FOOD AND DRUG ADMINISTRATION

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CENTER FOR DRUG EVALUATION AND RESEARCH

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PUBLIC HEARING ON

OTC PART 15

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WEDNESDAY

JUNE 28, 2000

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The Public Hearing was held at 8:30 a.m. in the Ballroom of the Holiday
Inn, Two Montgomery Avenue, Gaithersburg, Maryland, Dr. Robert DeLap,
Director, Office of Drug Evaluation V, CDER, presiding.

[FDA PANEL]{.underline}:

JANET WOODCOCK, M.D., Director, CDER

RUSSELL CAMPBELL, Office of the Commissioner, Consumer

Affairs

DAVID FOX, J.D., Office of the Chief Counsel

DIANNE MURPHY, M.D., Acting Director, Office of Review

Management

ROBERT TEMPLE, M.D., Assoc. Director for Medical

Policy, Director, ODE I

JOHN JENKINS, M.D., Director, ODE II

FLORENCE HOUN, M.D., Director, ODE III

ROBERT DeLAP, M.D., Director, ODE V

CHARLES GANLEY, M.D., PhD, Director, Division of OTC

Drug Products

GARY CHIKAMI, M.D., Director, Division of Anti-

Infective Drug Products

LOUIS CANTILENA, M.D., PhD, Acting Chair,

Nonprescription Drugs Advisory Committee

SANDRA TITUS, PhD, Executive Secretary Nonprescription

Drugs Advisory Committee

I-N-D-E-X

[Page]{.underline}

Opening Remarks, Robert DeLap, M.D., PH.D., 4

Director, Office of Drug Evaluation V, CDER

Consumer Healthcare Products Association (CHPA) 11

Michael Maves, President; Eve Bachrach, Esq.;

R. William Soller

The Cosmetic, Toiletry and Fragrance Association 39

Thomas J. Donegan; James Leyden

Francesco International 64

Steve Francesco, President

National Consumers League 85

Linda Golodner, President; Brett Kay

Kaiser Permanente 106

Anthony Barrueta, Counsel

Buchanan and Ingersoll, Attorneys at Law 121

Robert G. Pinco; Mary Johnson

Steinberg and Associates, Inc. 141

David C. Steinberg

American Pharmaceutical Association 149

Rebecca W. Chater, RPH, MPh

National Community Pharmacists Association 165

Doug Hoey, Vice President

Becton, Dickinson and Company 165

BD Consumer Healthcare

Anna M. Longwell, Esq.

American College of Obstetricians and 180

Gynecologists

Michael Greene, M.D.

MedImpact 190

Schumarry Chao, M.S., MBA

Public Citizen\'s Health Research Group 200

Sidney Wolfe, M.D.

I-N-D-E-X (continued)

[Page]{.underline}

PEGUS Research 215

David C. Bradford, PhD, MPH

National Women\'s Health Network 228

Amy Alhna

Pharmaceutical Research and Manufacturers of 236

America

Russell Bantham, Deputy General Counsel

Peter Barton Hutt 254

SmithKline Beecham 262

John Dent, Ph.D., Vice President

AMMSYS Research, Ind. 270

Gerald F. Dunaway, Ph.D., President

Infectious Diseases Society of America (IDSA) 284

Frederick P. Sparling, M.D., Chairman

Cholestech Corporation 296

Warren E. Pinchert II, President and CEO

Chris Kahlenborn, M.D. 306

P-R-O-C-E-E-D-I-N-G-S

(8:38 a.m.)

MODERATOR DeLAP: Well, we have a busy agenda. Good morning, and welcome
to our open public hearing regarding the regulation of OTC drug
products.

I\'m Dr. Bob DeLap. I work at the FDA, and I am going to be moderating
the session.

The purpose of our hearing is really to gather more information and
views from people who are affected by our regulation of OTC drug
products, which is just about everybody. We recognizes that health care
in the United States is changing, and more drug products are being
marketed directly to consumers, and we expect that trend will continue.

Again, we want to make sure that we have as much information and advice
as possible so that we can make the best decisions from our end as time
goes by. Next, please.

The law and regulations provide for a few reasons for which a product
may not be available over-the-counter. Those are products that have
potential for addiction or are habit forming; products that inherently
have safety issues or conditions of uses of product present issues that
require supervision by a licensed practitioner for safety; and finally
products that are restricted to prescription status under a FDA approved
marketing application.

