**COMMENTS: April 9, 2003.**

**TO: THE FOOD AND DRUG ADMINISTRATION**

**21 CFR Part 201**

**RE: DOCKET NUMBER ( 80N-0280 )**

> **Over-the-Counter Vaginal Contraceptive Drug Products Containing
> Nonoxynol 9: Required Labeling.**

**FROM: HOWARD MIRSKY, PHARM. B**

**EDITOR, [STD SPOTLIGHT]{.underline}**

**CITIZENS ALLIANCE FOR VD AWARENESS (CAVDA)**

**800 W. CENTRAL ROAD, SUITE 128,**

**MOUNT PROSPECT, IL 60056.**

**Phone: 847-398-3378 \-\-- FAX 847-398-7309**

**e-mail: cavdarx@ earthlink.net**

**I. Prefatory Statement**

Communicable disease control is more than prevention, treatment and
cure. It also involves a fragile relationship and interface among
private industry, public perception, and the baggage that the health
consumer, the health professional and the public health service bring
with them. When one or more of these factors are out of focus, they must
be refocused or corrected or we risk losing the focal point of the
process, namely [the safety of the patient]{.underline}.

An article in the March 2l, 2003, issue of [Science]{.underline}
directly addresses this problem:

\"There is still plenty of room to improve international efforts to
track and treat emerging

and existing infectious diseases, says a sobering new report from the
Institute of Medicine

(IOM). Its conclusions, released this week, echo those reached 11 years
ago in a similar

study.

\"To improve public health, the 18-member IOM panel, co-chaired by
Joshua Lederberg

of Rockefeller University in New York City, calls for an array of
changes, including

accelerated vaccine and antimicrobial drug development\....**and greater
cooperation among**

**governments, academia, and corporations\....\"**

In the case before us, we are talking about life, death, and health
issues. In this rule proposal, the bottom line is that the consumer must
be made aware of the dangers inherent in using these products more than
once a day, and how to further protect themselves and their partner by
communicating sensitive sexuality information. Our task is to determine
how that goal is best achieved and if the Food and Drug
Administration\'s rule proposal helps or hinders that case.

**PAGE TWO, CAVDA: DOCKET NO. 80N-0280**

**II. Opening Statement**

A. Considering the controversial nature of the subject, the Food and
Drug Administration should be commended for taking the lead in
presenting this issue to the drug manufacturers, health professionals
and the public-at-large for their comments.

B. While this proposed rule was lengthy in seeking to communicate
complex, scientific information to audiences consisting of highly
trained health professionals and lay persons, the FDA should be
applauded for researching, compiling and arranging all the necessary
documentation in a logical sequence.

In addition, the language used, while necessarily complex, did
communicate in understandable terms and well-defined jargon, the
essential and definitive parameters of the scientific documentation, by
liberally using definitions, which of course added to the reader\'s
understanding.

C. However, the conclusions reached by the FDA in expecting caution
labels to prevent a potentially deadly and/or a health problem for the
female consumer, due to the documented problems caused by nonoxynol 9
(N-9) in vaginal creams, aerosol sprays, sponges, and films, while
appearing to be logical, lacked some of the understanding both of what
exactly transpires, a) in the market place where all of these products
are displayed and sold over-the-counter (OTC), and b) in what can and
does happen where the sexual act actually occurs from the bedroom to the
back seat of a car.

D. It is obvious that the FDA believes that the consumer needs to be
informed about these products with nonoxynol 9. But how can they be, if
the products continue to be available OTC without professional
consultation from a physician or a pharmacist? The FDA is assuming that
the new package caution labels will accomplish that task. [I absolutely
disagree with that premise in the strongest terms]{.underline}.

E. I was reminded recently about the physicians Hippocratic Oath whose
main theme is \"Do No Harm.\" How does relabeling these potentially
deadly or debilitating OTC products accomplish that? It\'s a lot like
re-doing a basement wall that has mold. If the wall is painted over with
enough coats of paint, the wall may appear to be clean\-\--but the
underlying mold problem remains. So it is with a newly relabeled OTC
vaginal contraceptive with nonoxynol 9. With label warnings which may
not either be seen, read, or understood and without consultation
provided by a competent health professional, little will have
changed\-\--thus leaving the products in an OTC status and exacerbating
the current problems.

