overnight stay for one patient in the hospital.  It's
	3	not clear if these were life threatening.
	4		So, in conclusion, the safety issues
	5	previously identified remain a concern.  TSS appears
	6	to be the most serious adverse event reported with the
	7	Today Sponge.  Sponge removal difficulty appears to be
	8	the most frequently reported event.  The other
	9	commonly occurring events such as vaginitis appear to
10	be minor, however, a comprehensive review was not
11	conducted.
12		Based on our review of all serious events,
13	there were no apparent additional or unexpected safety
14	issues not already identified.
15		Thank you.  Next, Gloria Chang will be
16	discussing labeling.
17		MS. CHANG:  Good afternoon.  Guess what? 

18	I'm the final speaker.  By the way, I want to thank
19	Daniel Keravitch for all his help in doing these
20	slides.
21		My presentation will be covering our
22	proposed labeling for the Today Sponge.  Put it down. 
23	Okay.  Basically, I'll start with an overview of the
24	new OTC labeling rules, then the original carton

25	labeling for the Today Sponge, proposed carton

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	1	labeling for the Today Sponge and the proposed changes
	2	to the package insert.
	3	            On March 17th, 1999, the agency published

	4	an OTC labeling requirements final rule, codified in
	5	21 CFR 201.66.  That rulemaking required standardized
	6	content and format for all OTC drug products in what
	7	they call drug facts format, format and content.  The
	8	agency believed that these labeling requirements would
	9	make it easier for the consumer to recognize where to
10	find the information and also would make the labels
11	more legible and readable.
12	            The drug facts labeling content
13	requirements required the following:  that all
14	information would be organized under title, headings
15	and subheadings; that all drug facts label information
16	must appear on the outside of the container or wrapper
17	of the retail package or on the immediate container if
18	there was no outside container or wrapper; and that
19	the headings and subheadings appear in a specific
20	order which would allow the consumers to more quickly
21	make a decision as to whether they should use the
22	product, when to stop using the product and how to use
23	the product.
24	            The standardized headings are in the
25	following order:  title, which is always titled drug

			123
	1	facts; the active ingredients or ingredient and the
	2	amount; the purpose; the use or uses; the warnings. 

	3	And under the warnings, there is a standardized order
	4	for the subheadings.  For example, do not use; stop
	5	use and ask a doctor if.
	6	            Next comes the directions.  After the
	7	directions, there is a heading titled other
	8	information.  This section includes information not
	9	included in the other sections, but for which the
10	agency feels is pertinent to the safe and/or effective
11	use of the product, or information that is required
12	under an OTC drug monograph.
13	            The last section is the questions or
14	comment sections which provide phone numbers for
15	consumer inquiries.
16	            The labeling rule requires standardized
17	formats so that there is consistency in the format for
18	all labeling.  For example, there are type size
19	specifications for the headings, subheadings and text. 
20	There are also bulleted format to improve readability.
21	            The agency considers the labeling for OTC
22	drug products, considers the carton, which consists of
23	the principal display panel and promotional labeling

24	and the required labeling, for example, the drug facts
25	label, as part of the labeling.  Also, the package

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	1	insert.  Dan.
	2	            I'm going to make some comments on the

	3	1991 labeling.  As you can see, this part is called
	4	the principal display panel, and Dan's going to focus
	5	on the -- this section is the approved label which
	6	contains the directions and warnings.  Basically, as
	7	you can see, the directions are in a paragraph format
	8	which we believe is difficult to read.  Also, the
	9	important information is not emphasized.  For example,
10	the toxic shock statement is not prominently
11	emphasized.  And as you can see, they are in two
12	separate sections, this section, and also the symptoms
13	are in this section right here.
14	            Further, there is no statement in the
15	labeling that addresses or informs consumers of the
16	serious nature or potential life threatening nature of
17	this, of toxic shock syndrome.  Just, I think that's
18	that for that.
19	            I just want to show you the other
20	information as far as the inactive and active
21	ingredients are on the other, the back panel.  Can you
22	go back?  Should I just click?  Great.
23	            We have revised the Today Sponge labeling
24	as follows.  Oh, I have, is that the, did I click? 

25	Oh, I'm sorry.  I'll start with this one.

			125
	1	            Thus, there are some reasons for the
	2	labeling revisions are to remove misleading statements
	3	such as reliable protection without serious risks of
	4	dangerous side effects, and extremely effective.
	5	            Other reasons for the revisions are the,
	6	to improve the order of information so there is more
	7	emphasis on the warnings, in particular, the toxic
	8	shock syndrome warning.  Also, to add additional
	9	important information such as AStop use and ask a

10	doctor if@ statements, and to improve directions and
11	other information for better understanding of the

12	safety concerns and other public health issues.
13	            We have revised the Today Sponge labeling
14	as follows.  First of all is its standardized order in
15	accordance with the drug facts format.  And this is a
16	copy -- Helen, did you show the, you showed the copy
17	of the original label.  We're going to break this down
18	to make it more readable for all of you.
19	            Please note that the revisions are in red
20	font, are the new additions to the label or statements
21	which we have either moved or revised from the
22	original labeling, and the statements in the black
23	font are the statements pulled from the former
24	labeling which may have reformatted into the new drug
25	facts label.

				126
	1		I will be discussing particular sections
	2	of our proposed drug facts labeling.  And this section
	3	is the warning section.  Significant revisions were

	4	made to this section.  First and foremost, the TSS
	5	warning is prominently displayed as the first specific
	6	warning.  We have added the statement TSS is a rare
	7	but serious disease that may cause death.  Additional
	8	revisions are what you can see on the slide.
	9		In addition, we've added the allergy alert
10	section to inform consumers that this product contains
11	a sulfite, and also that this product contains
12	nonoxynol-9.
13		We have also asked that the various
14	revisions in red to this section.
15		I want to focus in primarily on the Astop
16	use and ask a doctor if.@  This section was provided
17	to alert consumers so that they would know if certain
18	conditions would develop during sponge use.  Note that
19	this information was not in the 1999 final printed
20	label.
21		Under the directions, we have bulleted the
22	information to make it easier for the consumer to read
23	and added additional directions.  I lost my pointer. 
24	We've, we've, we've moved the statement Ado not leave
25	in vagina for longer than 30 hours@ from the warnings

				127
	1	into this section and bolded for emphasis.  Next.
	2		Under the other information heading, we

	3	added two new bulleted statements.  The first is to
	4	inform consumers of the availability of the pregnancy
	5	rates, birth method, birth control methods table in
	6	the package insert and to provide public health
	7	information statement of the use of latex condoms to
	8	reduce the risks of the transmission of HIV and STDs.
	9		Now, I'm going to go and discuss the
10	changes to the package insert.  Because of time

11	restraints, I will only be discussing some of the
12	major ones.  First would be to improve the
13	presentation of the efficacy data.
14		Second is to include the pregnancy rate
15	birth control methods comparative table in the package
16	insert.
17		Third, we added, just wanted to basically
18	tell you that we added some references to reducing the
19	risk of sexually transmitted diseases in the package
20	insert.  I lost the pointer.  Okay.
21		Fourth, we made format and minor editorial
22	changes to the package insert.  As you, as you can see
23	from the original efficacy data statement and efficacy
24	table, I think it is basically, thank you, I think

25	it's basically very confusing to a layperson.  In

			128
	1	fact, I sort of got confused by reading it also.
	2	            What we did was we basically revised and
	3	simplified the statements on the efficacy statement to

	4	make it more consumer friendly, and I believe someone
	5	already discussed the revised statement.
	6	            I'll talk a little bit about the pregnancy
	7	rate table.  Back in 1997, the Center for Devices and
	8	Radiological Health in collaboration with CDRH, which
	9	is the Center for Drug Evaluation and Research, and
10	the Office of Women's Health adapted the pregnancy

11	rate table from Trussell's Contraceptive Technology
12	basically to, to provide the consumers with
13	information to make the informed, to -- let me start
14	over.  To provide consumers with information to make
15	informed choices as to the best birth control method
16	for them.  At present, the table is included with all
17	prescription oral contraceptives and is a regulatory
18	guidance for other CDRH and CDER birth control
19	products.
20	            In -- these are my conclusions.  Current
21	labeling can be improved.  The drug facts format
22	places emphasis on the warnings, such as the TSS
23	warning and the Astop use and ask a doctor if@ are

24	examples of that.  And provides more readable and
25	informative information to the consumer to improve the

				129
	1	safe and effective use of the Today Sponge.  Thank you
	2	very much.
	3		DR. CANTILENA:  Okay.  Thank you very much
	4	for actually staying ahead of schedule.
	5		MS. CHANG:  And I wanted to -- right.  I
	6	was going to turn the podium over to Dr. Cantilena for
	7	questions and comments.
	8		DR. CANTILENA:  I'm sorry.  I beat you to
	9	the punch.  I apologize.  Yes, actually, we are at the
10	point now where we have some time to ask the FDA
11	presenters specific questions that you may have.  So

12	let me open it up to the, to the committee.  Dr. Uden?
13		DR. UDEN:  We've had toxic shock syndrome
14	data presented a few times here today.  You have a
15	database here at the FDA.  There's also a database at
16	the CDC.  How many other places is, is the data, data
17	kept and has anybody compiled the data in one place so
18	that we can get a relatively good estimate of the
19	risk?
20		DR. KARWOSKI:  Well, I actually don't have
21	the answers for that.  Not that I'm aware of.  I would
22	imagine that CDC probably has the best numbers.  Ours
23	is a voluntary and a passive surveillance, and so we
24	only rely on consumers or health care providers to

25	report that information to us.

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	1		DR. UDEN:  Are those the two major sources
	2	of, other than primary literature, finding the
	3	incidence of toxic shock syndrome?
	4		DR. CHIN:  Let me clarify that a little
	5	bit more.  What we have in our database that was
	6	presented by Claudia is information that was
	7	voluntarily submitted or regulatorily (sic) required
	8	to be submitted to the FDA's spontaneous reporting
	9	system or the current AER as database.
10		What CDC has is TSS is a reportable
11	disease, and so it has to be reported to CDC.  And

12	they compile the statistics that you would see for a
13	lot of infectious disease.  The difference in the
14	database is that what we have in terms of the adverse
15	events, it would be adverse events that were reported
16	in conjunction with the use of a sponge.  It doesn't
17	mean that it causes the adverse event, but it was in
18	conjunction with the use.
19		What CDC's information has is the number
20	of TSS cases, but doesn't necessarily break it down
21	into what was used in association with the case
22	itself.  So they're really separate types of numbers. 
23		DR. CANTILENA:  Other questions?  Yes, Dr.
24	Davidson?  Your microphone?
25		DR. DAVIDSON:  Thank you, forgot.  I have

			131
	1	a couple, you know.  You reported cases of disability,
	2	but you didn't say what type of disability they were. 

	3	Could you tell us what disability meant in the cases?
	4	            DR. KARWOSKI:  The outcomes are very
	5	subjective.  That really depends on what the
	6	individual that reported the event may have thought. 
	7	For the disability, there was, in my opinion, there
	8	was no apparent disability that was caused.  One of
	9	them was the TSS cases.  They reported life
10	threatening hospitalization and disability, but there
11	was no apparent long-term type disability associated
12	with that.
13	            The second case was a disability. 
14	Essentially, what the patient reported was that
15	following the use of the sponge, her and her husband
16	were not able to perform sexually as they had prior to
17	the use of it.  So that was the, the second disability
18	that was reported.
19	            DR. DAVIDSON:  Thank you.  You know, we
20	already commented before from previous presenters that
21	the highest rate was seen in 1984, okay.  Do we have
22	any data of the exposure, you know, in 1984, 1985,
23	1986 of sponge use to see if there's, if it is a
24	relationship between the usage and the cases.  Or it
25	was the, you know, after 1984, people were better

				132
	1	educated, you know, to draw some conclusions why it
	2	really went down after 1984?
	3		DR. KARWOSKI:  After, actually it didn't
	4	really go down.  It stayed somewhat stable.  There

	5	were bumps throughout the years.  We don't have any
	6	actual usage data.  All we have is some data regarding
	7	the distribution of the product, so the sales of the
	8	product.
	9		But we don't have numbers of how many

10	people actually used the product or how frequently
11	they may have used it.  So we can't really put a

12	denominator on that.  But what we're somewhat sure of
13	that the use did decrease somewhat over the years, and
14	the rate of TSS, or at least, the reports that we had
15	received didn't really decline that much, at least
16	over, after 1985 to 1994, that they remained somewhat
17	stable with little, you know, small fluctuations,
18	varying, you know, throughout the years.
19		DR. DAVIDSON:  From the data you
20	presented, you know, even though there were some small
21	fluctuations, the tendency was to go down.  Maybe I,
22	no?  Okay.  Then it remained about 47 cases per year?
23		DR. KARWOSKI:  Well, we had only one case
24	reported in 1995, but the product at that point was --
25		DR. DAVIDSON:  But the product was

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	1	withdrawn, right.
	2		DR. KARWOSKI:  -- had stopped.
	3		DR. DAVIDSON:  Okay.  And one final
	4	question, when you report infections, and you report
	5	vaginitis in different sections, the vaginitis was
	6	also included in the infections or were they reported
	7	totally separate for everything?
	8		DR. KARWOSKI:  The vaginitis in our
	9	database are considered infectious type of
10	complications.
11		DR. DAVIDSON:  Then it was reported twice?

12		DR. KARWOSKI:  May have.  There may have
13	been an infection and vaginitis at the same time.
14		DR. DAVIDSON:  Thank you.
15		DR. CANTILENA:  Yes, Dr. Neill?
16		DR. NEILL:  I have two and a half
17	questions, the first to Dr. Karwoski.  You discussed
18	the, a couple of examples of monitoring systems.  Can
19	you give me an example of a system that's currently in
20	use that actively as opposed to passively monitors
21	adverse events for a currently marketed OTC product
22	that's subject to an FDA, NDA or OTC monograph?
23		DR. KARWOSKI:  We don't currently know of
24	or are aware of any type of systems that would do
25	that.

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	1		DR. NEILL:  So for other similar products
	2	to this that would fall under similar FDA  regulation,

	3	there's not an active process in place.  So if we were
	4	to shortly hear a charge that were to ask us to
	5	consider whether or not there should be some active
	6	collection or an active process for monitoring adverse
	7	events, this would be a first.  Is that safe to say?
	8		DR. KARWOSKI:  That, this would, as far as
	9	I'm aware.
10		DR. NEILL:  Okay.  My other questions have
11	to do with putting statements about efficacy on the
12	carton.  And it's sort of a question and a half, so
13	I'll ask them together, and whoever from the FDA or
14	Allendale wants to address this, please feel free.
15		Is FDA aware of any product that's
16	similarly under an NDA or OTC monograph that has
17	efficacy labeling on the carton by virtue of it being
18	required to be there by FDA, and if so, is there
19	language in the recent Federal Register regulations
20	that require that?  My understanding being that the
21	proposed label that you just reviewed includes all of
22	the bullets and components that are required.
23		And I guess my perception is that if we're
24	being asked to judge whether or not efficacy data for
25	this should be on the carton, comments about, you

				135
	1	know, having additional process hearings to make sure
	2	it happens for other products aside, I'm curious to
	3	know are there other products for which that's already
	4	happened, that the FDA has asked that that happen?
	5		DR. GANLEY:  Yeah, the one that comes to
	6	mind, at last on the carton is Rogaine or topical
	7	minoxidil, where it's included in other information,
	8	where it provides efficacy information to the consumer
	9	at the point of purchase.  There are other products

10	that provide efficacy information in package inserts. 
11	H2 blockers for heartburn, for example, would be an
12	example.
13		DR. NEILL:  Are, were those for Rogaine
14	and some of the H2 blockers required by the FDA to be
15	on the carton?
16		DR. GANLEY:  Yes, they're marketed under
17	NDAs and so we, we require that.  I don't believe
18	there's any monographs that would fall into that
19	category right now. 
20		That doesn't say that in the future there
21	won't be, but, but from a regulatory point of view,
22	you can require someone to do that.
23		DR. CANTILENA:  Yes, Dr. Blewitt?
24		DR. BLEWITT:  Just two, two points I think
25	that are relevant here.  First, I think that with

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	1	regard to comparative efficacy, that has not been
	2	required.  So you make, make a statement about
	3	individual efficacy.  You wouldn't have, at this point
	4	in time, there is no, there are no comparative
	5	efficacy statements required on labeling.
	6	            In addition, the, with regard to adverse
	7	events monitoring, it seems to me that any, any
	8	product that's subject of a new drug application has
	9	to both monitor and submit to the agency reports of
10	adverse events that they received, so, so that is
11	required.
12	            DR. GANLEY:  Yeah, I just think that, I
13	got the, my impression of your question was that there
14	was some type of phase four commitment where we
15	required a company to go out actively and look for
16	cases in a population as opposed to an individual

17	passively reporting it.  I think that's what your
18	question --
19	            DR. NEILL:  Yes, exactly.  For an OTC
20	product where, as a health care provider, I'm not
21	involved except in some circumstances in a decision to
22	go and pick it up off the shelf, I'm not going to fill
23	out a MedWatch form and send it in for a patient that
24	by all rights may never see me and may only speak to
25	the, may only speak to the company.  And so I'm

			137
	1	interested in active looking versus passive.
	2	            DR. CANTILENA:  Other questions for FDA,
	3	Dr. Johnson?
	4	            DR. JOHNSON:  Yes, my question is
	5	primarily directed to Dr. Chang, and that has to do
	6	with the comparator table of efficacy.  And I'm
	7	wondering if you can comment on Dr. Greenslade's
	8	comments about how that table was derived.  I mean,
	9	frankly, the sentence he read bothers me a little, and
10	the fact that it's in other contraceptive products
11	doesn't, doesn't necessarily make it what sounds like
12	good data.
13	            MS. CHANG:  I believe that the agency
14	wanted some kind of a method that, to have the
15	consumers basically make an informed choice.  It's
16	generally not to, to improve that process of selecting
17	their birth control method.  And it was mainly for

18	informational purposes so they can make that choice,
19	that maybe because of their condition they should not
20	use this product, because of, of the dangers of
21	getting pregnant, they should use another product that
22	may have more of a, a better pregnancy prevention
23	claim for an efficacy statement.
24	            DR. JOHNSON:  Well I, yes, I think it's a
25	great idea to provide information to consumers so they

			138
	1	can make decisions, but if the information is flawed
	2	or is not based on real data, then I'm not sure that
	3	that is useful information for a consumer.
	4	            MS. CHANG:  I believe, and I can ask Dr.