There are two primary mechanisms available for bringing products OTC in
this country at this time. There is the OTC Monograph System, also known
as the OTC drug review, which goes back many years and provides a
mechanism for marketing of products following monographs published by
the FDA that allows people to market products without pre-clearance, as
long as they follow the directions provided in the monographs. Next.

Then the other primary mechanism for OTC drug marketing is the New Drug
Application. This entails generally switching a product from
prescription-only status to an over-the-counter status. Considerations
here include safety and effectiveness in the OTC use and whether clear
and understandable labeling can be developed for self-medication without
help of a health professional.

As we said in the [Federal]{.underline} [Register]{.underline} notice
announcing this meeting, in light of the continuously changing health
care environment, including the growing self-care movement, the agency
continues to examine its overall philosophy and approach to regulating
OTC drug products.

We are interested in soliciting information from and the views of
interested persons, including health professional groups, scientists,
industry, and consumers on the agency\'s regulation of OTC drug
products.

Scope of the hearing, as outlined in the notice: Criteria for OTC
availability of drug products; classes of products appropriate for OTC;
consumer understanding; selection of treatment; OTC marketing systems;
and FDA\'s role in switches.

Regarding the first element, the questions that we raised in the FR
notice were: What criteria should FDA consider in deciding on the OTC
availability of drug products? What kinds of products are or are not
appropriate for OTC distribution? What types of illnesses are or are not
suitable for OTC drug products? How should individual risks/benefits and
public risks/benefits be balanced in decisions on OTC marketing?

Regarding classes of products appropriate for OTC, we asked: Are there
specific classes of products that are not currently marketed OTC that
should be? Which ones, and why? We also asked, are there specific
classes of products that should not be available OTC, and what specific
concerns do those classes raise?

We included with that last point a list of conditions that we had heard
discussion of bringing OTC for purposes of discussion.

The third area of interest to us was consumer understanding: How can FDA
be assured that consumers will adequately understand drug benefits and
risks and will be able to use products safely and effectively in the OTC
setting? What methodologies can be employed to evaluate consumer
understanding? How can we convey efficacy information, for example, for
products that are marginally effective or products that are used for
preventive indication, and can we label prevention type products in a
way that would not encourage ill advised behavior, such as not good
behavior for one\'s personal health followed by using a medicine to try
and make up for it?

Selection of treatment: How can we ensure good selection when there are
both OTC and prescription treatments available for the same illness?
When consumers are confronted by having a medicine available
over-the-counter and knowing that there are medicines available by
prescription only, how can we ensure that the consumers have the
information they need so that they can decide on the best course of
treatment for themselves? Are there public health concerns here?

Within a therapeutic class, should the first drug to enter the OTC
marketplace be the best drug? How should the availability of a better
OTC product affect the status of products already available OTC for the
same indication?

Then with respect to OTC marketing systems: Is the current structure for
marketing OTC products in the U.S. adequate? What lessons can we learn
from different OTC marketing systems?

FDA\'s role in switches \-- this is the last of the six categories of
questions we had: Under what circumstances should FDA actively propose
OTC marketing for a drug in the absence of support from the drug\'s
sponsor? Should FDA be more active in initiating switches of
prescription products to OTC use?

Now the schedule that we have, which was available outside as people
were coming in, divides the presentations into several sessions, and
this schedule was dictated by the requests that we received. So there
are certain categories for which we received a lot of requests to speak
and other categories where we didn\'t receive requests, and that\'s
reflected on the schedule here. Next.

The format for the open public hearing is that the hearings are
transcribed. Speakers are entitled to use their time as they wish. We
only request that the hearing be orderly.

If a person is not present at the scheduled time of their presentation,
we will try to accommodate them at the end of the hearing, but we will
try and stay on schedule.

Persons serving on the panel may ask questions of speakers. In these
kinds of public hearings, persons in the audience are not allowed to
interrupt or question speakers.

Finally, persons in the audience who do wish to speak and are not on the
schedule may request time to speak at the end of the scheduled
presentations.

Now at this point I\'m going to ask the members of the panel to briefly
introduce themselves and just a one-sentence description of their
position in the agency. Perhaps I\'ll start. Sandy, can I start with
you?

DR. TITUS: I\'m Sandy Titus, and I\'m the Executive Secretary for the
Nonprescription Drugs Advisory Committee.

DR. GANLEY: I\'m Charlie Ganley. I\'m the Director of the Division of
Over-the-Counter Drugs.