F. A frightening fact overrides this discussion: The Centers for Disease
Control and Prevention (CDC) recently announced that there are
approximately 900,000 people in the United States carrying the AIDS
virus. They also announced that approximately 280,000 of these people
are unaware that they are HIV positive. This is a frightening reality
when dealing with this nonoxynol 9 issue, because it increases the
possibility of spreading HIV and other STDs to an ever increasing number
of potential female contacts who may still be unaware of the dangers
that nonoxynol 9 or the deadly consequences their HIV positive partner
presents.

**PAGE THREE, CAVDA: DOCKET NO. 80N-0280**

G. If the numerous devastating health dangers which could occur as a
result of using these products with nonoxynol-9 in the manner described
in the monograph, were caused by a similar or dissimilar
over-the-counter drug, I would assume that drug would be **WITHDRAWN
FROM THE MARKETPLACE** until a safe replacement product could be
developed and approved eg: Tylenol, l982.

**III. The Significance of Adverse Effects**

For those of the review panel who demand, require or just want
quantified specific adverse events enumerated before you decide how to
act in this rule proposal, please consider the following:

The Federal Register detailed the results of more than 20 studies/trials
in which the results were observed, recorded and reported about the use
of these OTC N-9 vaginal contraceptive products. Of the studies, many
showed specific adverse events ranging from genital lesions, abrasions,
and epithelial disruption to inflammation. You may ask., \"How many
specific adverse events caused injury and how many people died?\" At the
end of the various study periods, a large number of specific adverse
events were reported from a majority of the studies.

As to the second question, \"How many people died?\", the AIDS virus
doesn\'t work on a timetable that can be reduced to a simple formula and
replicated. The AIDS virus (HIV) has as many time tables as people it
infects, although the sequellae may differ. The Federal Register did not
report any deaths during the various study periods. But, that doesn\'t
necessarily mean that no one died. To me, if one person expired, that is
ONE PERSON TOO MANY.

One additional point, when you read a study, which states that one
percent of the subjects died, that figure may not be statistically
significant to you or to the research world. But to the person who died,
their family, friends and colleagues, that one percent figure is highly
significant. In fact, to them that figure is really l00 percent, because
it means someone who they knew died from that condition or disease.

**IV. The Stealth Factor**

This dangerous game of semantic gymnastics is a sure loser; even if one
female doesn\'t see, read and understand the warning statements, fails
to discuss them with her partner to reach a logical decision about their
relationship\-\--and contracts AIDS and dies\-\--or contracts an STD
with symptoms\-\--this semantic exercise will have failed. With OTC
products, old buying habits are hard to break. And what if dozens or
hundreds of females miss the clues in this dangerous game and die or are
injured in the process? As a review panel member, how would you feel
knowing that you signed off on this proposed rule?

I believe that there are going to be many new cases of HIV and STD
infection across the country, because these vaginal contraceptives with
N-9 will [still be available]{.underline} on an OTC basis without
consultation with a health professional.

**PAGE FOUR, CAVDA: DOCKET NO. 80N-0280**

The female consumer will still be able to buy that contraceptive product
with N-9 she has been

accustomed to buying with no checks and balances. Months later, who will
be able to connect their OTC purchase of these products, with a certain
partner, and a resultant viral or bacterial infection? Nobody. HIV may
not produce signs/symptoms for six months or up to l0 years. And some
STDs have clear symptoms in women, while others do not. Relabeling
won\'t prevent that either.

Even if the woman\'s partner wears a condom, and she uses the OTC
vaginal contraceptive with N-9, and continues to have \"frequent\" sex,
she makes herself vulnerable to damaging the epithelium of her vagina or
cervix, with the lesions and other sequellae that N-9 products
reportedly produce.

A well meaning but ill-begotten act of adding warning statements to a
dangerous OTC product can easily convert what initially seemed like a
good idea, into a stealth consumer disaster. This action brings new
meaning to the phrase, caveat emptor, let the buyer beware\-\--for that
is what the consumer must be\-\--aware that these products can do
irreparable harm. And unless and until the FDA sees this problem for
what it is, namely, a stealth hazard, it will remain a hazard.