	5	Chang on that, Dr. Chin on that one, but basically,
	6	Dr. Trussell, it was more of a retrospective type of
	7	a data base.  Is that right, Ling?  Okay.
	8	            DR. CHIN:  Let me see if I, I'll try to
	9	clarify this.  The Trussell table is a reference
10	table.  In terms of trying to get a sense of birth
11	control rates for the different, or pregnancy rates
12	for the different birth control methods, we have to
13	come up with one reference, one table that hopefully
14	would give consumers a sense of how effective each

15	birth control method is.  And I agree.  If you look at
16	the methodology that was applied to how that table was
17	developed, it is definitely not consumer friendly. 
18	It's above most everyone's reading of it, and, and I
19	tried to get through it.  It's very difficult.
20	            But the agency undertook a point of
21	reference by which information that is from a reliable
22	source and Contraceptive Technology is an accepted
23	reliable source for contraceptive information.  And as
24	far as contraceptive rates, I mean as far as pregnancy
25	rates are concerned, that's an accepted point of

				139
	1	reference.
	2		Aside from that, the agency tried to make
	3	that table more consumer friendly.  We did adapt it
	4	somewhat and the table was subject to focus group
	5	discussions, so that the presentation of the table is
	6	slightly different than the table in Trussell's table. 
	7	It's more consumer friendly than that.  It is really
	8	just a means of providing information across the board
	9	of all the various methods, knowing that we do not

10	have one single clinical trial that will do head to
11	head comparisons of every method, and by which we can
12	come up with the usual standards of comparing
13	effectiveness by each method.  And that's the point of
14	the table.  Does that clarify it?
15		DR. JOHNSON:  I mean, it, it clarifies,
16	but I guess it doesn't sort of get at the base of how,
17	how valid is the data in that table.
18		DR. GANLEY:  Well, I think one of the

19	things you have to remember that this was a table
20	that's included in prescription products.  There's a
21	learned intermediary there who can read it and
22	hopefully understand it.
23		And I think there's two things to, to

24	understand here -- is conceptually, should we have
25	that information in OTC products, number one.  And

			140
	1	number two, is how should that information be
	2	prevented (sic)?  I would agree with the presentation
	3	that I find it very unconsumer, it's not consumer
	4	friendly and, but the question, I, the first question
	5	is should we have comparator information so the
	6	consumer can make that choice.  And then we can decide
	7	on what the adequate reference is and how to present
	8	that information.  I think that's what we're trying to
	9	get at.
10	            You're looking at a table that a, a
11	physician can read, understand certain caveats in it

12	and convey those to a consumer, and I would totally
13	agree that a consumer, and even I have a problem
14	looking at that table and understanding the rates in
15	the comparator columns that he had pointed out
16	earlier, so.
17	            DR. CANTILENA:  Yes, Dr. Blewitt?
18	            DR. BLEWITT:  Yes, I, I agree with Dr.
19	Johnson though, and I agree with the point that's

20	being made, but if the data are quote flawed, which is
21	a term that I've actually used myself, if there are
22	better data that exist, or if there are better ways to
23	find out what, what the real data are, then, you know,
24	that would be the ideal situation, but I think to take
25	data that, or, I ask that the sponsor speak to this,

				141
	1	too.  If these are not hard data, then you're taking
	2	soft data or inferential data it sounded like to me

	3	and now you're making it more consumer friendly.  So
	4	I don't think that that accomplishes what you want to
	5	accomplish either.
	6		I, I agree that in a situation like this,
	7	you know, where pregnancy is the risk, if you will,
	8	that the women should understand what the comparative
	9	benefits are, of products are.  The question is how
10	good are the data, the comparative data that they're
11	trying to interpret.
12		DR. CANTILENA:  Yes, you know, actually,
13	I have a, a question if I can ask the, the folks on
14	the committee who actually practice in this area just

15	to get sort of your read.  Are the numbers that are in
16	that table, Drs. Greene and Lerner, are they within,
17	you know, the ballpark, or --
18		DR. LERNER:  No.
19		DR. CANTILENA:  Okay.  Could you, could
20	you comment a little more on exactly what you mean by,
21	you know, they're not in the ballpark and especially
22	if there's a way in which you can present, you know,
23	relative information.
24		DR. LERNER:  In, in our out-patient clinic
25	which is just a very typical, you know, low socio-

			142
	1	economic Medicaid type patient population, we have a
	2	beautiful poster -- I don't know the source of the
	3	poster; I'm sure I can find out -- that actually has
	4	all the benefits and, you know, sort of the
	5	advantages, the disadvantages, a little, pretty
	6	graphic on all the different methods.  And the, you
	7	know, estimates on efficacy rates.  And you know,
	8	that's sort of what we, you know, use in all our, you
	9	know, OBGYN techs.
10	            I'm sure the American College of OBGYN or

11	the, you know, family planning organizations must have
12	reasonable data.  I'm sure there's data out there,
13	other than Contraceptive Technology, not that I'm
14	belittling that, but I kind of am.  That I think that
15	as a much more global scope, that we might, or you
16	might sort of do an, a detailed in-depth review of
17	some of the references and just try and find out with
18	some, you know, find out some reasonable numbers and
19	then just, you know, put them in all of the, all of
20	the inserts as needed because I, I don't think they
21	are.
22	            You know, we quote, you know, roughly what
23	we've seen which is barrier methods, roughly in the

24	ten percent range, so to think that the Today Sponge
25	has 40 percent, which was listed on that, just is

					143
	1	really way out of, of the realm of what we, we sort of
	2	quote to patients and our estimates.
	3		DR. GANLEY:  I think in the one column
	4	that was pointed out were typical use rates, and you

	5	know, I would agree with the comments earlier.  But I
	6	think something like the lowest expected rate of
	7	pregnancy, is that way out of the ballpark?  Where it
	8	actually lists the vaginal sponge as nine percent?
	9		DR. LERNER:  No, that's reasonable.

10		DR. GANLEY:  Yes, that's what I'm, so
11	there is some information there that shows you in
12	terms of order magnitude compared to other methods.

13		DR. LERNER:  But then the table needs to
14	be modified.
15		DR. GANLEY:  Right, I'm --
16		DR. LERNER:  No, then the table needs to
17	be modified.
18		DR. GANLEY:  Right, I -- 
19		DR. LERNER:  And just, you know, we
20	usually quote, you know, abstinence, a hundred
21	percent, you know, tubal ligation, you know, 99.5
22	percent, OCPs 98 to 99 percent, you know, condoms,
23	diaphragm, you know, everything, withdrawal, you know.
24		DR. CANTILENA:  Okay.  Further comments,
25	Dr. Greene?  Would you like to add to that?

			144
	1	            DR. GREENE:  Yes, I'd, I'd like to address
	2	that.  I certainly agree.  I think that the numbers

	3	quoted here are way out of line and much higher than
	4	we would normally quote our patients.  And most
	5	reference material that we would use, certainly, the
	6	American College of OBGYN does have a, a patient
	7	information literature that has numbers that don't
	8	resemble this even closely.
	9	            I would like to revisit, since we're at
10	this point, the issue that was brought up a little
11	earlier, which is your denominator.  And I would

12	certainly favor or recommend that the, sort of the
13	industry standard is how many pregnancies occur among
14	a hundred women using the method for one year, a
15	hundred women years.
16	            Now, that can be made, that can be made
17	readily understandable for patients.  And the problem
18	of having less than one woman per hundred women years
19	is understandable.  Patients understand that.  And

20	whether it's one in a thousand or one in two thousand,
21	most women don't worry about those differences too
22	much.  If you just say less than one woman in a
23	hundred using the method for a year, people understand
24	that.
25	            And with that as the standardization, I

				145
	1	think you could get numbers here that are very easy
	2	for lay people to understand, and much more in line
	3	with what we generally quote our patients.
	4		DR. CANTILENA:  Okay, thank you very much.

	5		DR. LERNER:  And just one further thing. 
	6	I, I do assume that we use all the American College of
	7	OBGYN.  They have tons of patient and physician
	8	information stuff, so I, I do encourage you all to
	9	sort of look into that.
10		DR. CANTILENA:  Okay.
11		DR. GANLEY:  Yes, I just want to point out
12	one thing that, you know, Dr. Greenslade hadn't really
13	touched on.  And one of the reasons, I think, in our
14	proposed labeling where it said one out of ten is we
15	really didn't know where that rate came from and what
16	it was pertaining to, because if you actually look at
17	the current labeling, it's written as in clinical
18	trials of today, vaginal contraceptive sponge since
19	1979, over 18,000 women worldwide have completed over
20	12,000 cycles of use.  The results of these clinical
21	trials are as follows, pregnancy rates per 100 women. 
22	And they just list them.
23		And I think it goes back to what Dr. Chin
24	had reported, that when this was initially approved,
25	if you remember, the, the pregnancy rates, it was 12

				146
	1	month pregnancy rates.  And then a year later, we're
	2	just talking about pregnancy rates without any time
	3	frame.  And that's why, you know, we went through the

	4	regulatory history, because we're a little confused as
	5	to what rate we're talking about there, too.  But I
	6	think we understand your point.
	7		DR. CANTILENA:  Okay, Dr. Uden?
	8		DR. UDEN:  If I can -- are we done with
	9	that?  Because I wanted to ask a question about the
10	allergy alert, so if we're not --
11		DR. CANTILENA:  Is this a question that's 
12	you know, specifically to FDA?
13		DR. UDEN:  Yes, it's specifically to FDA.
14		DR. CANTILENA:  Yes, okay.
15		DR. UDEN:  Dr. Karwoski, in the allergy
16	alert, it, in the suggested label changes, it was TSS
17	and then allergy alert was right after that, if you're
18	allergic to metabisulfites.
19		I noticed in the data that you reported
20	that there were only two allergic reactions.  Has
21	there been any allergic reactions associated with the
22	sponge that have been systemic allergic reactions or
23	are these local allergic reactions, and are they
24	presented in your, one of your graphs as pruritus?
25		DR. KARWOSKI:  We didn't, I didn't go back

				147
	1	and pull all cases of any, you know, allergic type of
	2	reactions.  These two were systemic type of reactions. 
	3	There are other cases, but we didn't review that.

	4		DR. CANTILENA:  Okay.  Dr. Krenzelok?
	5		DR. KRENZELOK:  Back to the more mundane,
	6	being the director of a poison center, I'm always
	7	sensitive to what children put in their mouths.  Now,
	8	I notice on the label it says keep out of the reach of
	9	children.  That seems right.
10		Unless I've missed it, I didn't see
11	anything about proper disposal methods of the sponge
12	after it's been used.  And it might get tossed into
13	the toilet inappropriately or into a garbage can or
14	wrapped up or whatever.  But children see those as
15	attractive nuisances, as disgusting as that might
16	seem.
17		I guess my question is in your passive
18	surveillance system review, did you find -- I'm not
19	worried about the toxicity of, of at least, the parent
20	product.  But did you find any instances of, of
21	choking among small children at all, who might have
22	gotten these, chewed them, swallowed them and had a
23	problem?
24		DR. KARWOSKI:  We didn't go and look at

25	those specifically, but the lowest age that we found

				148
	1	for an adverse event report was 12 years old, so I
	2	would assume that no, we haven't had any reports.
	3		DR. KRENZELOK:  Okay.  Thank you.
	4		DR. CANTILENA:  Okay, what I think I'd
	5	like to do now is move actually to the charge to the
	6	committee by Dr. Ganley and then we'll still have
	7	ample time for discussion prior to going into the
	8	questions.
	9		DR. GANLEY:  Yes, I'm just going to keep

10	my remarks brief since I had made some earlier remarks
11	to try to focus the discussion.  I think the one thing
12	I, I just want to emphasize again that, you know, one
13	of our purposes for reviewing the entire data base is
14	as a division, we weren't familiar with this product. 
15	And so we weren't familiar with the safety of the
16	product.  And we thought it warranted a safety review
17	to see if the other information needed to be included
18	in there.
19		In doing that, I think we developed a
20	comfort level that there was still a benefit, the risk
21	benefit still favored this product to be marketed. 
22	That's number one.
23		And I think the other thing that I want to
24	make a point of that in the years since the sponge

25	discontinued the marketing, the, the agency has gone

			149
	1	to great lengths to try to improve the OTC labels. 
	2	And we've developed standards now that are actually in
	3	the codified regulations.
	4	            And so, I think our position is that we

	5	should try to improve this label before it goes back
	6	on to the market, once they get their chemistry issues
	7	resolved.  And we can just go to the questions now.
	8	            And these are just the questions that we
	9	had brought up.  And one was given the material
10	provided in your briefing packages and presented
11	today, does the revised labeling adequately convey the
12	risk associated with the use of the product?  The
13	current carton label does not contain information on
14	the efficacy of the product.
15	            Should the carton label include efficacy
16	information so that the consumer will have this
17	information available at the point of purchase?  And
18	I think in writing this question, we were focusing

19	more on the information that had come from the
20	clinical trials, rather than the comparative.  But if
21	you want to comment on the comparative part -- and we
22	were looking at more in the vein, I think, of what is
23	currently on the topical minoxidil for hair growth as
24	providing that type of information.
25	            And if, yes, it's this type of

			150
	1	information, should it be on other OTC products? 
	2	That's the important thing there.
	3	            Are there other aspects to the labeling
	4	that we, that should be revised?  We're interested in
	5	any comments.  And the other thing is to please
	6	provide comments on the type of post-marketing
	7	surveillance for adverse events the sponsor should
	8	conduct.  And I think the reason for that is, as
	9	Claudia had pointed out, as years progress, the
10	reports that have come in have been lesser quality. 

11	It's very hard to look at these things as a safety
12	reviewer and make some determination of causality. 
13	And we, we think it's very important that these
14	reports, if they're, if they're given to a sponsor, be
15	well written, someone follows up on them, collects
16	information and then provides them to us.
17	            I think the other issue is the type of
18	information we should ask in terms of the company
19	getting calls from consumers about difficulty removing
20	the sponge.  And how should that be cataloged?  What
21	kind of follow-up should be provided?  Should the
22	company contact the consumer a day or two later just
23	to see that everything's okay?  And those are the

24	types of things that I think we're interested in. 
25	Thank you.