DR. CANTILENA: Hi. I\'m Lou Cantilena, head of Clinical Pharmacology at
the Uniform Services University and a member of the OTC Advisory
Committee.

DR. FOX: Hi. I\'m Dave Fox. I\'m an Associate Chief Counsel in FDA\'s
Office of the Chief counsel.

DR. CHIKAMI: I\'m Gary Chikami. I\'m the Director of the Division of
Anti-Infective Drug Products.

DR. MURPHY: I\'m Dianne Murphy, and I\'m the Acting Deputy Director of
the Office of Review Management.

DR. WOODCOCK: I\'m Janet Woodcock. I\'m Director of the Center for Drug
Evaluation and Research.

DR. TEMPLE: I\'m Bob Temple. I\'m Associate Director for Medical Policy
and Director of the Office of Drug Evaluation I.

DR. HOUN: I\'m Florence Houn. I\'m Office Director for Drug Evaluation
III.

DR. JENKINS: I\'m John Jenkins. I\'m the Director of the Office of Drug
Evaluation II.

DR. KWEDER: I\'m Sandra Kweder. I am the Acting Director of Office of
Drug Evaluation IV.

DR. CAMPBELL: I\'m Russell Campbell, Senior Consumer Affairs Specialist,
representing Patricia Kuntze, the Associate Commissioner for Consumer
Affairs.

MODERATOR DeLAP: We also have a few guests that are here to hear what is
presented at this session, members of our Nonprescription Drug Advisory
Committee, and if I could ask them just to briefly stand and identify
themselves.

(Guests introduced.)

MODERATOR DeLAP: I believe that was my last overhead. Yes. Okay, well
then, the only other thing I will remark to all the speakers is that we
do have one of those troublesome little signal lights here as to how
many minutes are left in the presentation time. We will try and do our
best to stay on schedule, and we ask you to observe the lights and try
and stay within the allotted time.

With that, I will turn the podium over to our guest speakers here. The
first session is on process issues, and I believe Dr. Michael Maves from
the Consumer Healthcare Products Association will be speaking first.

DR. MAVES: Thanks, Bob. Good morning. My name is Dr. Michael Maves, and
I am the President of the Consumer Healthcare Products Association and a
practicing physician at the Georgetown University Medical Center.

Our presentation today will be in three parts. I will be addressing the
overall policy issues of importance to the industry, while Ms. Bachrach
will speak to selected legal issues, and Dr. Soller will address the
scientific and regulatory perspective.

CHPA is the 199-year-old trade association representing the
manufacturers and distributors of nonprescription medicines and dietary
supplements. CHPA members represent over 90 percent of retail sales in
the OTC marketplace. We have worked collaboratively with the FDA, with
consumers and the administration over the years on all aspects of OTC
drug development, labeling, manufacturing and packaging.

Let me begin my presentation where I will end. Self-care with OTC
medicines is here to stay.

Secondly, the switch of drugs form prescription to nonprescription has
been phenomenally successful.

Finally, over the past 25 years, consumers, FDA and the industry have
faced increasingly difficult challenges regarding OTC availability of
prescription products. Together, we have created novel solutions to
difficult problems, and the consumers in the United States have
benefitted form these developments.

We speak about an OTC perspective within the industry. This perspective,
which we feel should be shared by all concerned parties, recognizes the
forces behind the self-care movement and captures the impetus for the
development of new OTC products.

As I\'m sure you\'re aware, consumers are extremely interested in their
own health care. For instance, 60 percent of adults follow news stories
about health, more than business, more than sports.

Secondly, consumers benefit from self-care. Access to self-medication
options empowers consumers and effectuates their desire to take control
of their own conditions. OTC medicines provide convenience, cost and
time savings.

Consumers turn to OTC self-care for 38 percent of all their health care
problems they experience. Yet for this vast volume, OTCs take up less
than two cents of every health care dollar.

The resource savings to the health care system through responsible
self-medication allows better allocation of limited health care
resources and physicians\' time to important issues beyond the scope of
self-care.

Self-care with OTC products spans a broad range of conditions and
diseases, ranging from acute conditions to recurrent conditions which
will require an initial physician diagnosis. Chronic disease prevention
strategies may also involve the use of things such as sunscreens to
prevent cutaneous solar damage and the development of skin cancer.