**V. The Proposed Rule**

In my opinion, \-\-\--considering the [devastating health
consequences]{.underline} which could occur to females who may purchase
and who may or may not see, read, understand and follow the advice
contained on the warning labels and then use these products in their
bodies, and to a lesser degree to males who may or may not see, read,
understand and follow the advice contained on the display carton or on
the vaginal contraceptive container itself,\-\--this scenario describes
a long list of serious questions and potential problems which, unless
resolved before sexual intercourse takes place, could devastate both
partners, but in particular, the [female consumer of the
products.]{.underline}

**VI. Consumer OTC Study.**

As the proposed rule regarding nonoxynol 9 depends on the consumer
seeing, reading and understanding the new caution statements, a
literature search of appropriate research has produced many blind
alleys, but at last, one study and one professional letter to the FDA
will be of particular interest to the review committee. The National
Council on Patient Information and Education (NCPIE) commissioned a
comprehensive study to survey the opinions influencing the
self-medicating behaviors of the American public.

Conducted by Harris Interactive, the survey consisted of two
complementary polls: one of 1,011 adult Americans aged 18 and over and
conducted between October and November, 2001, and the other involving
45l pharmacists, nurses and general practice physicians who were
surveyed in November and December, 2001. The results, pertinent to this
rule change are as follows:

l\. \"Of special concern to health professionals is a lack of
understanding about active ingredients in OTC medicines, especially
since different OTC products may contain the same active ingredient. Of
the 79 percent

**PAGE FIVE, CAVDA: DOCKET NO. 80N-0280**

of physicians, nurses and pharmacists in the poll who say that the
potential for inappropriate use of OTC remedies is a concern, seven in
ten (69 percent) cite not understanding active ingredients as the
biggest

problem.

2\. \"Although the vast majority of Americans (95 percent) read some
portion of the OTC drug label, the survey finds that many do so
selectively when buying or using a nonprescription medicine.

3\. \"When asked [what information they look for]{.underline} when
buying an OTC drug for the first time, two in five (4l percent) cite
usage information (e.g. directions for use, information on dosage level
and symptoms), one in three (34 percent) mention the active ingredient,
and **[one in five (2l percent) say warnings
information]{.underline}.\"**

**Considering that the major thrust of this FDA proposed rule is aimed
at relabeling OTC vaginal contraceptives with nonoxynol 9 for the
expressed purpose of adding warnings about their use, it appears that
such a move to inform this consumer base is doomed to failure, based on
the results of this survey.**

Even if one in five read warnings information, would the review panel
members feel comfortable knowing that four out of five who didn\'t read
the warnings were susceptible to possible infection by the AIDS virus
(HIV) or sexually transmitted diseases (STDs) because they did not read
warnings information? It certainly would make me anxious, and I would
presume the review panel members feel the same way.

**VII. OTC Drug Labeling**

In 1997, John Gans, Pharm.D, American Pharmacists Association (APhA),
executive vice-president, sent a letter to the FDA, Dockets Management
Branch, about an FDA rule published in The Federal Register, on February
27, l997, pertaining to labeling requirements for over-the-counter (OTC)
human drugs.

He said, \"A study of industry labeling practices by S. Sansgiry and
colleagues, at the College of Pharmacy at Idaho State University,
examined l00 nationally available analgesic and cough-cold OTC
preparations for the congruence of their labeling.

\"Sansgiry et al. found that as OTC package size increased, the font
size used for the product increased. [However, the font size for
warnings remained constant.]{.underline} This finding is relevant to a
recommendation of the American Association of Retired Persons (AARP)
that FDA require larger font size and/or more information, on the label
of larger size OTC packaging.

\"Sansgiry et al. also found that 22% of the product packages examined
used smaller than 6-point type for warnings.

\"**Bold Print**. In sharp contrast to the Nonprescription Drug
Manufacturers Association\'s (NDMA) guidelines, 63% of the OTC labels
studied by Sansgiry et al. used no bold print in the warnings section of
the labeling.

\"**Hyphenated text**. Although NDMA guidelines recommend against the
use of hyphens, 63% of the labels examined by Sansgiry et al. used
hyphens in the text.

\"**Uppercase print**. Thirty percent of the OTC labels studied used
uppercase lettering for about half of the text of their labeled
warnings. NDMA has recommended against the use of all capitol lettering.
\"

**PAGE SIX, CAVDA: DOCKET NO. 80N-0280**

\"It is extremely important that consumers have access to consistent,
and comprehensible information on OTC drug products. However, it is
neither optimal nor feasible for the OTC drug product label alone to
supply all the information of value. Space limitations mean only the
most important information regarding the product and other sources of
information can appear on an OTC container, not only to preserve
legibility, but to encourage the consumer to read the label.