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	1		DR. CANTILENA:  Okay.  Thank you, Dr.
	2	Ganley.
	3		I think, actually, just before we go to
	4	the, to the specific questions, what I'd like to do is
	5	invite the committee, actually, individually.  We'll
	6	sort of go around the table, just to offer sort of
	7	general comments regarding some of the issues in terms
	8	of what they've seen.
	9		Some of, you know, the conflicts that, you
10	know, they've identified, and then after we go around
11	and everyone's had a chance to sort of air their
12	concerns or express their opinions regarding sort of
13	the global issues, then we'll come back and go through
14	the questions, one by one.  So we'll, actually, if you
15	don't mind, perhaps we can start over on this side. 
16	Dr. Krenzelok, if you'd like to share with us your

17	thoughts at this point without actually specifically
18	answering questions.
19		DR. KRENZELOK:  All right.  Thank you very
20	much.
21		Just a couple of things that have, have
22	sort of dawned on me as we've discussed this.  From
23	the standpoint of, of this as a, a package that might
24	contain three or six or nine or twelve sponges, as I
25	stated earlier, it seems to me like there needs to be

			152
	1	information on each and every sponge that talks about
	2	how to use the product properly and so on, rather than

	3	there being a single package insert for the container. 
	4	Again, given the portability of them and the ease of
	5	taking them and throwing them into a purse or a
	6	briefcase or something of that nature.
	7	            Another thing that, that I'm sensitive to,
	8	again, working in a, in a 24-7 type of situation is
	9	the fact that I think here's an opportunity to be very
10	proactive with surveillance.  So that in sort of a

11	passive way, to have 24-7 availability, not just
12	through pagers, but have a real live body there, a
13	competent person.  And one of my thoughts on that is
14	perhaps that it might be wise to out-source something
15	like this to a nursing triage service, like Ask-A-
16	Nurse, who's there's 24 hours a day, seven days a week
17	as a, as a possibility.
18	            And then the other thing along those

19	lines, and, and it's been addressed before is the
20	importance of some of those people having bilingual
21	capabilities, at least Spanish and English for this
22	country.  So those are just the thoughts that I had.
23	            DR. CANTILENA:  Great.  Thank you for
24	those comments.
25	            I guess, you know, one possibility would

				153
	1	be to out-source through a poison control center.
	2		         (Laughter)
	3		DR. KRENZELOK:  That would be a conflict
	4	of interest.
	5		DR. CANTILENA:  Dr. Blewitt, would you
	6	like to share with us some comments?
	7		DR. BLEWITT:  I guess my, my own
	8	observation at this point is that the issues are very,
	9	very narrowly focused now.  I don't see a great deal

10	of difference between the sponsor and, and the agency
11	on, on, on the principles involved in the labeling. 
12	It's just a matter of how those things are worked out.
13		The only thing that we haven't discussed,
14	and I don't know whether it's up for discussion.  But
15	in the review package, there's a consumer information
16	leaflet.  And there's, there are about three pages
17	Of --
18		DR. CANTILENA:  Can you help find us that
19	--
20		DR. BLEWITT:  Well, two, two pages.  This
21	is in the section on 2000 label submission, and it
22	comes after the drug facts labeling.  And, again, I
23	don't know if this is up for discussion.  But it seems
24	to me that as I read through this, I had a few
25	concerns, that it's been significantly edited.  It's

			154
	1	been, as far as I can see, substantially expanded in
	2	size.  And I'm, without getting down to the details of
	3	it, a question again arises as to whether the
	4	consumer's receiving too much information here.
	5	            So I, for instance, on -- well, I will
	6	give you a for instance.  There's a comment in here
	7	you can avoid the risk of getting sponge-associated
	8	TSS by not using the sponge.  Well, that seems to be
	9	a rather reasonable and unnecessary statement.  I
10	mean, you won't get it if you don't use it, for sure.

11	            But the, the major point is that there are
12	a lot of red additions.  There are black, there are
13	deletions, but it's a much larger consumer information
14	leaflet than it was originally.  And without being
15	judgmental about it, I would just ask people to
16	consider whether that's just overloading the consumer
17	with information to the point where they won't read
18	it.
19	            DR. CANTILENA:  All right.  If you use, if
20	you use headers in the format, though, isn't, you
21	know, isn't it sort of easier to, to help sort of the
22	scanner to be able to?
23	            DR. BLEWITT:  I have no question about

24	the, the format.  It's, it's only in terms of the
25	amount of content, the volume of content.

				155
	1		DR. CANTILENA:  Great.  Thank you very
	2	much, Dr. Blewitt.  Dr. Johnson, would you like to
	3	share some comments?
	4		DR. JOHNSON:  Most of my comments probably

	5	relate specifically to the questions.  I mean, I think
	6	that it's pretty clear that this is a safe product,
	7	and that there's not much question that another
	8	contraceptive method for women is a good thing.  And
	9	so, I think that it, it really does seem to be just a
10	matter of working out the, the little details in the
11	labeling.
12		DR. CANTILENA:  Okay.  Dr. Uden?
13		DR. UDEN:  The only thing I'll add is, is
14	I'm concerned about the consumer comprehension of the
15	present label.  The old one, the new one that's been
16	submitted, suggested by the FDA and that, that maybe
17	a consumer comprehension study needs to be done to
18	determine whether they can, somebody can understand
19	it.  And, you know, maybe it needs to have cartoons
20	on, cartoons in the, in the package insert so that
21	people can really understand how to use it.
22		DR. CANTILENA:  How do, how do you feel
23	the 2000, you know, proposed label compares, you know,
24	to the `91?
25		DR. UDEN:  Much better.

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	1		DR. CANTILENA:  Dr. Williams?
	2		DR. WILLIAMS:  I agree with what has been

	3	said previously.  I have no new, I guess, information,
	4	more than I've used in the past.  I've used this
	5	product when I was in my practice and it was
	6	available.  So we were very conscious of the pitfalls
	7	about the use of it as well as the literacy of the
	8	patients that we had to deal with who had to come in
	9	contact with it.  And so we had to use more counsel in
10	our private office to, to ensure that they knew well
11	about this product.  So I think the cautions have been
12	expressed are ones that I, I concur with.
13		DR. CANTILENA:  All right.  Thank you very
14	much.
15		Dr. Davidson?
16		DR. DAVIDSON:  Well, I'm pleased to hear
17	everybody actually making some redundant conclusions. 
18	You know, I'm going back to, to the clarity of the
19	message, you know.  I don't mind if we have more
20	material.  It's up to the patient to read what we give
21	them, you know.  But there are some messages that need
22	to be clear, and I think we clearly stated what are
23	the messages that, that need to be out there.
24		I want to remind that the translation to
25	Spanish needs to be friendly, you know.  It needs to

			157
	1	be basic and to the point.  And, you know, not to
	2	forget that we really want to have an 800 number that
	3	covers minorities as well.
	4	            DR. CANTILENA:  Okay.  Thank you very
	5	much.
	6	            Dr. Lerner?
	7	            DR. LERNER:  I made plenty of comments so
	8	far.  You know, again, I think it's great.  I think
	9	one of the most important aspects will be that 800

10	number.  And I don't mean to sort of trivialize your
11	intention or purpose, but I think that that's going to
12	be, I think our main concerns are the toxic, toxic
13	shock and the questions of removal.  And that clearly
14	is going to be where the patients head first.
15	            So I think they're going to, the training
16	of people is going to be very important. 
17	Additionally, I think just, I can't overestimate where
18	the placement on the label or on the carton needs to
19	be.  There's a, a section that just sort of said
20	questions and comments, but that sort of didn't give
21	it enough impact.  I know within the, you know,
22	narrative it said, you know, if you have trouble
23	removing it, call the, the talk line.  But I think
24	maybe if the phone number is written in, you know,
25	larger font or bolder numbers or something.  Just sort

				158
	1	of if the patients are ill or having problems, they
	2	can just key right into it.
	3		DR. CANTILENA:  Dr. Gilliam?
	4		DR. GILLIAM:  A couple comments.  The
	5	first goes back to one of the earlier speakers today,
	6	talking about incidents of vaginal irritation if it's
	7	used for several days in a row.  And, on a quick
	8	glance, I don't see that that's really mentioned in
	9	the package insert, and possibly that should be added.
10		I do think that a efficacy statement
11	should be added.  And I like the one that Dr.
12	Greenslade had used earlier.
13		I think there should possibly be stronger
14	warnings not to use it while a woman in menstruating,
15	and possibly move that statement up to underneath the
16	toxic shock.  Or, in addition, as a lot of the women

17	that do, did get toxic shock, it happened, they were
18	menstruating and using the sponge.  And they were not,
19	they were, shouldn't have been doing so.
20		And then lastly, I, I think that there
21	really needs to be a package insert in the carton in
22	both Spanish and English, since you can't really
23	control the distribution of the product in, because of
24	our growing Hispanic population in this country. 
25	That's all.

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	1		DR. CANTILENA:  Thank you.  Dr Greene?
	2		DR. GREENE:  I'll reserve my specific

	3	comments for the answers to the questions.  I just
	4	generally feel strongly that this should be made
	5	available, and I don't think there's a big difference
	6	between the sponsor and the agencies, just a matter of
	7	getting the details of the wording of the insert and
	8	the carton.
	9		DR. CANTILENA:  Thank you.  Dr. Neill?

10		DR. NEILL:  A couple of questions that
11	will help me in later answering charge three about
12	specific items of the label to be revised, and I'll

13	direct these to Dr. Krenzelok.  I'm less worried about
14	children eating these than sex partners, and I'm
15	wondering -- I have no idea about the toxicity of
16	nonoxynol-9 or the sponge itself, which I presume
17	would simply be passed right out the other end when it
18	ends up in the mouth and alimentary tract of a sex

19	partner.  Do I need to be worried about nonoxynol-9
20	when it's ingested?
21		DR. KRENZELOK:  No, it's, it's very
22	innocuous, from my experience.  As a toxicologist,
23	that is.
24		         (Laughter)
25		DR. CANTILENA:  Thank you for adding that

			160
	1	clarification.
	2	                     (Laughter)
	3	            DR. CANTILENA:  We were starting, starting
	4	to worry about Pittsburgh.
	5	                     (Laughter)
	6	            DR. NEILL:  Well, since you brought it up,
	7	Ed, you know, the other question that came to mind
	8	aside from this, you know, oral ingestion that I had
	9	was in occupying my mind with all of the different

10	permutations that might occur in the course of sex as
11	it happens, I was -- and this does not pertain to any
12	of our charge.  It was just I thought interesting and
13	maybe a little entertaining.  I was wondering what
14	happened to the efficacy of this product with food,
15	alcohol, any or all of the above in many different
16	kinds of combinations.  Please, don't anybody feel
17	compelled to answer that.  And then, I've got a couple
18	other specific questions that we'll get to when we get
19	to the charge.
20	            DR. CANTILENA:  Okay.  Thank you very
21	much.  I think in the, in the interest of time, I'll,
22	I'll just reserve my comments to, as, as they sort of
23	pertain to the questions.  So if there are no other
24	issues that people want to discuss, why don't we
25	proceed with the questions then?

				161
	1		First question, given the material
	2	provided in your briefing packages and presented
	3	today, does the revised labeling -- and here, we're
	4	specifically talking about the 2000 proposed labeling

	5	that's in your document -- adequately convey the risks
	6	associated with the use of the product?
	7		And what I'd like to do is, this is a yes,
	8	no answer.  And as opposed to going around the table,
	9	why don't we just ask for a show of hands.  So all

10	those who feel that the answer is yes, that is, the
11	revised labeling does adequately convey the risks,
12	please raise your hand.
13		      (Hand vote taken)

14		DR. CANTILENA:  It looks like nine.  Okay. 
15	All those who feel it does not adequately convey the
16	risks.
17		      (Hand vote taken)
18		DR. CANTILENA:  One, and can I ask you to
19	actually comment in terms of what is, you know,
20	missing?
21		DR. KRENZELOK:  I think that, that the
22	information about toxic shock should be emphasized in
23	bold so it really stands out.  That's the only reserve
24	I have.
25		DR. CANTILENA:  Okay.  Thank you very

			162
	1	much.  Second question is the current carton label
	2	does not include information on the efficacy of this
	3	product.  Should the carton label include efficacy
	4	information so that the consumer will have this
	5	information available at the point of purpose?  So,
	6	specifically, we're talking about including efficacy
	7	on the outside, on the carton, as opposed to on the
	8	inside, in the package insert.
	9	            And here, again, I'd like to ask for all
10	those who answer in the affirmative that the label,
11	the carton label should include efficacy on the
12	outside, please indicate by raising your hand now.
13	                  (Hand vote taken)
14	            DR. CANTILENA:  Okay.  Nine in the
15	affirmative, and can I ask Dr. Neill, I assume you're
16	voting no and not abstaining.  Could you tell us, you
17	know, what your concern was?
18	            DR. NEILL:  If we include only efficacy on

19	this product, and we say this is effective -- in 100
20	women years of use, there will be X many pregnancies
21	and do not include information about other products,
22	I don't know that I or consumers would naturally come
23	by the information to make that isolated nugget
24	useful.
25	            If we include the other comparative

			163
	1	information, that's something, given what I understand
	2	now about how Rogaine and some other medicines have

	3	been marketed, that I don't feel comfortable getting
	4	into.
	5	            I mean, that gets to the second part of
	6	this, which we'll get to in a minute, which is, if
	7	yeah, should it be required of all OTC contraceptive
	8	products.  If the answer to the first part is yes,
	9	there's an implied question in my mind which is okay,
10	what kind of efficacy.  And that's going to require a
11	whole another day of hearings.
12	            And I think we also need to take into
13	consideration the comments that were made very early
14	today about the extent to which our discussion of
15	inclusion of that information on all OTC contraceptive
16	products would require that kind of process.  I think
17	that it's probably that important.
18	            DR. CANTILENA:  So, so you're saying then
19	if, if the information on the outside was comparative
20	in nature and valid, I assume, then, you would favor
21	that.  And, you know, as it is, in isolation with, you
22	know, one and ten, it's not adequate, or it's not
23	advisable.
24	            DR. NEILL:  Well, I, I would not oppose --
25	well, it's nine to one, so it doesn't matter what I

				164
	1	think, but --
	2		DR. CANTILENA:  It always matters.
	3		DR. NEILL:  Oh, of course.  All right.  I
	4	think that if it's just in isolation, that might be

	5	preferable.  As somebody who has to counsel patients
	6	all the time, I actually find it less useful for me to
	7	say, or incompletely useful for me to say this is, you
	8	know, will result in X numbers of pregnancies per 100
	9	women years.  But rather, I find it more useful for me
10	to put my patients' risks in the context of the risks
11	that they face daily in their life.
12		I, for -- I don't like telling my patients
13	and having them think this is a very risky thing, if
14	they don't understand that walking across Market
15	Street outside my office is even riskier.  Do you
16	understand what I'm saying?  And that -- 
17		DR. LERNER:  Just, just as a comment with
18	that, I think that the decisions here are made at the
19	corner drug store at 3:30 in the morning.  And so I
20	think that as much information as we can provide,
21	comparative or otherwise, is going to be much more
22	than they're going to get, you know, beeping any of us
23	at that time of the morning.
24		DR. NEILL:  I guess, then, my plea would
25	be to include meaningful, comprehendible efficacy

			165
	1	data.  For something where the outcome is as
	2	measurable as a pregnancy, that's useful.  The
	3	difficulty for the agency, I think, is going to be for
	4	OTC products for which this may become an issue, for
	5	which there's an outcome which is much more
	6	subjective, like Rogaine.
	7	            DR. CANTILENA:  Okay, I guess, can we ask
	8	another question then, Dr. Ganley, of, of the
	9	committee and, you know, regarding the format of the

10	information, whether it's now comparative or just, you
11	know, isolated for the product?  If, if you're not
12	opposed, then I would like to propose a question to
13	the committee then.  If efficacy label, if, if the
14	efficacy information on the outside of the carton
15	contained, you know, comparative information to other
16	methods of information, would you favor it included on
17	the outside of the carton with this product?
18	            DR. GANLEY:  Can, can I just make a
19	comment for anyone?
20	            DR. CANTILENA:  Okay.
21	            DR. GANLEY:  I'm, I think the one thing
22	that we have to be sensitive to is that the size of
23	these boxes are a certain size.  And there's so much
24	information you can get on it.  And I think you have
25	to take into account that if you're going to put

			166
	1	comparator information, it is going to take up a lot
	2	of room.
	3	            And so, I think you need to keep that in
	4	mind when, you know, if, if -- and that's, that's

	5	become a problem for us in, and certainly, I think
	6	that Allendale would agree with that.  And if there's
	7	another way to show or to direct a consumer to the
	8	package insert, I think that, you know, that we, we
	9	cannot forget those things, that there's a limited
10	size on these boxes.
11	            DR. CANTILENA:  I guess the --
12	            DR. GANLEY:  Unless we just sell 12 packs,
13	or 18 packs or something.
14	            DR. CANTILENA:  Yeah, I guess, I guess,
15	you know, the reason I was suggesting, you know, this
16	question is really at, at the time the consumer is

17	making the choice about, you know, purchase, should
18	they know how this compares to other methods, which

19	are over the counter or, or otherwise?  And that, but,
20	I guess it's sort of a, a hypothetical because, all
21	right, you know, obviously if, if the box has to be,
22	you know, five by six feet in order to get all the
23	information that, it would not be  a practical thing. 
24	So I guess that's where that where was coming from. 
25	Any other, any other comments?  Dr. Johnson?