Finally, adjunctive treatment with OTC medicines, coupled with lifestyle
changes, can make a real difference to patients who, for instance, are
attempting to stop smoking.

Next, industry experience has shown that consumers use the OTC label and
responsibly self-medicate. Ninety-five percent of consumers read the
label prior to the first product use, and there is a high level of label
comprehension.

Importantly, OTC does not necessarily mean that the MD is out of the
picture. In fact, for conditions such as vaginal yeast infections, an
important part of the OTC treatment program is the initial diagnosis of
the condition by a physician.

Finally, the OTC industry and CHPA are proud of their leadership in
providing comprehensive, easily understood information on the package
label.

The potential for further self-care empowerment of consumers is based
upon a scientific paradigm which defines specific target populations
with readily recognizable conditions, previously diagnosed conditions,
or self-diagnosable diseases, and determining which drugs at the
appropriate dosage and with the appropriate labeling can provide a
reasonable expectation of benefit with a low potential for toxicity.

These new products are best determined on a case-by-case, data driven
approach that is initiated by the drug manufacturer, in collaboration
with the FDA, in such a way that the individual, not comparative, merits
of the switch are assessed through the appropriate research
methodologies.

This type of perspective has provided the consumer with a wide variety
of products and some truly remarkable success stories for all of us.
Over 80 ingredients, dosage forms and strengths have been switched from
Rx status or introduced as new OTC drugs since the start of the OTC
Review in 1972, accounting for over 700 marketed products. Some examples
are listed here.

To summarize this point, the OTC perspective or approach recognizes all
of these features: Consumers are interested in health care and benefit
from self-care; self care is potentially applicable to a wide variety of
conditions; consumers read and use the OTC label and can responsible
self-medicate; a scientific, research driven paradigm drives the
evaluation of new OTC products which should be evaluated on a
case-by-case basis using company provided data from carefully designed
research questions.

The process allows changes in labeling as further information develops.
Success will ensue from such a perspective being jointly pursued by the
FDA and industry in a collaborative fashion to benefit the consumers who
use these products.

I\'d like now to address three FDA questions. FDA asked whether
preventive claims can promote ill advised behavior. Let\'s step back.

How patients and consumers behave rests with them, irrespective of our
best intentions. This is not unique or limited to OTC products. We feel
that the more relevant questions are if this does happen, to what extent
does it occur, and how would OTC availability provide a similar or
greater public health benefit to consumers than prescription
alternatives. Again, we would feel that this should be evaluated on a
case-by-case specific basis.

FDA asks about the impact of co-existing treatments, including how to
determine appropriate self-selection of OTC and Rx treatments.

This is not a new issue for both self-care and physician directed care.
We already have the availability of both Rx and OTC products with the
same ingredients but with different formulations, strengths or
indications.

In fact, a casual perusal of the PDR reveals many conditions which have
both Rx and OTC options available to the patient and to the consumer.
Many conditions exist across a spectrum of severity and symptomatology
where it is entirely appropriate to provide products for both self-care
and physician directed care.

FDA asks about how the availability of a better OTC product would affect
the status of products already on the OTC market for treatment of the
same condition.

It\'s well known that individuals, consumers, patients and physicians,
vary in their response and preferences for different treatments. This
can lead to individual differences in compliance that may further vary
the response to treatment.

Therefore, we feel that the definition of \"better\" is not easily
defined for this purpose. For that matter, on the prescription side,
medical practice welcomes a wide armamentarium where many older drugs
play a critical role. We feel that consumers should have the same
choice.

In concluding my portion of the comments of our remarks, let me again
emphasize that self-care is here to stay. Consumers demand it. They are
aware of it, and want more control over self-care.

Secondly, the switch of drugs from prescription to nonprescription has
been phenomenally successful. This success has stemmed from the
collaborative efforts of the industry and FDA working together to
evaluate the specific merits of a case and make a scientifically
documented decision, to the benefit of the consumers we serve.

Finally, if past is prologue to the future, over the past 25 years, FDA
and industry have faced increasingly difficult challenges regarding the
availability of prescription products. Together, we have created novel
solutions to difficult problems. Consumers have benefitted from this
collaboration in the past and will continue to do so in the future.
Thank you.

MS. BACHRACH: Good morning. I\'m Eve Bachrach, General Counsel of the
CHPA. I will focus on four issues this morning. First, who should
initiate a switch? Second, the role of comparative assessments. Third,
the use of a single brand name to identify a line of OTC products; and
fourth, the two-class system for distributing drugs in the United
States.