\"APhA agrees that OTC product labeling should advise the consumer to
speak with a physician or pharmacist before purchasing or using a
nonprescription drug. APhA suggests two principles or guidelines for FDA
in making the decision as to which health professionals the label might
most usefully direct the consumer to consult.

l\. Labeling should direct the consumer to health professionals who have
the requisite information and training. And,

2\. Labeling should direct the consumer to the health professional who
is most likely to be accessible when and where a decision regarding OTC
purchase or use is going to be made.

Taking into consideration these two principles, APhA believes that the
in-depth education of the pharmacist in pharmacotherapy\-\--as well as
the tremendous advantage of having the pharmacist located precisely
where and when most OTC drug purchasing decisions are made\-\--argues in
favor of including the pharmacist on the label as a primary and
explicitly identified source of OTC drug information.\"

**VIII. Alternatives To Relabeling**

In proposing alternatives to relabeling in order to continue to provide
open access of these products to consumers, the advocates of open access
or OTC, continue to say that these products be made available OTC, still
closing their eyes to the facts, clearly established in the NCPIE study
above, that,

**CONSUMERS DO NOT CONSISTENTLY READ CAUTION LABELS.**

> The fact that too many consumers are now buying these potentially
> dangerous products with N-9, completely unaware of the dangers of N-9,
> doesn\'t seem to resonate with them. Thus, they continue to cling to
> the carefree OTC days of the past. I imagine that for many of them,
> \"Ignorance is Bliss\" could be their credo. Nevertheless, the mission
> of the FDA is clear\-\-- namely, to provide SAFE AND EFFECTIVE
> MEDICATIONS TO THE PUBLIC.
>
> The question remains, how do you communicate the fact that N-9 is
> dangerous, and protect the consumer unless the product is used within
> the strict parameters set forth on the warning labels, if the
> consumers continue to have free access to the OTC vaginal
> contraceptive products with N-9?

It seems logical and obvious to me that the sooner the OTC status of
these vaginal contraceptives is changed either to provide restricted
access or having the products removed from the marketplace, the better
off these female consumers will be. In short, I am suggesting that,

**PAGE SEVEN, CAVDA: DOCKET NO. 80N-0280**

I. The manufacturers could voluntarily recall and remove these products
from the marketplace.

II\. FDA could convert the current OTC status to Rx only. Restricted
access would limit consumers to visiting a physician for an examination
and a new prescription with multi-refills noted (to avoid extra office
visits).

III\. FDA could order the removal of OTC vaginal contraceptives with
N-9, which could stimulate contraceptive manufacturers to find and add
other safe and effective spermicides or microbicides to their products.
I know this would require research, which is expensive, but the dollar
costs would certainly be less than the human cost borne by the heirs of
the female victims, should the products remain in the marketplace, as
OTC items.

IV\. FDA could mandate the removal of the existing OTCs, and the
manufacturers might decide, based on market data, to not respond.

**IX. Lurking in the Shadows**

It should come as no surprise to any member of the review panel that
communicating about human sexuality issues from parent to child, and
from school teachers to students, are not among our strong points in the
United States. As a result, the U.S. leads the developed world in
sexually related abuses of various types from sexual assault, rape,
child abuse, to pornography.

Therefore, when a topic such as vaginal contraceptive products is on the
table, and we discuss \"frequent sex\" there are too many who assume
that we are talking, by-and-large, about prostitutes and the many
separate and unique issues surrounding that topic. In fact, many males
and females from \"middle America\" actually enjoy having sex with their
partner more than once a day. The point here is that these, too, are the
females who may use the N-9 products in question more than once a day,
and represent a large number of citizens in the U.S., who are putting
themselves in jeopardy,

This is the target audience who use the N-9 products \"frequently\" and
to whom this relabeling provision would largely be directed. When the
FDA recounts the devastating results of the studies resulting from using
N-9, as listed in the Federal Register, and relabeling is suggested as
the solution, we should be asking some very serious questions about
relabeling in view of the NCPIE study quoted in this paper, as well as
the anecdotal evidence that most pharmacists can provide about this
subject, specifically, that consumers rarely read product labels, leave
alone warning labels.

In short, while relabeling may offer a solution for other OTC products
which do not produce life threatening or life altering results, in the
case of N-9 products, in my opinion, relabeling is neither an ideal nor
a partially acceptable alternative.

**X. Questions from the Federal Register**

l\. Do the proposed warnings\....adequately convey the safety concerns
to consumers?