			167
	1	            DR. JOHNSON:  Well, I think, already in
	2	the package insert, there's a statement this is much

	3	less effective than the pill and IUD.  So it might be
	4	possible to put on there in 100 women over one year,
	5	you would, there would be approximately ten
	6	pregnancies.  This is much less effective than
	7	hormonal methods such as the pill or Norplant and the
	8	IUD.  And I think, you know, that doesn't go into a
	9	lot of real specific comparator data, but does give,
10	give them a point of reference.  Because I think most
11	women understand that the pill was a very effective
12	birth control method and can sort of use that as a
13	comparison.
14	            DR. CANTILENA:  Yes.  Dr. Lerner?
15	            DR. LERNER:  But sort of to answer the
16	second part, the part A, and then sort of reflect it
17	back, I think that if we say then that we do agree

18	that this kind of information should be required of
19	all over the counter contraceptive products, then we
20	can sort of, or you guys can sort of make some sort of
21	standardized mechanism so that you can put it in a
22	certain sort of well-circumscribed way that's
23	consistent so that when the consumer is going down the
24	aisle, you know, there's sort of a particular place

25	that they can look and see, you know, the comparative

			168
	1	efficacies, and therefore, sort of save room, sort of
	2	in the same way that you'd go down and look at the
	3	saturated fat in your Snackwell cookies or something,
	4	you know.  Just sort of the number of grams or
	5	whatever per any given serving.
	6	            DR. CANTILENA:  Okay.  Well, then, how
	7	about if we -- I'm sorry.  Dr. Neill?
	8	            DR. NEILL:  I, I similarly would favor a
	9	condensation into a single sentence which made sure to
10	include the other OTC.  If the point is to allow
11	people to make a decision about condom, semicid, foam,
12	jelly or sponge versus, you know, pill, et cetera. 
13	While pill's important, if they're there at three in
14	the morning, they ain't going to get it.
15	            The, the other issue related to this
16	second part of the question -- I'm trying to imagine

17	how, in the bathrooms of all of the gas stations that
18	I stopped at on my way to Tennessee, the condom
19	dispensing machine is going to include that
20	comparative information for shelfkeeping units are
21	like, that are a single condom.  And I don't know,
22	does, you know, this doesn't need to be addressed
23	right now, but I could imagine that for some of the
24	other forms that aren't as bulky and don't have the

25	advantage of having a six-pack box that it might raise

				169
	1	some more practical issues for them, more so than the
	2	sponge.  And it's just something to sort of keep in
	3	the back of the mind.
	4		DR. CANTILENA:  Okay.  Well, how about if

	5	we actually call that question that I posed, which is
	6	basically to have the comparative efficacy available
	7	on the outside of the carton with all the caveats in
	8	terms of how it should be simplified, et cetera, et
	9	cetera, which I think is an excellent comment.  All,
10	all in favor of having the comparator information on
11	the outside of the carton, please raise your hand.

12		      (Hand vote taken)
13		DR. CANTILENA:  Dr. Davidson, did you
14	vote?  Yes?
15		DR. DAVIDSON:  No.
16		DR. CANTILENA:  Okay.  So we have nine in
17	favor, and perhaps I can just ask you to comment why
18	you did not.
19		DR. DAVIDSON:  You know, I, I think it's
20	important but I think that, you know, we can have that
21	information inside.  If you give the information of
22	that product on the outside, because if you look at
23	the package, you know, there's other more important

24	information that should be outside, including you're
25	going to state that this is not a 100 percent

			170
	1	effective, you know.
	2	            For, for the information, see the package

	3	insert.  You know, I think we need to make it a little
	4	simpler for the people, you know, that buy these
	5	products.  Otherwise, if you put a lot of information
	6	outside the package, you know, people are going just
	7	to read a couple of things and then no more.  That's
	8	my recommendation.
	9	            DR. CANTILENA:  Okay.  Thank you.  I

10	believe we haven't formally answered 2A although we
11	started to a couple of times.  2A, if yes -- yes,

12	meaning it should be on the carton, should this kind
13	of information be required of all OTC contraceptive
14	products?  And again, we'll first ask all those in
15	favor of having it available on all OTC contraceptive
16	products, please raise your hand?

17	                  (Hand vote taken)
18	            DR. CANTILENA:  I think this time we are
19	unanimous.  Okay, the next question, question three,
20	are there other aspects of the labeling that should be
21	revised?  And here, I guess, we'll just open it up to
22	comments, perhaps going around the room, starting
23	around this side with Dr. Neill.  Any other aspects of
24	labeling that should be revised when we're now, our
25	frame of reference is the 2000 label?

				171
	1		DR. NEILL:  Yeah, I have I think three
	2	questions that I would propose be considered for

	3	inclusion in the section, other questions you may
	4	have.  The first is what if it comes out?  I realize
	5	that difficulty with removal is, you know, the single

	6	biggest complaint or reason for phone calls, but if it
	7	comes out, can you put the same one back in?  Do you
	8	have to use a different one?  If it comes out and you
	9	don't have another one, is that the end of sex?
10		The other question would be, there's just
11	two, not three.  It's related to one that Dr. Gilliam
12	asked a few minutes ago.  Can this be used several
13	days in a row?  And I think that would also allow an
14	appropriately prioritized discussion of the extent to
15	which increased sensitivity may occur if it's used
16	several days in a row.  My perception being, yeah,
17	certainly, it can be.  However, you may experience
18	more irritation with this.  And I think that's a valid
19	concern that needs to be in there somewhere.
20		DR. CANTILENA:  And here, you're talking
21	about in the package insert and not the label?  I mean
22	the front part?
23		DR. NEILL:  In the package insert, right.
24		DR. CANTILENA:  Right.  Thank you.  Dr.

25	Greene, any, any comments about other issues of

				172
	1	labeling?
	2		DR. GREENE:  Not really; just minor.  I

	3	was glad to see under six, there are other questions
	4	you may have, that the first thing it addresses is the
	5	use of a latex condom.  And I do think that's
	6	important.  And the only minor sort of editorial
	7	suggestion is that in that section where it says will
	8	help reduce the risk of transmission of human
	9	immunodeficiency virus, HIV, and acquired immune

10	deficiency syndrome.  I, I would just suggest that
11	that just be changed to read the virus that causes
12	acquired immune deficiency syndrome.  That's just
13	technically a little more correct, but I don't have
14	any major problems.

15		DR. CANTILENA:  Thank you very much.  Dr.
16	Gilliam?
17		DR. GILLIAM:  Just the comments I, I made
18	earlier, especially regarding the irritation and
19	stronger warnings not to use during menses.
20		DR. CANTILENA:  Dr. Lerner?  No further
21	comments.  Dr. Davidson?  Dr. Williams?  Dr. Uden?
22		DR. UDEN:  Only that I think it could be
23	written in a lot less technical terms than what it is,
24	so.
25		DR. CANTILENA:  The insert, the?

				173
	1		DR. UDEN:  Yes, the package insert, yes.
	2		DR. CANTILENA:  Thank you.  Dr. Johnson?

	3		DR. JOHNSON:  My comment is primarily a
	4	practical one regarding what goes on the outside of
	5	the box.  And it has to do with the directions.  I
	6	mean it's not very clear to my, me, why we need to

	7	tell them on the outside of the box that they need to
	8	wash their hands, wet the sponge, put the, the dimple
	9	side facing up.  I mean, it seems to me if you're

10	trying to save space, those are things that someone
11	will look for once they buy the package, once they

12	open it and they're ready to use it.  So it seems like
13	you could get rid of a lot of the things in that
14	direction section.  And then you would have more room
15	for things like how effective is this product, which
16	I think is much more important.
17		DR. CANTILENA:  Yes, follow up to that,
18	Dr. Neill?
19		DR. NEILL:  Yeah, I -- while there's
20	probably room for some editing there, I think at least
21	part of the purpose is to allow people to make a
22	decision about whether they want to use it.  And if
23	there's an advantage to having that kind of explicit
24	direction, it's that some consumers may see that and
25	decide as a result yes, they really want to use this,

			174
	1	as opposed to another method or they really don't want
	2	to use that.  And simply directing somebody to the

	3	package insert inside removes that portion of the
	4	information that helped them use it. 
	5	            And, you know, it's just, who knows
	6	whether that would be the major contributor about a
	7	decision to purchase?  Personally, I think for
	8	information on the outside of the package, if the FDA
	9	or somebody doesn't say something about where the
10	price sticker goes, everything we're talking about
11	means nothing.  And I'm not suggesting that we talk
12	about where the price sticker goes.
13	            DR. CANTILENA:  Further comments, Dr.
14	Johnson?  Thank you.  Dr. Blewitt?  Dr. Krenzelok? 
15	Yeah, I guess, really, I would concur with a lot that
16	has been said.  I, I would also just, under number

17	seven, points to remember, it's not, it doesn't jump
18	right out at you that the product needs to be left in
19	place for six hours after the last act of intercourse. 
20	And I, I would understand, or I understand that if you
21	remove it shortly after, it's high likelihood to, you
22	know, not be effective.
23	            So if there's some way to emphasize that

24	clearly on the insert.  It, you know, doesn't have to
25	be on the outside, but just to make sure that people

			175
	1	don't use it like some other methods where, you know,
	2	you remove it right away after you -- yeah, it's,
	3	right.  But it's sort of, you know buried down there. 

	4	And that's sort of the final point, so if there's some
	5	way to emphasize that, that I think would be helpful.
	6	            DR. UDEN:  Can I make a comment on that? 
	7	Because what that does is effectively you cannot have
	8	sexual intercourse from 24 hours to 30 hours.  So if
	9	somebody has it from 24 to 30 hours, they can't leave
10	it in for six more hours.  So this is only good for
11	sexual intercourse for 24 hours, and then it has to be
12	left in.  And then there's that window there where
13	they're not supposed to have sexual intercourse if
14	they're going to follow the directions explicitly.
15	            DR. CANTILENA:  Yes, Dr. Johnson?
16	            DR. JOHNSON:  I, I did find one other
17	thing I wanted to comment on.  And that was the
18	pregnancy rate tables.  I mean, I think I sort of made
19	it clear I really dislike that table, one because I
20	think they can't understand it.  And secondly, because
21	it sounds like the data has at least some problems.
22	            And I think certainly we need some
23	comparator data, but I think written in the form that
24	Dr. Greenslade suggested is, is much more useful for
25	the patient.

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	1	            DR. CANTILENA:  Okay.  Thank you.  What
	2	I'd like to now do is just turn to the final question. 
	3	And I know the hour is late, but I would really ask
	4	your, you know, patience to, to really give this some

	5	thought because I think it's possibly a very important
	6	issue.
	7	            Question four, please provide comments on
	8	the type of post-marketing surveillance for adverse
	9	events the sponsor should contact, excuse me, should
10	conduct.  And here, we have issues of active
11	collection, follow-up reporting analysis of cases of
12	difficult sponge removal, provisions in place and, to
13	facilitate adequate adverse event reporting.
14	            So again, we started here last time. 
15	Perhaps we can start with you, Dr. Krenzelok, and have
16	you address some of these issues on post-marketing
17	surveillance.
18	            DR. KRENZELOK:  Well, I don't think we
19	should hold them to a higher standard and ask them to
20	have active surveillance on, on this particular
21	product.  But I would strongly encourage, as I
22	mentioned earlier, that a 24-7 server should be really
23	encouraged, competent people, and they should in some
24	way encourage the people that use the product to use
25	that service if it's there.  And then I think that

				177
	1	would really help identify adverse events should they
	2	occur.
	3		DR. CANTILENA:  Thank you.  Dr. Blewitt,
	4	any comments on this area?
	5		DR. BLEWITT:  No.  I would simply agree
	6	with what Dr. Krenzelok has said.
	7		DR. CANTILENA:  Thank you.  Dr. Johnson?
	8		DR. JOHNSON:  Same thing.  I, I agree that
	9	active marketing or active surveillance is not
10	something probably necessary and maybe the sponsor
11	just needs to present a very detailed plan about their
12	consumer hotline and, and how they'll collect their
13	data.
14		DR. CANTILENA:  Thank you.  Dr. Uden?
15		DR. UDEN:  Yeah, I don't think we should
16	hold them to a higher standard.  I mean, unless this
17	question, I mean if, if we did, then we would be

18	setting a precedent for every, every product that
19	would come in front of this advisory committee or in
20	front of the FDA from here until the end, I would, I
21	would assume.  I mean, what would be special about
22	this product that we would ask this versus other
23	products that might, that might become OTC?  Other
24	than that comment, I just hope that the sponsors would
25	have complete and consistent information in, in their

				178
	1	system, so that it's as complete as possible. 
	2		DR. CANTILENA:  Thank you.  Dr. Williams?

	3		DR. WILLIAMS:  The only concern I have is
	4	to look at the CDC data as that comes available
	5	regarding the reintroduction of the product.  We have
	6	a reportable disease and that could be easily
	7	monitored.
	8		DR. CANTILENA:  Thank you.  Dr. Davidson?
	9		DR. DAVIDSON:  I agree with everybody but,
10	you know, one thing I forgot maybe for the low
11	literacy people, you know, a video on how to use the,
12	you know, the device will help us.  And I don't know
13	if the sponsor is willing to, you know, make a video
14	for those very low literacy people.
15		DR. CANTILENA:  Thank you.  Dr. Lerner?
16		DR. LERNER:  Well, we've discussed a lot
17	about the consumer hotline.  But I think also a
18	physician hotline or some way to get the practicing

19	clinicians, you know, sort of plugged into the system
20	so that when they do encounter any adverse outcome,
21	there's a, either a phone number or something
22	accessible -- medical letter or in the journals or
23	however you do that with other stuff.
24		DR. CANTILENA:  Thank you.  Dr. Gilliam? 
25	No further comments.  Dr. Neill?

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	1	            DR. NEILL:  I would never make it on
	2	Jeopardy pushing this button.  The, it's a generic
	3	comment that has to do with the repetitive nature of

	4	this question which I think goes to the question of
	5	the MedWatch system.  If I were to ask my residents,
	6	okay, what's MedWatch, you know, I'd get a 1 out of 36
	7	response rate.
	8	            And, so generically, I guess I would put
	9	in a plea to the agency or some higher up muckety-
10	mucks that have, you know, budget dollars to do
11	whatever might be done to help improve that system as
12	a monitoring system given that it's, you know, relying
13	on lazy physicians like me to both understand that I'm
14	seeing an adverse event and pick it up and report it.
15	            And I realize that there have been a lot
16	of things done to make that easier.  I used to
17	literally go and photocopy the little form out of the
18	back of the PDR.  But I threw all the PDRs out of my
19	office because I hate them as a drug reference and
20	have taught my residents not to use them.  And so now,
21	we've got to go to the web and do all this other
22	stuff, and then the network's down so, again, just a
23	long plea, you know.  Whatever you can do to improve
24	that, make it easier, market it.
25	            Here's a, here's an idea.  We can take

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	1	these FDA NDA fees and take a portion of those or, you
	2	know, we can always hit the sponsors up for something,

	3	right?  Rather than making them pay for an adverse, an
	4	active adverse event reporting system, we, we take
	5	some portion of the money that we, I mean ask from
	6	them for their NDA and put that specifically towards
	7	some of this MedWatch -- I don't know, a MedWatch czar
	8	or something, however that works.
	9	            DR. CANTILENA:  Okay.  Thank you very
10	much.  I, I guess I would only add just a couple of
11	small comments on this issue.  One, one is, you know
12	when I hear a couple things about being a small start-
13	up company and all the employees being here at the
14	meeting, I get concerned that the follow-up and, you
15	know, safety is not going to be adequate.  I'm sure
16	that the plans would be, and I would hope that, you

17	know, you would have agreement on this with, with the
18	FDA that as it goes on the market or hopefully just
19	before the cash flow starts that you would clearly
20	invest in having adequate, you know, facilities,
21	adequate, you know, personnel.  And just make sure
22	there's a very tight, you know, linkage between the
23	800 number and follow-up and the adverse events.
24	            And, and I would say that even because
25	this has not been on the market for basically five or

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	1	six years, it's an opportunity to see how well the
	2	system actually works.  So even if you could agree on

	3	perhaps, you know, quarterly reports instead of annual
	4	reports to see sort of the linkage between the 800
	5	number and the adverse events and, and the follow-up
	6	on the adverse events.
	7	            And I would just, as some free advice to
	8	the sponsors, invest in quality individuals who have
	9	experience in this area because it'll, you know, make,
10	you know, your job a lot easier, and all the people
11	who are watching a lot easier as well if there's good,
12	you know, documentation and follow-up.
13	            So that's my two cents.  Now, I guess,
14	I'll, I just have to ask the FDA if there are any
15	other issues that we have not addressed, any questions
16	that were not adequately answered that you'd like us
17	to address at this time?
18	            DR. GANLEY:  No, I think we got an idea of
19	what your position is, and we appreciate all the
20	comments.  I, I think Dr. Neill made a interesting
21	point there, you know, about the reporting to FDA. 
22	And, and one of the things that was not included in
23	the, the labeling rule was a requirement to include a
24	MedWatch number on there.  And I get a sense that you
25	would actually, or to have some information that you

			182
	1	could, if people could complain to FDA, if not to the
	2	sponsor.  And I'll just point out that the questions
	3	and comment
	4	            MS. CHANG:  Good afternoon.  Guess what? 
	5	I'm the final speaker.  By the way, I want to thank
	6	Daniel Keravitch for all his help in doing these
	7	slides.
	8	            My presentation will be covering our
	9	proposed labeling for the Today Sponge.  Put it down. 
10	Okay.  Basically, I'll start with an overview of the
11	new OTC labeling rules, then the original carton