FDA asks if it should propose OTC marketing in the absence of support
from the drug sponsor and, more generally, if it should be more active
in initiating switches.

Today virtually every switch is accomplished through the new drug
approval process. This makes public health sense. The company that
developed the drug in the first place and obtained the NDA for the Rx
drug knows the most about the drug.

The company is also in the best position to design and perform the
studies necessary to establish whether a drug can be adequately labeled
for OTC use.

Where FDA believes that a drug should be considered for OTC use, the
agency should consult with the company about this. However, the
suggestion that FDA might switch a drug without the company\'s active
participation or, worse, over its opposition could lead to the switch of
drugs that should remain prescription.

The only instance where FDA undertook to switch a drug without the
active support and participation of the company was metaproterenol. The
agency soon reversed its decision, acknowledging that it had not taken
into account all of the pertinent information and views.

Valuable lessons were learned from that experience, and the switch
process has since evolved to a collaborative approach between the NDA
company and FDA. This has been successful and has benefitted consumers.

If a switch were to be undertaken without consent of the NDA company,
the Act requires that due process be followed. The Rx legend is part of
the approved NDA. To remove it over the objection of the company, FDA
would have to follow notice and hearing requirements.

Neither the switch regulation procedure nor OTC Review rulemaking could
be substituted for statutory hearing rights. In any event, the switch
regulation procedure is an anachronism in today\'s environment, because
it only provides for removal of the Rx legend, not for development of
extensive data and labeling needed to support OTC use.

In addition to due process, almost any switch would also have to rely,
at least in part, on data submitted as part of the original NDA for the
prescription drug. The company has proprietary rights in its NDA data
which could not be used without its consent, regardless of the
regulatory switch option used.

For all of these reasons, FDA should continue to rely upon the NDA
company to initiate the switch process.

FDA asks about comparative assessments. Should the \"best\" prescription
drug in a class be switched first? Should older OTC therapies be taken
off the market after \"better\" ones are introduced?

Consumers benefit from the widest possible availability of drug products
that are safe, effective, and properly labeled. Because of individual
variability and preference, what is best for one person may not be for
another.

The process of comparing drugs to one another is a decision for the
consumer. FDA should not foreclose potentially useful options. Rather,
FDA should evaluate drugs on their individual merits.

The statute was carefully and deliberately written to provide that drugs
should be made available to consumers if FDA concludes that they are
safe, effective, and labeled properly. If a drug meets these criteria
for OTC use, FDA must and should approve the application, regardless of
whether the agency believes that other products are \"better\" in one
respect or another.

Once approved, a product can only be withdrawn based on a similar
finding that it is no longer safe and effective. The availability of
\"better\" drugs is not a criterion for withdrawal.

When genuine safety or effectiveness issues are presented with a
marketed product, industry has a long history of working cooperatively
with FDA in the public interest through labeling changes and, where
appropriate, by taking products off the market.

It is good public health policy for consumers to have access both to new
switch drugs and to older drugs that may be appropriate choices. For
that reason, there is nothing in the statute that permits FDA to make
the sort of comparative assessments contemplated by the questions in the
hearing notice.

FDA asks, third, how to assure that consumers understand the benefits
and risks of particular products when the same brand name is used for a
line of OTCs.

Use of a family brand name for a line of drug products benefits
consumers who use the brand to identify trusted product sources.
Manufacturers are able to develop useful new products based on an
established brand heritage, thus expanding the range of consumer
self-care.

FDA also recently addressed the issue of product selection through its
OTC label format rule, which requires active ingredients to be
identified first in the \"Drug Facts\" section of the labeling. The
agency said that this placement will help ensure proper product
selection, especially for product line extensions.

Brand name line extensions are beneficial to the health care system by
contributing to the OTC armamentarium. We also believe that any attempt
by FDA to restrict brand name line extensions generally would violate
First Amendment protection for truthful and nonmisleading commercial
speech, and would violate the property rights of manufacturers in their
trade names. FDA precedent also makes trade name restrictions a matter
of last resort.

Finally, FDA asks if we can learn from countries where nonprescription
drugs are sold \"behind the counter.\"

Convenience and access are hallmarks of the effective self-medication
system in the United States. A third class of drugs would reduce both
without providing a benefit to consumers.