**PAGE EIGHT, CAVDA: DOCKET NO. 80N-0280**

If one assumes the consumer sees the warnings on the container and the
product wrapper; or if the consumer actually goes to the trouble of
reading the consumer package insert (CPI), and if one further assumes
that the CPI is printed in type larger than the usual and customary
small point type in which many CPI\'s are now printed, and then still
further assumes that the consumer can understand the copy, PERHAPS the
consumer will

receive the message, comprehend the message, and follow through. Still,
these are BIG undocumented questions in this process which still may
leave this and other issues unresolved.

What revisions would be useful?

Placing a bug or violator on the product carton and/or on the product
itself, might assist in making the warning more visible. It may help if
the consumer actually removes the CPI, unfolds the CPI, is not turned
off by its length, tries to read it and is able to understand the copy;
it will also help if the copy is [large enough]{.underline} to read
without difficulty.

2\. Are there other data to support, expand, or refute the proposed
warnings?

The study data appears to be conclusive that females having sex with a
vaginal contraceptive product containing nonoxynol 9 more than once a
day would be hazardous to their health. Therefore, the proposed warnings
appear to be appropriate.

3\. The \"frequent use\" definition of \"more than once a day\"
\...\.....

According to the studies, that definition seems to be appropriate.

However, another question continues to beg for an answer:

If a woman using a nonoxynol 9 vaginal contraceptive has sex with a man
using a nonoxynol 9 condom, would this exceed the \"once a day\"
definition of frequent use of nonoxynol-9?

4\. Are the symptoms of vaginal irritation adequately defined?

The symptoms seem to be adequately defined.

5\. Are there additional data to correlate an increase in vaginal
irritation with an increased risk of transmission of HIV and STD\'s?

I don\'t know that this data is forthcoming.

If so, how should such information be conveyed in labeling?

That would depend on the nature of the data. And if necessary, it might
be appropriate to incorporate the alternative suggestions such as those
described in item VII. OTC Drug Labeling, above.

6\. Is a package insert the best way to provide additional information
to consumers or should this information appear on the outer carton?

**PAGE NINE, CAVDA: DOCKET NO. 80N-0280**

The package insert **IS NOT** the best way to communicate information;
experience with prescription package inserts (PPI) shows that RARELY
does the patient ask for such information because the information is
offered in type which is usually too tiny to read, leave alone
comprehend. It is an established fact that critical information, and
that IS what we are discussing here, is best communicated one on one,
FACE TO FACE.

The obvious communicators here are the physician and the pharmacist,
however, experience indicates that since the l970\'s physicians are less
willing and able to communicate with patients due to a host of reasons,
none the least of which is the shortage of time. It is estimated that a
private practice physician spends only eight to nine minutes with each
patient. It is hard to imagine this physician having enough time to
clearly explain all the problems present in OTC vaginal contraceptives
with nonoxynol 9 (N-9) let alone the definitions of these products terms

Pharmacists historically have been the first choice for information for
patients; however, since the l980\'s, when prescription activity
dramatically increased and pharmacists have been in short supply,
pharmacists have turned to large type, one-page, one side information
sheets and oral communication to communicate critical prescription
information.

7\. Are the proposed statements for the package insert appropriate?

I would suggest adding the following **bold** words in parenthesis or
brackets to the statement in the Federal Register for this labeling;

> \"Correct use of a **(dry)** latex condom**, (or a silicone lubricated
> latex condom, but NOT a condom lubricated with nonoxynol 9)** with
> every vaginal sexual act will help reduce the risk of transmitting the
> AIDS virus (HIV) and other STDs**.\"**

I also suggest the following statement as a substitute for the final
labeling addition;

**Studies suggest the possibility between increased vaginal irritation
from frequent**

> **use, and the risk of passing on the AIDS virus (HIV) and other STDs.
> to your partner. With \"frequent use\" being defined as using
> nonoxynol 9 (N-9) products, [more than once a day]{.underline}.**

What revisions or additional information, if any, would be useful to
make the package insert more informative and consumer friendly?

If you add any more information it will lengthen the insert and add yet
another visual and emotional obstacle for the consumer to navigate.
[Adding color, larger type, and less copy would make the insert more
consumer friendly. Of course, this would assume that the consumer seeks
further information, or is queued to find the insert and read
it.]{.underline}

**\-\-\-\-- END \-\-\-\--**