12	labeling for the Today Sponge, proposed carton
13	labeling for the Today Sponge and the proposed changes
14	to the package insert.
15	            On March 17th, 1999, the agency published
16	an OTC labeling requirements final rule, codified in
17	21 CFR 201.66.  That rulemaking required standardized
18	content and format for all OTC drug products in what
19	they call drug facts format, format and content.  The
20	agency believed that these labeling requirements would
21	make it easier for the consumer to recognize where to
22	find the information and also would make the labels
23	more legible and readable.
24	            The drug facts labeling content
25	requirements required the following:  that all

			183
	1	information would be organized under title, headings
	2	and subheadings; that all drug facts label information

	3	must appear on the outside of the container or wrapper
	4	of the retail package or on the immediate container if
	5	there was no outside container or wrapper; and that
	6	the headings and subheadings appear in a specific
	7	order which would allow the consumers to more quickly
	8	make a decision as to whether they should use the
	9	product, when to stop using the product and how to use
10	the product.
11	            The standardized headings are in the
12	following order:  title, which is always titled drug
13	facts; the active ingredients or ingredient and the
14	amount; the purpose; the use or uses; the warnings. 
15	And under the warnings, there is a standardized order
16	for the subheadings.  For example, do not use; stop
17	use and ask a doctor if.
18	            Next comes the directions.  After the
19	directions, there is a heading titled other
20	information.  This section includes information not
21	included in the other sections, but for which the
22	agency feels is pertinent to the safe and/or effective
23	use of the product, or information that is required
24	under an OTC drug monograph.
25	            The last section is the questions or

			184
	1	comment sections which provide phone numbers for
	2	consumer inquiries.
	3	            The labeling rule requires standardized
	4	formats so that there is consistency in the format for
	5	all labeling.  For example, there are type size
	6	specifications for the headings, subheadings and text. 
	7	There are also bulleted format to improve readability.
	8	            The agency considers the labeling for OTC
	9	drug products, considers the carton, which consists of
10	the principal display panel and promotional labeling

11	and the required labeling, for example, the drug facts
12	label, as part of the labeling.  Also, the package
13	insert.  Dan.
14	            I'm going to make some comments on the
15	1991 labeling.  As you can see, this part is called
16	the principal display panel, and Dan's going to focus
17	on the -- this section is the approved label which

18	contains the directions and warnings.  Basically, as
19	you can see, the directions are in a paragraph format
20	which we believe is difficult to read.  Also, the
21	important information is not emphasized.
22	            For example, the toxic shock statement is
23	not prominently emphasized.  And as you can see, they
24	are in two separate sections, this section, and also
25	the symptoms are in this section right here.

				185
	1		Further, there is no statement in the
	2	labeling that addresses or informs consumers of the
	3	serious nature or potential life threatening nature of
	4	this, of toxic shock syndrome.  Just, I think that's
	5	that for that.
	6		I just want to show you the other
	7	information as far as the inactive and active
	8	ingredients are on the other, the back panel.  Can you
	9	go back?  Should I just click?  Great.
10		We have revised the Today Sponge labeling

11	as follows.  Oh, I have, is that the, did I click? 
12	Oh, I'm sorry.  I'll start with this one.
13		Thus, there are some reasons for the
14	labeling revisions are to remove misleading statements
15	such as reliable protection without serious risks of
16	dangerous side effects, and extremely effective.
17		Other reasons for the revisions are the,
18	to improve the order of information so there is more
19	emphasis on the warnings, in particular, the toxic
20	shock syndrome warning.  Also, to add additional
21	important information such as AStop use and ask a
22	doctor if@ statements, and to improve directions and
23	other information for better understanding of the

24	safety concerns and other public health issues.
25		We have revised the Today Sponge labeling

			186
	1	as follows.  First of all is its standardized order in
	2	accordance with the drug facts format.  And this is a

	3	copy -- Helen, did you show the, you showed the copy
	4	of the original label.  We're going to break this down
	5	to make it more readable for all of you.
	6	            Please note that the revisions are in red
	7	font, are the new additions to the label or statements
	8	which we have either moved or revised from the
	9	original labeling, and the statements in the black
10	font are the statements pulled from the former
11	labeling which may have reformatted into the new drug
12	facts label.
13	            I will be discussing particular sections
14	of our proposed drug facts labeling.  And this section
15	is the warning section.  Significant revisions were
16	made to this section.  First and foremost, the TSS
17	warning is prominently displayed as the first specific
18	warning.  We have added the statement TSS is a rare
19	but serious disease that may cause death.  Additional
20	revisions are what you can see on the slide.
21	            In addition, we've added the allergy alert
22	section to inform consumers that this product contains
23	a sulfite, and also that this product contains
24	nonoxynol-9.
25	            We have also asked that the various

			187
	1	revisions in red to this section.
	2	            I want to focus in primarily on the Astop

	3	use and ask a doctor if.@  This section was provided
	4	to alert consumers so that they would know if certain
	5	conditions would develop during sponge use.  Note that
	6	this information was not in the 1999 final printed
	7	label.
	8	            Under the directions, we have bulleted the
	9	information to make it easier for the consumer to read
10	and added additional directions.  I lost my pointer. 
11	We've, we've, we've moved the statement Ado not leave
12	in vagina for longer than 30 hours@ from the warnings
13	into this section and bolded for emphasis.  Next.
14	            Under the other information heading, we
15	added two new bulleted statements.  The first is to
16	inform consumers of the availability of the pregnancy
17	rates, birth method, birth control methods table in

18	the package insert and to provide public health
19	information statement of the use of latex condoms to
20	reduce the risks of the transmission of HIV and STDs.
21	            Now, I'm going to go and discuss the
22	changes to the package insert.  Because of time
23	restraints, I will only be discussing some of the
24	major ones.  First would be to improve the
25	presentation of the efficacy data.

				188
	1		Second is to include the pregnancy rate
	2	birth control methods comparative table in the package
	3	insert.
	4		Third, we added, just wanted to basically

	5	tell you that we added some references to reducing the
	6	risk of sexually transmitted diseases in the package
	7	insert.  I lost the pointer.  Okay.
	8		Fourth, we made format and minor editorial
	9	changes to the package insert.  As you, as you can see
10	from the original efficacy data statement and efficacy
11	table, I think it is basically, thank you, I think
12	it's basically very confusing to a layperson.  In
13	fact, I sort of got confused by reading it also.
14		What we did was we basically revised and
15	simplified the statements on the efficacy statement to
16	make it more consumer friendly, and I believe someone
17	already discussed the revised statement.
18		I'll talk a little bit about the pregnancy
19	rate table.  Back in 1997, the Center for Devices and
20	Radiological Health in collaboration with CDRH, which
21	is the Center for Drug Evaluation and Research, and
22	the Office of Women's Health adapted the pregnancy
23	rate table from Trussell's Contraceptive Technology
24	basically to, to provide the consumers with
25	information to make the informed, to -- let me start

				189
	1	over.  To provide consumers with information to make
	2	informed choices as to the best birth control method

	3	for them.  At present, the table is included with all
	4	prescription oral contraceptives and is a regulatory
	5	guidance for other CDRH and CDER birth control
	6	products.
	7		In -- these are my conclusions.  Current
	8	labeling can be improved.  The drug facts format
	9	places emphasis on the warnings, such as the TSS

10	warning and the Astop use and ask a doctor if@ are
11	examples of that.  And provides more readable and

12	informative information to the consumer to improve the
13	safe and effective use of the Today Sponge.  Thank you
14	very much.
15		DR. CANTILENA:  Okay.  Thank you very much
16	for actually staying ahead of schedule.
17		MS. CHANG:  And I wanted to -- right.  I
18	was going to turn the podium over to Dr. Cantilena for
19	questions and comments.
20		DR. CANTILENA:  I'm sorry.  I beat you to
21	the punch.  I apologize.  Yes, actually, we are at the
22	point now where we have some time to ask the FDA
23	presenters specific questions that you may have.  So
24	let me open it up to the, to the committee.  Dr. Uden?
25		DR. UDEN:  We've had toxic shock syndrome

			190
	1	data presented a few times here today.  You have a
	2	database here at the FDA.  There's also a database at

	3	the CDC.  How many other places is, is the data, data
	4	kept and has anybody compiled the data in one place so
	5	that we can get a relatively good estimate of the
	6	risk?
	7	            DR. KARWOSKI:  Well, I actually don't have
	8	the answers for that.  Not that I'm aware of.  I would
	9	imagine that CDC probably has the best numbers.  Ours
10	is a voluntary and a passive surveillance, and so we
11	only rely on consumers or health care providers to
12	report that information to us.
13	            DR. UDEN:  Are those the two major sources
14	of, other than primary literature, finding the
15	incidence of toxic shock syndrome?
16	            DR. CHIN:  Let me clarify that a little
17	bit more.  What we have in our database that was
18	presented by Claudia is information that was
19	voluntarily submitted or regulatorily (sic) required
20	to be submitted to the FDA's spontaneous reporting
21	system or the current AER as database.
22	            What CDC has is TSS is a reportable
23	disease, and so it has to be reported to CDC.  And

24	they compile the statistics that you would see for a
25	lot of infectious disease.  The difference in the

				191
	1	database is that what we have in terms of the adverse
	2	events, it would be adverse events that were reported

	3	in conjunction with the use of a sponge.  It doesn't
	4	mean that it causes the adverse event, but it was in
	5	conjunction with the use.
	6		What CDC's information has is the number
	7	of TSS cases, but doesn't necessarily break it down
	8	into what was used in association with the case

	9	itself.  So they're really separate types of numbers. 
10		DR. CANTILENA:  Other questions?  Yes, Dr.
11	Davidson?  Your microphone?
12		DR. DAVIDSON:  Thank you, forgot.  I have
13	a couple, you know.  You reported cases of disability,
14	but you didn't say what type of disability they were. 
15	Could you tell us what disability meant in the cases?
16		DR. KARWOSKI:  The outcomes are very
17	subjective.  That really depends on what the
18	individual that reported the event may have thought. 
19	For the disability, there was, in my opinion, there
20	was no apparent disability that was caused.  One of
21	them was the TSS cases.  They reported life
22	threatening hospitalization and disability, but there
23	was no apparent long-term type disability associated
24	with that.
25		The second case was a disability. 

			192
	1	Essentially, what the patient reported was that
	2	following the use of the sponge, her and her husband
	3	were not able to perform sexually as they had prior to

	4	the use of it.  So that was the, the second disability
	5	that was reported.
	6	            DR. DAVIDSON:  Thank you.  You know, we
	7	already commented before from previous presenters that
	8	the highest rate was seen in 1984, okay.  Do we have
	9	any data of the exposure, you know, in 1984, 1985,
10	1986 of sponge use to see if there's, if it is a
11	relationship between the usage and the cases.  Or it
12	was the, you know, after 1984, people were better
13	educated, you know, to draw some conclusions why it
14	really went down after 1984?
15	            DR. KARWOSKI:  After, actually it didn't
16	really go down.  It stayed somewhat stable.  There
17	were bumps throughout the years.  We don't have any
18	actual usage data.  All we have is some data regarding
19	the distribution of the product, so the sales of the
20	product.  But we don't have numbers of how many people
21	actually used the product or how frequently they may
22	have used it.
23	            So we can't really put a denominator on

24	that.  But what we're somewhat sure of that the use
25	did decrease somewhat over the years, and the rate of

					193
	1	TSS, or at least, the reports that we had received
	2	didn't really decline that much, at least over, after

	3	1985 to 1994, that they remained somewhat stable with
	4	little, you know, small fluctuations, varying, you
	5	know, throughout the years.
	6		DR. DAVIDSON:  From the data you
	7	presented, you know, even though there were some small
	8	fluctuations, the tendency was to go down.  Maybe I,
	9	no?  Okay.  Then it remained about 47 cases per year?
10		DR. KARWOSKI:  Well, we had only one case
11	reported in 1995, but the product at that point was --
12		DR. DAVIDSON:  But the product was
13	withdrawn, right.
14		DR. KARWOSKI:  -- had stopped.
15		DR. DAVIDSON:  Okay.  And one final
16	question, when you report infections, and you report
17	vaginitis in different sections, the vaginitis was
18	also included in the infections or were they reported
19	totally separate for everything?
20		DR. KARWOSKI:  The vaginitis in our
21	database are considered infectious type of
22	complications.
23		DR. DAVIDSON:  Then it was reported twice?
24		DR. KARWOSKI:  May have.  There may have
25	been an infection and vaginitis at the same time.

				194
	1		DR. DAVIDSON:  Thank you.
	2		DR. CANTILENA:  Yes, Dr. Neill?
	3		DR. NEILL:  I have two and a half
	4	questions, the first to Dr. Karwoski.  You discussed

	5	the, a couple of examples of monitoring systems.  Can
	6	you give me an example of a system that's currently in
	7	use that actively as opposed to passively monitors
	8	adverse events for a currently marketed OTC product
	9	that's subject to an FDA, NDA or OTC monograph?
10		DR. KARWOSKI:  We don't currently know of
11	or are aware of any type of systems that would do
12	that.
13		DR. NEILL:  So for other similar products
14	to this that would fall under similar FDA  regulation,
15	there's not an active process in place.  So if we were
16	to shortly hear a charge that were to ask us to
17	consider whether or not there should be some active
18	collection or an active process for monitoring adverse
19	events, this would be a first.  Is that safe to say?
20		DR. KARWOSKI:  That, this would, as far as
21	I'm aware.
22		DR. NEILL:  Okay.  My other questions have
23	to do with putting statements about efficacy on the

24	carton.  And it's sort of a question and a half, so
25	I'll ask them together, and whoever from the FDA or

			195
	1	Allendale wants to address this, please feel free.
	2	            Is FDA aware of any product that's
	3	similarly under an NDA or OTC monograph that has
	4	efficacy labeling on the carton by virtue of it being
	5	required to be there by FDA, and if so, is there
	6	language in the recent Federal Register regulations
	7	that require that?  My understanding being that the
	8	proposed label that you just reviewed includes all of
	9	the bullets and components that are required.
10	            And I guess my perception is that if we're

11	being asked to judge whether or not efficacy data for
12	this should be on the carton, comments about, you
13	know, having additional process hearings to make sure
14	it happens for other products aside, I'm curious to
15	know are there other products for which that's already
16	happened, that the FDA has asked that that happen?
17	            DR. GANLEY:  Yeah, the one that comes to
18	mind, at last on the carton is Rogaine or topical
19	minoxidil, where it's included in other information,
20	where it provides efficacy information to the consumer
21	at the point of purchase.  There are other products
22	that provide efficacy information in package inserts. 
23	H2 blockers for heartburn, for example, would be an
24	example.
25	            DR. NEILL:  Are, were those for Rogaine

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	1	and some of the H2 blockers required by the FDA to be
	2	on the carton?
	3		DR. GANLEY:  Yes, they're marketed under
	4	NDAs and so we, we require that.  I don't believe

	5	there's any monographs that would fall into that
	6	category right now. 
	7		That doesn't say that in the future there
	8	won't be, but, but from a regulatory point of view,
	9	you can require someone to do that.
10		DR. CANTILENA:  Yes, Dr. Blewitt?
11		DR. BLEWITT:  Just two, two points I think
12	that are relevant here.  First, I think that with
13	regard to comparative efficacy, that has not been
14	required.  So you make, make a statement about
15	individual efficacy.  You wouldn't have, at this point
16	in time, there is no, there are no comparative
17	efficacy statements required on labeling.
18		In addition, the, with regard to adverse
19	events monitoring, it seems to me that any, any
20	product that's subject of a new drug application has
21	to both monitor and submit to the agency reports of
22	adverse events that they received, so, so that is
23	required.
24		DR. GANLEY:  Yeah, I just think that, I
25	got the, my impression of your question was that there

			197
	1	was some type of phase four commitment where we
	2	required a company to go out actively and look for

	3	cases in a population as opposed to an individual
	4	passively reporting it.  I think that's what your
	5	question --
	6	            DR. NEILL:  Yes, exactly.  For an OTC
	7	product where, as a health care provider, I'm not

	8	involved except in some circumstances in a decision to
	9	go and pick it up off the shelf, I'm not going to fill
10	out a MedWatch form and send it in for a patient that
11	by all rights may never see me and may only speak to
12	the, may only speak to the company.  And so I'm
13	interested in active looking versus passive.
14	            DR. CANTILENA:  Other questions for FDA,
15	Dr. Johnson?
16	            DR. JOHNSON:  Yes, my question is
17	primarily directed to Dr. Chang, and that has to do
18	with the comparator table of efficacy.  And I'm
19	wondering if you can comment on Dr. Greenslade's
20	comments about how that table was derived.  I mean,
21	frankly, the sentence he read bothers me a little, and
22	the fact that it's in other contraceptive products
23	doesn't, doesn't necessarily make it what sounds like
24	good data.
25	            MS. CHANG:  I believe that the agency

			198
	1	wanted some kind of a method that, to have the
	2	consumers basically make an informed choice.  It's
	3	generally not to, to improve that process of selecting
	4	their birth control method.  And it was mainly for
	5	informational purposes so they can make that choice,
	6	that maybe because of their condition they should not
	7	use this product, because of, of the dangers of
	8	getting pregnant, they should use another product that
	9	may have more of a, a better pregnancy prevention
10	claim for an efficacy statement.
11	            DR. JOHNSON:  Well I, yes, I think it's a

12	great idea to provide information to consumers so they
13	can make decisions, but if the information is flawed
14	or is not based on real data, then I'm not sure that
15	that is useful information for a consumer.
16	            MS. CHANG:  I believe, and I can ask Dr.
17	Chang on that, Dr. Chin on that one, but basically,

18	Dr. Trussell, it was more of a retrospective type of
19	a data base.  Is that right, Ling?  Okay.
20	            DR. CHIN:  Let me see if I, I'll try to
21	clarify this.  The Trussell table is a reference
22	table.  In terms of trying to get a sense of birth
23	control rates for the different, or pregnancy rates
24	for the different birth control methods, we have to
25	come up with one reference, one table that hopefully

			199
	1	would give consumers a sense of how effective each
	2	birth control method is.  And I agree.  If you look at

	3	the methodology that was applied to how that table was
	4	developed, it is definitely not consumer friendly. 