A third class of drugs in the U.S. has been exhaustively studied for 120
years and rejected. The definitive study was undertaken by the U.S.
General Accounting Office. In its 1995 report, the title tells the
story: \"Nonprescription Drugs: Value of a Pharmacist-Controlled Class
Has Yet to Be Demonstrated.\"

Since 1974, FDA has repeatedly rejected a third class of drugs on the
grounds that a public health benefit has not been demonstrated. Both the
agency and the Department of Justice have acknowledged that FDA lacks
statutory authority to establish any such class.

In short, the U.S. system of unrestricted OTC drug distribution works,
and other countries are starting to follow America\'s lead.

In conclusion, the public interest and public health support switches
initiated by the company with the NDA, the part with the most
comprehensive knowledge about the drug.

The public health is best served by having the broadest range of safe
and effective OTC therapies available.

Use of a brand name to identify a line of products facilitates product
choice and enables manufacturers to develop and bring to market useful
new self-care products.

Finally, a third class of drugs has been exhaustively studied and
rejected for over a century on the ground that no public health benefit
has been demonstrated. It would be a backward step for the U.S. to
consider restrictions on OTC availability as the rest of the world is
starting to follow America\'s lead by expanding unrestricted access to
OTC drugs.

DR. SOLLER: Good morning. My name is Dr. Bill Soller. I\'m Senior Vice
President and Director of Science & Technology for the Consumer
Healthcare Products Association.

I\'ve been involved in the OTC industry for over 20 years, and over that
time have consulted with many of our members on many switches that have
been undertaken during that time.

I plan to concentrate on three areas of FDA\'s questions by describing
the Rx to OTC switch process, specifically covering switch criteria,
consumer understanding, and category exemptions.

FDA asks what criteria the agency should use for switch. We interpret
switch criteria to mean the standards for making the benefit/risk
decision for OTC availability.

Switch criteria should be the current statutory and regulatory criteria
that have been the basis for the many successful switches undertaken
since the start of the OTC Review.

The foundational statutory criterion is basically the demonstration that
labeling can be written for consumers to use a product safely and
effectively without a prescription.

On this statutory basis, the regulatory definitions of safety,
effectiveness and labeling were developed in 1972 as the scientific
underpinning for the OTC Review. In practice, they have been used
subsequently as the basis for evaluation of OTC New Drug Applications.

Specifically, the regulatory interpretation of the statute interprets
safety, effectiveness and labeling in relative terms, meaning a
reasonable expectation of effectiveness, a low incidence of side
effects, a low potential for abuse, not an absence of toxicity or an
expectation that 100 percent of the target population will have a 100
percent benefit 100 percent of the time.

These regulatory criteria are fulfilled through the application of the
basic principles of toxicology, clinical pharmacology and epidemiology,
using the standard scientific/regulatory paradigm, which is the
case-by-case, weight of the evidence, data driven, dialogue driven
approach that we use as scientists to determine drug availability.

Specifically, companies are well equipped to address the sorts of
potential issues that typically arise in the context of OTC availability
and switch. Companies consider potential safety issues with respect to
potential toxicities which are often already worked out in the parent
drug\'s New Drug Application, and safety issues relating to potential
therapeutic hazards, including issues associated with misdiagnosis,
potential treatment failure, incorrect use, and drug interactions.

Key effectiveness issues are also considered, and companies consider the
ability of the label to convey core communication objectives of safe and
effective use of the product by consumers without a prescription. After
all, this is the basic statutory criterion.

Based on this framework, the compulsory benefit/risk assessment
integrates safety, effectiveness and labeling within the question: Is
the benefit of self-care through OTC availability worth the risk of
access without a prescription?

Because the switch process is case specific, it often requires
substantial data development. This is best developed through a company
initiated approach that includes early and frequent dialogue with the
agency during the OTC R&D process.

Case specificity is universal to switch, often necessitating a data
intensive approach and close company-agency interaction. For example,
quit rates for Nicotine Replacement Therapy were much better in high
support settings versus lower support settings. Yet the limitation to
access to prescriptions was actually thwarting usage of NRT and,
therefore, total quit rates on a population basis. Actual use studies
showed OTC access could resolve this problem.

Pediatric ibuprofen involved the largest trial in the company\'s
history, and this was one of our largest members, to assess the relative
risk of rare side effects when used a sa fever reducer.

Vaginal antifungals posed the question of the ability of women to
recognize symptoms of recurrent vaginal candidiasis after a physician
diagnosis, and the core issue for OTC Cimetidine related to potential
drug-drug interactions.