	5	It's above most everyone's reading of it, and, and I
	6	tried to get through it.  It's very difficult.
	7	            But the agency undertook a point of
	8	reference by which information that is from a reliable
	9	source and Contraceptive Technology is an accepted
10	reliable source for contraceptive information.  And as
11	far as contraceptive rates, I mean as far as pregnancy
12	rates are concerned, that's an accepted point of
13	reference.
14	            Aside from that, the agency tried to make
15	that table more consumer friendly.  We did adapt it
16	somewhat and the table was subject to focus group
17	discussions, so that the presentation of the table is
18	slightly different than the table in Trussell's table. 
19	It's more consumer friendly than that.
20	            It is really just a means of providing
21	information across the board of all the various
22	methods, knowing that we do not have one single
23	clinical trial that will do head to head comparisons

24	of every method, and by which we can come up with the
25	usual standards of comparing effectiveness by each

			200
	1	method.  And that's the point of the table.  Does that
	2	clarify it?
	3	            DR. JOHNSON:  I mean, it, it clarifies,
	4	but I guess it doesn't sort of get at the base of how,
	5	how valid is the data in that table.
	6	            DR. GANLEY:  Well, I think one of the
	7	things you have to remember that this was a table
	8	that's included in prescription products.  There's a
	9	learned intermediary there who can read it and
10	hopefully understand it.
11	            And I think there's two things to, to

12	understand here -- is conceptually, should we have
13	that information in OTC products, number one.  And
14	number two, is how should that information be
15	prevented (sic)?  I would agree with the presentation
16	that I find it very unconsumer, it's not consumer
17	friendly and, but the question, I, the first question
18	is should we have comparator information so the
19	consumer can make that choice.  And then we can decide
20	on what the adequate reference is and how to present
21	that information.  I think that's what we're trying to
22	get at.
23	            You're looking at a table that a, a
24	physician can read, understand certain caveats in it
25	and convey those to a consumer, and I would totally

			201
	1	agree that a consumer, and even I have a problem
	2	looking at that table and understanding the rates in
	3	the comparator columns that he had pointed out
	4	earlier, so.
	5	            DR. CANTILENA:  Yes, Dr. Blewitt?
	6	            DR. BLEWITT:  Yes, I, I agree with Dr.
	7	Johnson though, and I agree with the point that's
	8	being made, but if the data are quote flawed, which is
	9	a term that I've actually used myself, if there are

10	better data that exist, or if there are better ways to
11	find out what, what the real data are, then, you know,
12	that would be the ideal situation, but I think to take
13	data that, or, I ask that the sponsor speak to this,
14	too.  If these are not hard data, then you're taking
15	soft data or inferential data it sounded like to me
16	and now you're making it more consumer friendly.  So
17	I don't think that that accomplishes what you want to
18	accomplish either.
19	            I, I agree that in a situation like this,
20	you know, where pregnancy is the risk, if you will,
21	that the women should understand what the comparative
22	benefits are, of products are.  The question is how
23	good are the data, the comparative data that they're
24	trying to interpret.
25	            DR. CANTILENA:  Yes, you know, actually,

			202
	1	I have a, a question if I can ask the, the folks on
	2	the committee who actually practice in this area just

	3	to get sort of your read.  Are the numbers that are in
	4	that table, Drs. Greene and Lerner, are they within,
	5	you know, the ballpark, or --
	6	            DR. LERNER:  No.
	7	            DR. CANTILENA:  Okay.  Could you, could
	8	you comment a little more on exactly what you mean by,
	9	you know, they're not in the ballpark and especially
10	if there's a way in which you can present, you know,
11	relative information.
12	            DR. LERNER:  In, in our out-patient clinic
13	which is just a very typical, you know, low socio-
14	economic Medicaid type patient population, we have a
15	beautiful poster -- I don't know the source of the
16	poster; I'm sure I can find out -- that actually has
17	all the benefits and, you know, sort of the
18	advantages, the disadvantages, a little, pretty
19	graphic on all the different methods.  And the, you
20	know, estimates on efficacy rates.  And you know,
21	that's sort of what we, you know, use in all our, you
22	know, OBGYN techs.
23	            I'm sure the American College of OBGYN or
24	the, you know, family planning organizations must have
25	reasonable data.  I'm sure there's data out there,

			203
	1	other than Contraceptive Technology, not that I'm
	2	belittling that, but I kind of am.  That I think that
	3	as a much more global scope, that we might, or you

	4	might sort of do an, a detailed in-depth review of
	5	some of the references and just try and find out with
	6	some, you know, find out some reasonable numbers and
	7	then just, you know, put them in all of the, all of
	8	the inserts as needed because I, I don't think they
	9	are.
10	            You know, we quote, you know, roughly what
11	we've seen which is barrier methods, roughly in the
12	ten percent range, so to think that the Today Sponge
13	has 40 percent, which was listed on that, just is
14	really way out of, of the realm of what we, we sort of
15	quote to patients and our estimates.
16	            DR. GANLEY:  I think in the one column

17	that was pointed out were typical use rates, and you
18	know, I would agree with the comments earlier.  But I
19	think something like the lowest expected rate of
20	pregnancy, is that way out of the ballpark?  Where it
21	actually lists the vaginal sponge as nine percent?
22	            DR. LERNER:  No, that's reasonable.
23	            DR. GANLEY:  Yes, that's what I'm, so

24	there is some information there that shows you in
25	terms of order magnitude compared to other methods.

					204
	1		DR. LERNER:  But then the table needs to
	2	be modified.
	3		DR. GANLEY:  Right, I'm --
	4		DR. LERNER:  No, then the table needs to
	5	be modified.
	6		DR. GANLEY:  Right, I -- 
	7		DR. LERNER:  And just, you know, we
	8	usually quote, you know, abstinence, a hundred
	9	percent, you know, tubal ligation, you know, 99.5

10	percent, OCPs 98 to 99 percent, you know, condoms,
11	diaphragm, you know, everything, withdrawal, you know.
12		DR. CANTILENA:  Okay.  Further comments,
13	Dr. Greene?  Would you like to add to that?
14		DR. GREENE:  Yes, I'd, I'd like to address
15	that.  I certainly agree.  I think that the numbers
16	quoted here are way out of line and much higher than
17	we would normally quote our patients.  And most
18	reference material that we would use, certainly, the
19	American College of OBGYN does have a, a patient
20	information literature that has numbers that don't
21	resemble this even closely.
22		I would like to revisit, since we're at
23	this point, the issue that was brought up a little

24	earlier, which is your denominator.  And I would
25	certainly favor or recommend that the, sort of the

				205
	1	industry standard is how many pregnancies occur among
	2	a hundred women using the method for one year, a
	3	hundred women years.
	4		Now, that can be made, that can be made
	5	readily understandable for patients.  And the problem
	6	of having less than one woman per hundred women years
	7	is understandable.  Patients understand that.  And
	8	whether it's one in a thousand or one in two thousand,
	9	most women don't worry about those differences too
10	much.  If you just say less than one woman in a
11	hundred using the method for a year, people understand
12	that.
13		And with that as the standardization, I
14	think you could get numbers here that are very easy
15	for lay people to understand, and much more in line
16	with what we generally quote our patients.
17		DR. CANTILENA:  Okay, thank you very much.

18		DR. LERNER:  And just one further thing. 
19	I, I do assume that we use all the American College of
20	OBGYN.  They have tons of patient and physician
21	information stuff, so I, I do encourage you all to
22	sort of look into that.
23		DR. CANTILENA:  Okay.
24		DR. GANLEY:  Yes, I just want to point out
25	one thing that, you know, Dr. Greenslade hadn't really

			206
	1	touched on.  And one of the reasons, I think, in our
	2	proposed labeling where it said one out of ten is we

	3	really didn't know where that rate came from and what
	4	it was pertaining to, because if you actually look at
	5	the current labeling, it's written as in clinical
	6	trials of today, vaginal contraceptive sponge since
	7	1979, over 18,000 women worldwide have completed over
	8	12,000 cycles of use.  The results of these clinical
	9	trials are as follows, pregnancy rates per 100 women. 
10	And they just list them.
11	            And I think it goes back to what Dr. Chin
12	had reported, that when this was initially approved,
13	if you remember, the, the pregnancy rates, it was 12
14	month pregnancy rates.  And then a year later, we're
15	just talking about pregnancy rates without any time
16	frame.  And that's why, you know, we went through the
17	regulatory history, because we're a little confused as
18	to what rate we're talking about there, too.  But I
19	think we understand your point.
20	            DR. CANTILENA:  Okay, Dr. Uden?
21	            DR. UDEN:  If I can -- are we done with
22	that?  Because I wanted to ask a question about the
23	allergy alert, so if we're not --
24	            DR. CANTILENA:  Is this a question that's 
25	you know, specifically to FDA?

				207
	1		DR. UDEN:  Yes, it's specifically to FDA.
	2		DR. CANTILENA:  Yes, okay.
	3		DR. UDEN:  Dr. Karwoski, in the allergy
	4	alert, it, in the suggested label changes, it was TSS

	5	and then allergy alert was right after that, if you're
	6	allergic to metabisulfites.
	7		I noticed in the data that you reported
	8	that there were only two allergic reactions.  Has
	9	there been any allergic reactions associated with the
10	sponge that have been systemic allergic reactions or
11	are these local allergic reactions, and are they

12	presented in your, one of your graphs as pruritus?
13		DR. KARWOSKI:  We didn't, I didn't go back
14	and pull all cases of any, you know, allergic type of
15	reactions.  These two were systemic type of reactions. 
16	There are other cases, but we didn't review that.

17		DR. CANTILENA:  Okay.  Dr. Krenzelok?
18		DR. KRENZELOK:  Back to the more mundane,
19	being the director of a poison center, I'm always
20	sensitive to what children put in their mouths.  Now,
21	I notice on the label it says keep out of the reach of
22	children.  That seems right.
23		Unless I've missed it, I didn't see
24	anything about proper disposal methods of the sponge
25	after it's been used.  And it might get tossed into

				208
	1	the toilet inappropriately or into a garbage can or
	2	wrapped up or whatever.  But children see those as

	3	attractive nuisances, as disgusting as that might
	4	seem.
	5		I guess my question is in your passive
	6	surveillance system review, did you find -- I'm not
	7	worried about the toxicity of, of at least, the parent
	8	product.  But did you find any instances of, of
	9	choking among small children at all, who might have

10	gotten these, chewed them, swallowed them and had a
11	problem?
12		DR. KARWOSKI:  We didn't go and look at
13	those specifically, but the lowest age that we found
14	for an adverse event report was 12 years old, so I
15	would assume that no, we haven't had any reports.
16		DR. KRENZELOK:  Okay.  Thank you.
17		DR. CANTILENA:  Okay, what I think I'd
18	like to do now is move actually to the charge to the
19	committee by Dr. Ganley and then we'll still have
20	ample time for discussion prior to going into the
21	questions.
22		DR. GANLEY:  Yes, I'm just going to keep

23	my remarks brief since I had made some earlier remarks
24	to try to focus the discussion.  I think the one thing
25	I, I just want to emphasize again that, you know, one

			209
	1	of our purposes for reviewing the entire data base is
	2	as a division, we weren't familiar with this product. 
	3	And so we weren't familiar with the safety of the
	4	product.  And we thought it warranted a safety review

	5	to see if the other information needed to be included
	6	in there.
	7	            In doing that, I think we developed a
	8	comfort level that there was still a benefit, the risk
	9	benefit still favored this product to be marketed. 
10	That's number one.
11	            And I think the other thing that I want to
12	make a point of that in the years since the sponge
13	discontinued the marketing, the, the agency has gone
14	to great lengths to try to improve the OTC labels. 
15	And we've developed standards now that are actually in
16	the codified regulations.
17	            And so, I think our position is that we
18	should try to improve this label before it goes back
19	on to the market, once they get their chemistry issues
20	resolved.  And we can just go to the questions now.
21	            And these are just the questions that we
22	had brought up.  And one was given the material
23	provided in your briefing packages and presented
24	today, does the revised labeling adequately convey the
25	risk associated with the use of the product?  The

			210
	1	current carton label does not contain information on
	2	the efficacy of the product.
	3	            Should the carton label include efficacy
	4	information so that the consumer will have this
	5	information available at the point of purchase?  And
	6	I think in writing this question, we were focusing
	7	more on the information that had come from the
	8	clinical trials, rather than the comparative.  But if
	9	you want to comment on the comparative part -- and we

10	were looking at more in the vein, I think, of what is
11	currently on the topical minoxidil for hair growth as
12	providing that type of information.
13	            And if, yes, it's this type of
14	information, should it be on other OTC products? 
15	That's the important thing there.
16	            Are there other aspects to the labeling
17	that we, that should be revised?  We're interested in
18	any comments.  And the other thing is to please

19	provide comments on the type of post-marketing
20	surveillance for adverse events the sponsor should
21	conduct.  And I think the reason for that is, as
22	Claudia had pointed out, as years progress, the
23	reports that have come in have been lesser quality. 
24	It's very hard to look at these things as a safety
25	reviewer and make some determination of causality. 

			211
	1	And we, we think it's very important that these
	2	reports, if they're, if they're given to a sponsor, be
	3	well written, someone follows up on them, collects
	4	information and then provides them to us.
	5	            I think the other issue is the type of
	6	information we should ask in terms of the company
	7	getting calls from consumers about difficulty removing
	8	the sponge.  And how should that be cataloged?  What
	9	kind of follow-up should be provided?  Should the

10	company contact the consumer a day or two later just
11	to see that everything's okay?  And those are the

12	types of things that I think we're interested in. 
13	Thank you.
14	            DR. CANTILENA:  Okay.  Thank you, Dr.
15	Ganley.
16	            I think, actually, just before we go to
17	the, to the specific questions, what I'd like to do is
18	invite the committee, actually, individually.  We'll
19	sort of go around the table, just to offer sort of
20	general comments regarding some of the issues in terms
21	of what they've seen.  Some of, you know, the
22	conflicts that, you know, they've identified, and then
23	after we go around and everyone's had a chance to sort
24	of air their concerns or express their opinions
25	regarding sort of the global issues, then we'll come

			212
	1	back and go through the questions, one by one.  So
	2	we'll, actually, if you don't mind, perhaps we can
	3	start over on this side.  Dr. Krenzelok, if you'd like
	4	to share with us your thoughts at this point without
	5	actually specifically answering questions.
	6	            DR. KRENZELOK:  All right.  Thank you very
	7	much.
	8	            Just a couple of things that have, have
	9	sort of dawned on me as we've discussed this.  From

10	the standpoint of, of this as a, a package that might
11	contain three or six or nine or twelve sponges, as I
12	stated earlier, it seems to me like there needs to be
13	information on each and every sponge that talks about
14	how to use the product properly and so on, rather than

15	there being a single package insert for the container. 
16	Again, given the portability of them and the ease of
17	taking them and throwing them into a purse or a
18	briefcase or something of that nature.
19	            Another thing that, that I'm sensitive to,
20	again, working in a, in a 24-7 type of situation is
21	the fact that I think here's an opportunity to be very
22	proactive with surveillance.  So that in sort of a
23	passive way, to have 24-7 availability, not just

24	through pagers, but have a real live body there, a
25	competent person.  And one of my thoughts on that is

				213
	1	perhaps that it might be wise to out-source something
	2	like this to a nursing triage service, like Ask-A-
	3	Nurse, who's there's 24 hours a day, seven days a week
	4	as a, as a possibility.
	5		And then the other thing along those
	6	lines, and, and it's been addressed before is the
	7	importance of some of those people having bilingual
	8	capabilities, at least Spanish and English for this
	9	country.  So those are just the thoughts that I had.
10		DR. CANTILENA:  Great.  Thank you for
11	those comments.
12		I guess, you know, one possibility would
13	be to out-source through a poison control center.
14		         (Laughter)
15		DR. KRENZELOK:  That would be a conflict
16	of interest.
17		DR. CANTILENA:  Dr. Blewitt, would you
18	like to share with us some comments?
19		DR. BLEWITT:  I guess my, my own
20	observation at this point is that the issues are very,
21	very narrowly focused now.  I don't see a great deal
22	of difference between the sponsor and, and the agency
23	on, on, on the principles involved in the labeling. 