We can expect, therefore, that every future switch will have its own
unique set of issues that can only be resolved by a data driven,
dialogue driven approach.

On the subject of consumer understanding FDA asks: How can it be assured
of consumer understanding of the benefits and risks of specific OTC drug
products and the ability of consumers to use OTC products safely and
effectively?

FDA can continue to gain assurance by using the established switch
process and the consumer behavioral research studies that have been
refined over the last decade to address case specific switch questions.

Consumer behavioral research includes attitudinal and comprehension as
well as observational research. Examples include actual use studies,
label comprehension studies, research defining OTC target populations,
research on educational programs and materials that form part of the
labeling of the switch candidate.

Any and all of these studies can be essential to the OTC benefit/risk
decision. FDA\'s questions suggest a need for further dialogue on this
matter, and we ask for that at this meeting.

FDA also asks: What types of drugs or classes of products should not be
available OTC?

In the context of the statutory criteria for OTC-ness and the
established switch process, FDA should not create presumptive negative
lists.

As a conceptual matter, no drug or category of drugs should be listed as
off limits to scientific research when we cannot predict technological
developments or the results of future studies. To do so would be in
conflict with the statutory criterion for switch and the associated case
by case, data driven scientific/regulatory paradigm.

Remember, eleven years ago at a national symposium, it was predicted
that H2 blockers would not go OTC. Yet today, through a collaborative
effort by companies and FDA, they are a major part of the OTC
antacid/acid reducer category. The point is, presumptive negative lists
should be avoided.

In summary to our remarks: The switch process has been very successful
in providing significant therapeutic benefits to consumers.

FDA must use the statutory criterion for switch and should continue to
use the regulatory definitions of safety, effectiveness, and labeling,
practice the scientific/regulatory paradigm, review drugs on an
individual basis, and avoid presumptive negative lists.

We seek additional dialogue on consumer behavioral research. Switch
should be initiated by the NDA company who has the most knowledge about
the drug.

A third class of drugs has been thoroughly reviewed and rejected for
over a century on the grounds that no public health benefit has been
shown. Most importantly, we should seek collaborative, not
confrontational, approaches for the company-agency dialogue that is
vital to creating a thorough, yet reasonable, OTC R&D program to address
future switch proposals. Thank you very much.

MODERATOR DeLAP: Thank you, Dr. Soller. At this point I\'d like to hear
any questions that members of the panel may have for CHPA.

DR. TEMPLE: This is a question for Ms. Bachrach. You emphasized that the
switch initiative should pretty much always come from the company. There
is legislation, a statute that says that \-- the Durham-Humphrey Act
that says the drugs that can be appropriately used by patients should
be. At least, that\'s how we read it.

Sometimes companies defer the desire to switch, because they are not
ready, because of commercial considerations. Don\'t you think there is
some role under that law or some obligation by the company under that
law that should make us be more bold? You need to go to a mike or it
won\'t be recorded.

MS. BACHRACH: Well, Dr. Temple, I would first preface by saying that the
Durham-Humphrey amendment was designed to address a system where there
was a number of drugs on the marketplace where the Congress and the
agency were trying to bring some kind of consistency to their
regulation. There would be drugs that were both, identical drugs sold by
two companies. One was prescription; one was sold OTC.

It had a very narrow purpose at the time. The switch \-- That switch
regulation procedure that you referred to as a result of Durham-Humphrey
really is long since become an antique museum piece in the current
environment.

It was last used in 1971, and the only ability it provides is to remove
the Rx legend. It doesn\'t provide for what we now have long since come
to recognize as necessary to develop the kinds of data that Dr. Soller
was describing to assure appropriate safety, effectiveness and labeling
for an OTC drug, which usually is at a different \-- in today\'s
environment, usually sold at a different dose and for different
indications.

In terms of the company, the company clearly has the most knowledge, the
most knowledge both in terms of its development of the Rx drug NDA in
the first place, and then during the course of the marketing of the Rx
drug it is very typical for the company to have conducted dozens, if not
sometimes hundreds, of studies that may bear on aspects of the drug\'s
use that will have accumulated an important decision making factor in
whether or not and when that particular drug is appropriate to switch
OTC.

So the agency certainly has a role in approaching a company and asking
where they believe a particular drug may be appropriate for OTC, but to
undertake on its own initiative without active participation and support
of the sponsor, I think, would not be wise in today\'s environment.