24	It's just a matter of how those things are worked out.
25		The only thing that we haven't discussed,

			214
	1	and I don't know whether it's up for discussion.  But
	2	in the review package, there's a consumer information

	3	leaflet.  And there's, there are about three pages of
	4	--
	5	            DR. CANTILENA:  Can you help find us that
	6	--
	7	            DR. BLEWITT:  Well, two, two pages.  This
	8	is in the section on 2000 label submission, and it
	9	comes after the drug facts labeling.  And, again, I

10	don't know if this is up for discussion.  But it seems
11	to me that as I read through this, I had a few
12	concerns, that it's been significantly edited.  It's
13	been, as far as I can see, substantially expanded in
14	size.  And I'm, without getting down to the details of
15	it, a question again arises as to whether the
16	consumer's receiving too much information here.
17	            So I, for instance, on -- well, I will
18	give you a for instance.  There's a comment in here
19	you can avoid the risk of getting sponge-associated
20	TSS by not using the sponge.  Well, that seems to be
21	a rather reasonable and unnecessary statement.  I
22	mean, you won't get it if you don't use it, for sure.
23	            But the, the major point is that there are
24	a lot of red additions.  There are black, there are
25	deletions, but it's a much larger consumer information

				215
	1	leaflet than it was originally.  And without being
	2	judgmental about it, I would just ask people to
	3	consider whether that's just overloading the consumer
	4	with information to the point where they won't read
	5	it.
	6		DR. CANTILENA:  All right.  If you use, if
	7	you use headers in the format, though, isn't, you
	8	know, isn't it sort of easier to, to help sort of the
	9	scanner to be able to?
10		DR. BLEWITT:  I have no question about

11	the, the format.  It's, it's only in terms of the
12	amount of content, the volume of content.
13		DR. CANTILENA:  Great.  Thank you very
14	much, Dr. Blewitt.  Dr. Johnson, would you like to
15	share some comments?
16		DR. JOHNSON:  Most of my comments probably
17	relate specifically to the questions.  I mean, I think
18	that it's pretty clear that this is a safe product,
19	and that there's not much question that another
20	contraceptive method for women is a good thing.  And
21	so, I think that it, it really does seem to be just a
22	matter of working out the, the little details in the
23	labeling.
24		DR. CANTILENA:  Okay.  Dr. Uden?
25		DR. UDEN:  The only thing I'll add is, is

				216
	1	I'm concerned about the consumer comprehension of the
	2	present label.  The old one, the new one that's been

	3	submitted, suggested by the FDA and that, that maybe
	4	a consumer comprehension study needs to be done to

	5	determine whether they can, somebody can understand
	6	it.  And, you know, maybe it needs to have cartoons
	7	on, cartoons in the, in the package insert so that
	8	people can really understand how to use it.
	9		DR. CANTILENA:  How do, how do you feel

10	the 2000, you know, proposed label compares, you know,
11	to the `91?
12		DR. UDEN:  Much better.
13		DR. CANTILENA:  Dr. Williams?
14		DR. WILLIAMS:  I agree with what has been
15	said previously.  I have no new, I guess, information,
16	more than I've used in the past.  I've used this
17	product when I was in my practice and it was
18	available.  So we were very conscious of the pitfalls
19	about the use of it as well as the literacy of the
20	patients that we had to deal with who had to come in
21	contact with it.  And so we had to use more counsel in
22	our private office to, to ensure that they knew well
23	about this product.  So I think the cautions have been
24	expressed are ones that I, I concur with.
25		DR. CANTILENA:  All right.  Thank you very

				217
	1	much.
	2		Dr. Davidson?
	3		DR. DAVIDSON:  Well, I'm pleased to hear
	4	everybody actually making some redundant conclusions. 
	5	You know, I'm going back to, to the clarity of the
	6	message, you know.  I don't mind if we have more
	7	material.  It's up to the patient to read what we give
	8	them, you know.  But there are some messages that need
	9	to be clear, and I think we clearly stated what are
10	the messages that, that need to be out there.
11		I want to remind that the translation to

12	Spanish needs to be friendly, you know.  It needs to
13	be basic and to the point.  And, you know, not to
14	forget that we really want to have an 800 number that
15	covers minorities as well.
16		DR. CANTILENA:  Okay.  Thank you very
17	much.  Dr. Lerner?
18		DR. LERNER:  I made plenty of comments so
19	far.  You know, again, I think it's great.  I think
20	one of the most important aspects will be that 800
21	number.  And I don't mean to sort of trivialize your
22	intention or purpose, but I think that that's going to
23	be, I think our main concerns are the toxic, toxic
24	shock and the questions of removal.  And that clearly
25	is going to be where the patients head first.

				218
	1		So I think they're going to, the training
	2	of people is going to be very important. 
	3	Additionally, I think just, I can't overestimate where
	4	the placement on the label or on the carton needs to
	5	be.  There's a, a section that just sort of said
	6	questions and comments, but that sort of didn't give
	7	it enough impact.  I know within the, you know,
	8	narrative it said, you know, if you have trouble
	9	removing it, call the, the talk line.  But I think

10	maybe if the phone number is written in, you know,
11	larger font or bolder numbers or something.  Just sort
12	of if the patients are ill or having problems, they
13	can just key right into it.
14		DR. CANTILENA:  Dr. Gilliam?
15		DR. GILLIAM:  A couple comments.  The
16	first goes back to one of the earlier speakers today,
17	talking about incidents of vaginal irritation if it's
18	used for several days in a row.  And, on a quick
19	glance, I don't see that that's really mentioned in
20	the package insert, and possibly that should be added.
21		I do think that a efficacy statement
22	should be added.  And I like the one that Dr.
23	Greenslade had used earlier.
24		I think there should possibly be stronger
25	warnings not to use it while a woman in menstruating,

				219
	1	and possibly move that statement up to underneath the
	2	toxic shock.  Or, in addition, as a lot of the women

	3	that do, did get toxic shock, it happened, they were
	4	menstruating and using the sponge.  And they were not,
	5	they were, shouldn't have been doing so.
	6		And then lastly, I, I think that there
	7	really needs to be a package insert in the carton in
	8	both Spanish and English, since you can't really
	9	control the distribution of the product in, because of
10	our growing Hispanic population in this country. 
11	That's all.
12		DR. CANTILENA:  Thank you.  Dr Greene?
13		DR. GREENE:  I'll reserve my specific
14	comments for the answers to the questions.  I just
15	generally feel strongly that this should be made
16	available, and I don't think there's a big difference
17	between the sponsor and the agencies, just a matter of
18	getting the details of the wording of the insert and
19	the carton.
20		DR. CANTILENA:  Thank you.  Dr. Neill?
21		DR. NEILL:  A couple of questions that
22	will help me in later answering charge three about
23	specific items of the label to be revised, and I'll
24	direct these to Dr. Krenzelok.  I'm less worried about
25	children eating these than sex partners, and I'm

			220
	1	wondering -- I have no idea about the toxicity of
	2	nonoxynol-9 or the sponge itself, which I presume
	3	would simply be passed right out the other end when it
	4	ends up in the mouth and alimentary tract of a sex

	5	partner.  Do I need to be worried about nonoxynol-9
	6	when it's ingested?
	7	            DR. KRENZELOK:  No, it's, it's very
	8	innocuous, from my experience.  As a toxicologist,
	9	that is.
10	                     (Laughter)
11	            DR. CANTILENA:  Thank you for adding that
12	clarification.
13	                     (Laughter)
14	            DR. CANTILENA:  We were starting, starting
15	to worry about Pittsburgh.
16	                     (Laughter)
17	            DR. NEILL:  Well, since you brought it up,
18	Ed, you know, the other question that came to mind

19	aside from this, you know, oral ingestion that I had
20	was in occupying my mind with all of the different
21	permutations that might occur in the course of sex as
22	it happens, I was -- and this does not pertain to any
23	of our charge.  It was just I thought interesting and
24	maybe a little entertaining.  I was wondering what

25	happened to the efficacy of this product with food,

				221
	1	alcohol, any or all of the above in many different
	2	kinds of combinations.  Please, don't anybody feel
	3	compelled to answer that.  And then, I've got a couple

	4	other specific questions that we'll get to when we get
	5	to the charge.
	6		DR. CANTILENA:  Okay.  Thank you very
	7	much.  I think in the, in the interest of time, I'll,
	8	I'll just reserve my comments to, as, as they sort of
	9	pertain to the questions.  So if there are no other
10	issues that people want to discuss, why don't we
11	proceed with the questions then?
12		First question, given the material
13	provided in your briefing packages and presented
14	today, does the revised labeling -- and here, we're
15	specifically talking about the 2000 proposed labeling
16	that's in your document -- adequately convey the risks
17	associated with the use of the product?
18		And what I'd like to do is, this is a yes,
19	no answer.  And as opposed to going around the table,
20	why don't we just ask for a show of hands.  So all
21	those who feel that the answer is yes, that is, the
22	revised labeling does adequately convey the risks,
23	please raise your hand.
24		      (Hand vote taken)
25		DR. CANTILENA:  It looks like nine.  Okay. 

				222
	1	All those who feel it does not adequately convey the
	2	risks.
	3		      (Hand vote taken)
	4		DR. CANTILENA:  One, and can I ask you to
	5	actually comment in terms of what is, you know,
	6	missing?
	7		DR. KRENZELOK:  I think that, that the
	8	information about toxic shock should be emphasized in
	9	bold so it really stands out.  That's the only reserve
10	I have.
11		DR. CANTILENA:  Okay.  Thank you very
12	much.
13		Second question is the current carton
14	label does not include information on the efficacy of
15	this product.  Should the carton label include
16	efficacy information so that the consumer will have

17	this information available at the point of purpose? 
18	So, specifically, we're talking about including
19	efficacy on the outside, on the carton, as opposed to
20	on the inside, in the package insert.
21		And here, again, I'd like to ask for all
22	those who answer in the affirmative that the label,
23	the carton label should include efficacy on the
24	outside, please indicate by raising your hand now.
25		      (Hand vote taken)

				223
	1		DR. CANTILENA:  Okay.  Nine in the
	2	affirmative, and can I ask Dr. Neill, I assume you're

	3	voting no and not abstaining.  Could you tell us, you
	4	know, what your concern was?
	5		DR. NEILL:  If we include only efficacy on
	6	this product, and we say this is effective -- in 100
	7	women years of use, there will be X many pregnancies
	8	and do not include information about other products,
	9	I don't know that I or consumers would naturally come
10	by the information to make that isolated nugget
11	useful.
12		If we include the other comparative
13	information, that's something, given what I understand
14	now about how Rogaine and some other medicines have
15	been marketed, that I don't feel comfortable getting
16	into.
17		I mean, that gets to the second part of

18	this, which we'll get to in a minute, which is, if
19	yeah, should it be required of all OTC contraceptive
20	products.  If the answer to the first part is yes,
21	there's an implied question in my mind which is okay,
22	what kind of efficacy.  And that's going to require a
23	whole another day of hearings.
24		And I think we also need to take into
25	consideration the comments that were made very early

				224
	1	today about the extent to which our discussion of
	2	inclusion of that information on all OTC contraceptive

	3	products would require that kind of process.  I think
	4	that it's probably that important.
	5		DR. CANTILENA:  So, so you're saying then
	6	if, if the information on the outside was comparative
	7	in nature and valid, I assume, then, you would favor
	8	that.  And, you know, as it is, in isolation with, you
	9	know, one and ten, it's not adequate, or it's not
10	advisable.
11		DR. NEILL:  Well, I, I would not oppose --
12	well, it's nine to one, so it doesn't matter what I
13	think, but --
14		DR. CANTILENA:  It always matters.
15		DR. NEILL:  Oh, of course.  All right.  I
16	think that if it's just in isolation, that might be
17	preferable.  As somebody who has to counsel patients
18	all the time, I actually find it less useful for me to
19	say, or incompletely useful for me to say this is, you
20	know, will result in X numbers of pregnancies per 100
21	women years.  But rather, I find it more useful for me
22	to put my patients' risks in the context of the risks
23	that they face daily in their life.
24		I, for -- I don't like telling my patients
25	and having them think this is a very risky thing, if

			225
	1	they don't understand that walking across Market
	2	Street outside my office is even riskier.  Do you
	3	understand what I'm saying?  And that -- 
	4	            DR. LERNER:  Just, just as a comment with

	5	that, I think that the decisions here are made at the
	6	corner drug store at 3:30 in the morning.  And so I
	7	think that as much information as we can provide,
	8	comparative or otherwise, is going to be much more
	9	than they're going to get, you know, beeping any of us
10	at that time of the morning.
11	            DR. NEILL:  I guess, then, my plea would
12	be to include meaningful, comprehendible efficacy
13	data.  For something where the outcome is as
14	measurable as a pregnancy, that's useful.  The
15	difficulty for the agency, I think, is going to be for
16	OTC products for which this may become an issue, for
17	which there's an outcome which is much more
18	subjective, like Rogaine.
19	            DR. CANTILENA:  Okay, I guess, can we ask
20	another question then, Dr. Ganley, of, of the
21	committee and, you know, regarding the format of the
22	information, whether it's now comparative or just, you
23	know, isolated for the product?  If, if you're not

24	opposed, then I would like to propose a question to
25	the committee then.  If efficacy label, if, if the

				226
	1	efficacy information on the outside of the carton
	2	contained, you know, comparative information to other

	3	methods of information, would you favor it included on
	4	the outside of the carton with this product?
	5		DR. GANLEY:  Can, can I just make a
	6	comment for anyone?
	7		DR. CANTILENA:  Okay.
	8		DR. GANLEY:  I'm, I think the one thing
	9	that we have to be sensitive to is that the size of

10	these boxes are a certain size.  And there's so much
11	information you can get on it.  And I think you have
12	to take into account that if you're going to put
13	comparator information, it is going to take up a lot
14	of room.  And so, I think you need to keep that in
15	mind when, you know, if, if -- and that's, that's
16	become a problem for us in, and certainly, I think
17	that Allendale would agree with that.  And if there's
18	another way to show or to direct a consumer to the

19	package insert, I think that, you know, that we, we
20	cannot forget those things, that there's a limited
21	size on these boxes.
22		DR. CANTILENA:  I guess the --
23		DR. GANLEY:  Unless we just sell 12 packs,
24	or 18 packs or something.
25		DR. CANTILENA:  Yeah, I guess, I guess,

			227
	1	you know, the reason I was suggesting, you know, this
	2	question is really at, at the time the consumer is

	3	making the choice about, you know, purchase, should
	4	they know how this compares to other methods, which

	5	are over the counter or, or otherwise?  And that, but,
	6	I guess it's sort of a, a hypothetical because, all
	7	right, you know, obviously if, if the box has to be,
	8	you know, five by six feet in order to get all the
	9	information that, it would not be  a practical thing. 
10	So I guess that's where that where was coming from. 
11	Any other, any other comments?  Dr. Johnson?
12	            DR. JOHNSON:  Well, I think, already in
13	the package insert, there's a statement this is much
14	less effective than the pill and IUD.  So it might be
15	possible to put on there in 100 women over one year,
16	you would, there would be approximately ten
17	pregnancies.  This is much less effective than
18	hormonal methods such as the pill or Norplant and the
19	IUD.  And I think, you know, that doesn't go into a
20	lot of real specific comparator data, but does give,
21	give them a point of reference.  Because I think most
22	women understand that the pill was a very effective
23	birth control method and can sort of use that as a
24	comparison.
25	            DR. CANTILENA:  Yes.  Dr. Lerner?

			228
	1	            DR. LERNER:  But sort of to answer the
	2	second part, the part A, and then sort of reflect it
	3	back, I think that if we say then that we do agree

	4	that this kind of information should be required of
	5	all over the counter contraceptive products, then we
	6	can sort of, or you guys can sort of make some sort of
	7	standardized mechanism so that you can put it in a
	8	certain sort of well-circumscribed way that's
	9	consistent so that when the consumer is going down the
10	aisle, you know, there's sort of a particular place
11	that they can look and see, you know, the comparative
12	efficacies, and therefore, sort of save room, sort of
13	in the same way that you'd go down and look at the
14	saturated fat in your Snackwell cookies or something,
15	you know.  Just sort of the number of grams or
16	whatever per any given serving.
17	            DR. CANTILENA:  Okay.  Well, then, how
18	about if we -- I'm sorry.  Dr. Neill?
19	            DR. NEILL:  I, I similarly would favor a
20	condensation into a single sentence which made sure to
21	include the other OTC.  If the point is to allow
22	people to make a decision about condom, semicid, foam,
23	jelly or sponge versus, you know, pill, et cetera. 

24	While pill's important, if they're there at three in
25	the morning, they ain't going to get it.

			229
	1	            The, the other issue related to this
	2	second part of the question -- I'm trying to imagine

	3	how, in the bathrooms of all of the gas stations that
	4	I stopped at on my way to Tennessee, the condom
	5	dispensing machine is going to include that
	6	comparative information for shelfkeeping units are
	7	like, that are a single condom.  And I don't know,
	8	does, you know, this doesn't need to be addressed
	9	right now, but I could imagine that for some of the
10	other forms that aren't as bulky and don't have the

11	advantage of having a six-pack box that it might raise
12	some more practical issues for them, more so than the
13	sponge.  And it's just something to sort of keep in
14	the back of the mind.
15	            DR. CANTILENA:  Okay.  Well, how about if
16	we actually call that question that I posed, which is
17	basically to have the comparative efficacy available
18	on the outside of the carton with all the caveats in
19	terms of how it should be simplified, et cetera, et
20	cetera, which I think is an excellent comment.  All,
21	all in favor of having the comparator information on
22	the outside of the carton, please raise your hand.
23	                  (Hand vote taken)
24	            DR. CANTILENA:  Dr. Davidson, did you
25	vote?  Yes?

			230
	1	            DR. DAVIDSON:  No.
	2	            DR. CANTILENA:  Okay.  So we have nine in

	3	favor, and perhaps I can just ask you to comment why
	4	you did not.
	5	            DR. DAVIDSON:  You know, I, I think it's
	6	important but I think that, you know, we can have that
	7	information inside.  If you give the information of
	8	that product on the outside, because if you look at
	9	the package, you know, there's other more important
10	information that should be outside, including you're
11	going to state that this is not a 100 percent
12	effective, you know.  For, for the information, see
13	the package insert.  You know, I think we need to make
14	it a little simpler for the people, you know, that buy
15	these products.  Otherwise, if you put a lot of
16	information outside the package, you know, people are
17	going just to read a couple of things and then no
18	more.  That's my recommendation.
19	            DR. CANTILENA:  Okay.  Thank you.  I
20	believe we haven't formally answered 2A although we
21	started to a couple of times.  2A, if yes -- yes,
22	meaning it should be on the carton, should this kind
23	of information be required of all OTC contraceptive

24	products?  And again, we'll first ask all those in
25	favor of having it available on all OTC contraceptive

			231
	1	products, please raise your hand?
	2	                  (Hand vote taken)
	3	            DR. CANTILENA:  I think this time we are

	4	unanimous.  Okay, the next question, question three,
	5	are there other aspects of the labeling that should be
	6	revised?  And here, I guess, we'll just open it up to
	7	comments, perhaps going around the room, starting
	8	around this side with Dr. Neill.  Any other aspects of
	9	labeling that should be revised when we're now, our
10	frame of reference is the 2000 label?
11	            DR. NEILL:  Yeah, I have I think three
12	questions that I would propose be considered for
13	inclusion in the section, other questions you may
14	have.  The first is what if it comes out?  I realize
15	that difficulty with removal is, you know, the single
16	biggest complaint or reason for phone calls, but if it
17	comes out, can you put the same one back in?  Do you
18	have to use a different one?  If it comes out and you
19	don't have another one, is that the end of sex?
20	            The other question would be, there's just
21	two, not three.  It's related to one that Dr. Gilliam
22	asked a few minutes ago.  Can this be used several
23	days in a row?  And I think that would also allow an
24	appropriately prioritized discussion of the extent to
25	which increased sensitivity may occur if it's used

				232
	1	several days in a row.  My perception being, yeah,
	2	certainly, it can be.  However, you may experience
	3	more irritation with this.  And I think that's a valid
	4	concern that needs to be in there somewhere.
	5		DR. CANTILENA:  And here, you're talking
	6	about in the package insert and not the label?  I mean
	7	the front part?
	8		DR. NEILL:  In the package insert, right.
	9		DR. CANTILENA:  Right.  Thank you.  Dr.
10	Greene, any, any comments about other issues of
11	labeling?
12		DR. GREENE:  Not really; just minor.  I
13	was glad to see under six, there are other questions
14	you may have, that the first thing it addresses is the
15	use of a latex condom.  And I do think that's
16	important.  And the only minor sort of editorial
17	suggestion is that in that section where it says will
18	help reduce the risk of transmission of human
19	immunodeficiency virus, HIV, and acquired immune
20	deficiency syndrome.  I, I would just suggest that
21	that just be changed to read the virus that causes
22	acquired immune deficiency syndrome.  That's just
23	technically a little more correct, but I don't have
24	any major problems.
25		DR. CANTILENA:  Thank you very much.

				233
	1		Dr. Gilliam?
	2		DR. GILLIAM:  Just the comments I, I made
	3	earlier, especially regarding the irritation and
	4	stronger warnings not to use during menses.
	5		DR. CANTILENA:  Dr. Lerner?  No further
	6	comments.  Dr. Davidson?  Dr. Williams?  Dr. Uden?
	7		DR. UDEN:  Only that I think it could be
	8	written in a lot less technical terms than what it is,
	9	so.
10		DR. CANTILENA:  The insert, the?
11		DR. UDEN:  Yes, the package insert, yes.

12		DR. CANTILENA:  Thank you.  Dr. Johnson?
13		DR. JOHNSON:  My comment is primarily a
14	practical one regarding what goes on the outside of
15	the box.  And it has to do with the directions.  I
16	mean it's not very clear to my, me, why we need to
17	tell them on the outside of the box that they need to
18	wash their hands, wet the sponge, put the, the dimple
19	side facing up.
20		I mean, it seems to me if you're trying to
21	save space, those are things that someone will look
22	for once they buy the package, once they open it and
23	they're ready to use it.  So it seems like you could
24	get rid of a lot of the things in that direction
25	section.  And then you would have more room for things

			234
	1	like how effective is this product, which I think is
	2	much more important.
	3	            DR. CANTILENA:  Yes, follow up to that,
	4	Dr. Neill?
	5	            DR. NEILL:  Yeah, I -- while there's
	6	probably room for some editing there, I think at least
	7	part of the purpose is to allow people to make a
	8	decision about whether they want to use it.  And if
	9	there's an advantage to having that kind of explicit

10	direction, it's that some consumers may see that and
11	decide as a result yes, they really want to use this,
12	as opposed to another method or they really don't want
13	to use that.  And simply directing somebody to the
14	package insert inside removes that portion of the
15	information that helped them use it. 
16	            And, you know, it's just, who knows
17	whether that would be the major contributor about a
18	decision to purchase?  Personally, I think for
19	information on the outside of the package, if the FDA
20	or somebody doesn't say something about where the
21	price sticker goes, everything we're talking about
22	means nothing.  And I'm not suggesting that we talk
23	about where the price sticker goes.
24	            DR. CANTILENA:  Further comments, Dr.

25	Johnson?  Thank you.  Dr. Blewitt?  Dr. Krenzelok? 

			235
	1	Yeah, I guess, really, I would concur with a lot that
	2	has been said.  I, I would also just, under number
	3	seven, points to remember, it's not, it doesn't jump

	4	right out at you that the product needs to be left in
	5	place for six hours after the last act of intercourse. 
	6	And I, I would understand, or I understand that if you
	7	remove it shortly after, it's high likelihood to, you
	8	know, not be effective.
	9	            So if there's some way to emphasize that

10	clearly on the insert.  It, you know, doesn't have to
11	be on the outside, but just to make sure that people
12	don't use it like some other methods where, you know,
13	you remove it right away after you -- yeah, it's,
14	right.  But it's sort of, you know buried down there. 
15	And that's sort of the final point, so if there's some
16	way to emphasize that, that I think would be helpful.
17	            DR. UDEN:  Can I make a comment on that? 
18	Because what that does is effectively you cannot have
19	sexual intercourse from 24 hours to 30 hours.  So if
20	somebody has it from 24 to 30 hours, they can't leave
21	it in for six more hours.  So this is only good for
22	sexual intercourse for 24 hours, and then it has to be
23	left in.  And then there's that window there where

24	they're not supposed to have sexual intercourse if
25	they're going to follow the directions explicitly.

				236
	1		DR. CANTILENA:  Yes, Dr. Johnson?
	2		DR. JOHNSON:  I, I did find one other
	3	thing I wanted to comment on.  And that was the
	4	pregnancy rate tables.  I mean, I think I sort of made
	5	it clear I really dislike that table, one because I
	6	think they can't understand it.  And secondly, because
	7	it sounds like the data has at least some problems.
	8		And I think certainly we need some
	9	comparator data, but I think written in the form that
10	Dr. Greenslade suggested is, is much more useful for
11	the patient.
12		DR. CANTILENA:  Okay.  Thank you.  What
13	I'd like to now do is just turn to the final question. 
14	And I know the hour is late, but I would really ask
15	your, you know, patience to, to really give this some
16	thought because I think it's possibly a very important
17	issue.
18		Question four, please provide comments on

19	the type of post-marketing surveillance for adverse
20	events the sponsor should contact, excuse me, should
21	conduct.  And here, we have issues of active
22	collection, follow-up reporting analysis of cases of
23	difficult sponge removal, provisions in place and, to
24	facilitate adequate adverse event reporting.
25		So again, we started here last time. 

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	1	Perhaps we can start with you, Dr. Krenzelok, and have
	2	you address some of these issues on post-marketing
	3	surveillance.
	4		DR. KRENZELOK:  Well, I don't think we
	5	should hold them to a higher standard and ask them to
	6	have active surveillance on, on this particular
	7	product.  But I would strongly encourage, as I
	8	mentioned earlier, that a 24-7 server should be really
	9	encouraged, competent people, and they should in some
10	way encourage the people that use the product to use

11	that service if it's there.  And then I think that
12	would really help identify adverse events should they
13	occur.
14		DR. CANTILENA:  Thank you.  Dr. Blewitt,
15	any comments on this area?
16		DR. BLEWITT:  No.  I would simply agree
17	with what Dr. Krenzelok has said.
18		DR. CANTILENA:  Thank you.  Dr. Johnson?
19		DR. JOHNSON:  Same thing.  I, I agree that
20	active marketing or active surveillance is not
21	something probably necessary and maybe the sponsor
22	just needs to present a very detailed plan about their
23	consumer hotline and, and how they'll collect their
24	data.
25		DR. CANTILENA:  Thank you.  Dr. Uden?

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	1		DR. UDEN:  Yeah, I don't think we should
	2	hold them to a higher standard.  I mean, unless this
	3	question, I mean if, if we did, then we would be

	4	setting a precedent for every, every product that
	5	would come in front of this advisory committee or in
	6	front of the FDA from here until the end, I would, I
	7	would assume.  I mean, what would be special about
	8	this product that we would ask this versus other
	9	products that might, that might become OTC?  Other
10	than that comment, I just hope that the sponsors would
11	have complete and consistent information in, in their
12	system, so that it's as complete as possible. 
13		DR. CANTILENA:  Thank you.  Dr. Williams?
14		DR. WILLIAMS:  The only concern I have is
15	to look at the CDC data as that comes available
16	regarding the reintroduction of the product.  We have
17	a reportable disease and that could be easily
18	monitored.
19		DR. CANTILENA:  Thank you.
20		Dr. Davidson?
21		DR. DAVIDSON:  I agree with everybody but,
22	you know, one thing I forgot maybe for the low
23	literacy people, you know, a video on how to use the,
24	you know, the device will help us.  And I don't know
25	if the sponsor is willing to, you know, make a video

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	1	for those very low literacy people.
	2		DR. CANTILENA:  Thank you.  Dr. Lerner?

	3		DR. LERNER:  Well, we've discussed a lot
	4	about the consumer hotline.  But I think also a
	5	physician hotline or some way to get the practicing
	6	clinicians, you know, sort of plugged into the system
	7	so that when they do encounter any adverse outcome,
	8	there's a, either a phone number or something
	9	accessible -- medical letter or in the journals or
10	however you do that with other stuff.
11		DR. CANTILENA:  Thank you.  Dr. Gilliam?
12	No further comments.
13		Dr. Neill?
14		DR. NEILL:  I would never make it on
15	Jeopardy pushing this button.  The, it's a generic
16	comment that has to do with the repetitive nature of
17	this question which I think goes to the question of
18	the MedWatch system.  If I were to ask my residents,

19	okay, what's MedWatch, you know, I'd get a 1 out of 36
20	response rate.  And, so generically, I guess I would
21	put in a plea to the agency or some higher up muckety-
22	mucks that have, you know, budget dollars to do
23	whatever might be done to help improve that system as
24	a monitoring system given that it's, you know, relying
25	on lazy physicians like me to both understand that I'm

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	1	seeing an adverse event and pick it up and report it.
	2	            And I realize that there have been a lot
	3	of things done to make that easier.  I used to
	4	literally go and photocopy the little form out of the

	5	back of the PDR.  But I threw all the PDRs out of my
	6	office because I hate them as a drug reference and
	7	have taught my residents not to use them.  And so now,
	8	we've got to go to the web and do all this other
	9	stuff, and then the network's down so, again, just a
10	long plea, you know.  Whatever you can do to improve
11	that, make it easier, market it.
12	            Here's a, here's an idea.  We can take
13	these FDA NDA fees and take a portion of those or, you
14	know, we can always hit the sponsors up for something,
15	right?  Rather than making them pay for an adverse, an
16	active adverse event reporting system, we, we take
17	some portion of the money that we, I mean ask from
18	them for their NDA and put that specifically towards
19	some of this MedWatch -- I don't know, a MedWatch czar
20	or something, however that works.
21	            DR. CANTILENA:  Okay.  Thank you very
22	much.  I, I guess I would only add just a couple of
23	small comments on this issue.  One, one is, you know
24	when I hear a couple things about being a small start-
25	up company and all the employees being here at the

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	1	meeting, I get concerned that the follow-up and, you
	2	know, safety is not going to be adequate.  I'm sure

	3	that the plans would be, and I would hope that, you
	4	know, you would have agreement on this with, with the
	5	FDA that as it goes on the market or hopefully just
	6	before the cash flow starts that you would clearly
	7	invest in having adequate, you know, facilities,
	8	adequate, you know, personnel.  And just make sure
	9	there's a very tight, you know, linkage between the
10	800 number and follow-up and the adverse events.

11	            And, and I would say that even because
12	this has not been on the market for basically five or
13	six years, it's an opportunity to see how well the
14	system actually works.  So even if you could agree on
15	perhaps, you know, quarterly reports instead of annual
16	reports to see sort of the linkage between the 800
17	number and the adverse events and, and the follow-up
18	on the adverse events.
19	            And I would just, as some free advice to
20	the sponsors, invest in quality individuals who have
21	experience in this area because it'll, you know, make,
22	you know, your job a lot easier, and all the people
23	who are watching a lot easier as well if there's good,
24	you know, documentation and follow-up.  So that's my
25	two cents.  Now, I guess, I'll, I just have to ask the

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	1	FDA if there are any other issues that we have not
	2	addressed, any questions that were not adequately
	3	answered that you'd like us to address at this time?
	4	            DR. GANLEY:  No, I think we got an idea of
	5	what your position is, and we appreciate all the
	6	comments.  I, I think Dr. Neill made a interesting
	7	point there, you know, about the reporting to FDA. 
	8	And, and one of the things that was not included in
	9	the, the labeling rule was a requirement to include a

10	MedWatch number on there.  And I get a sense that you
11	would actually, or to have some information that you
12	could, if people could complain to FDA, if not to the
13	sponsor.
14	            I'll just point out that the questions and
15	comment portion of the labeling is not required unless
16	the sponsor decides to do it.  In the NDA route, we
17	can more or less encourage them to do it but in the
18	monograph system it's not a requirement for a company
19	to do that.
20	            DR. NEILL:  I wouldn't suggest putting the
21	MedWatch number anywhere, I mean, if it were going to
22	be any place, it ought to be on the actual product
23	itself that gets pulled out in the emergency room at
24	three in the morning.  So, you can say, oh, I'm
25	suppose to call so and so.  With the other obvious

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	1	places for that to be -- would be, you know, in more
	2	generic education programs and that would require, I

	3	think in about, you know, how do we get physicians to
	4	change behavior and good luck.
	5	            DR. CANTILENA:  Well, on that pleasant
	6	note, why don't we adjourn for today and thank you
	7	very much for your attention and all of your comments.
	8	            DR. TITUS:  And would the Committee please
	9	take their information off the table because it's
10	going to be reset before tomorrow morning.  So,
11	take -- you can leave your name tags and your name

12	plates but take any of your paper with you, please.
13	            (Whereupon, the meeting of the
14	Nonprescription Drugs Advisory Committee regarding
15	Labeling Issues on the Today Sponge, was concluded.)
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