DR. TEMPLE: Okay. That\'s fine. Not to focus on particular drugs, which
will be discussed later, there are some circumstances in which you might
not even think that use studies are necessary and things like that. So I
guess you would say that there is more of a role for the FDA in that.

MS. BACHRACH: I would say it would be appropriate to consult with the
company on that.

MODERATOR DeLAP: I had one other point that I would like to hear a
little more elaboration on.

There was discussion of how we should take into consideration the
availability of \-- the continued availability of older products, for
example, when a newer, better product comes along. One of the points
that I thought I heard was that, even if the older product presented
some kinds of safety problems, that there would likely continue to be a
role for it, at least for selected individuals.

I know that, clearly, in the prescription drug process, we have at times
had products go off the market because of safety issues, and part of
that decision making process was that there were now newer, better
alternatives.

I\'d like to hear a little bit more again as to what the rationale would
be for keeping an older product in the marketplace that has more safety
problems.

DR. MURPHY: Bob, could I ask them to add to that, because I think it\'s
the same category. They have addressed many of the benefits and
mentioned not a lot on risk. They might want to incorporate that into
their comments, what they see as some of the risks.

MS. BACHRACH: Well, Dr. DeLap, with respect to older drugs, whether they
are OTC or prescription, if there is a legitimate safety question that
arises, regardless of comparative benefits of drug A versus drug B, if
drug A has substantial safety questions about it, the agency certainly
should raise those and, if they can be addressed, as sometimes they
certainly can be through labeling, that would be the appropriate way to
approach the product.

It is certainly a matter of last resort where benefit/risk ratio is such
that the risks outweigh the benefit that pulling a drug from the market,
particularly an older OTC, would have to be considered.

Certainly, in the case of OTC drugs, we are dealing \-- The neutral
principle is that these drugs have a very wide margin of safety. So it
would be a rare circumstance under which such a drug would present such
a significant safety problem that removal from the market should be a
consideration, quite apart from the issue of a comparative \--
comparative questions of whether that drug is better than another one.

In the context of how the questions were framed in your hearing notice,
you spoke generally about should drugs be removed if, quote, \"better\"
drugs come on the market. In the context of your particular question,
that is not contemplated under the statute, in our view, and we will
certainly be addressing that in greater detail in our written comments
following the hearing.

DR. SOLLER: Bob, I have a brief add-on. If the agency has a legitimate
safety concern, and this has happened throughout the OTC Review and
subsequently to the end of the panel discussions in the Eighties, then
typically the agency has come forward and asked for information on it.

What has happened through the OTC review is the development of a very
well worked out policy to manage that, and it has been used over and
over again, and it\'s the policy about availability, the policy about
warnings. That is that warnings, availability must be scientifically
documented, clinically significant, and important to the safe and
effective use of the product by the consumer.

This three-part hurdle has been played out time and again through the
advisory committee meetings dealing with currently marketed drugs as
well as switch drugs. So you have a policy and process in place that\'s
been working quite well and, I would envision, would continue to work
quite well in the future.

MODERATOR DeLAP: Okay. Well, thank you very much. One more question?

DR. TEMPLE: One of the major points made was the importance of the
consumers\' ability to choose and their responsibility for choosing
among available therapies.

If you got to a relatively complicated situation, like cholesterol
lowering agents \-- not to raise that issue prematurely \-- what exactly
do you contemplate as the contents of labeling? Would it say this one
hasn\'t been shown to have any effect on survival, but others have?

I mean, what\'s a realistic level of information to provide in labeling?
I guess I should note that in the past there\'s been some reluctance to
put efficacy data in labeling for OTC drugs on the grounds that it
wouldn\'t be well interpreted, could be misleading, and so on.

DR. MAVES: Thanks. I appreciate that. Without getting into specifics, I
think the point that we were trying to make is this, that if you look at
each one of the new switches that have come up over the past 25 years,
in almost every instance the need for new labeling or a way to explain
to the consumer in an easily understood fashion has been part and parcel
of that particular switch process.

If you look back at things like nicotine replacement therapy where
there\'s a rather exhaustive type of instruction for the particular
consumer that\'s necessary so they can intelligently use the product,
we\'ve seen time and again that that kind of inventiveness can be put
together, that we can have those kind of instructions available to the
consumer, and that they, in point of fact, can use these products in an
intelligent, reproducible fashion.

So without getting into specifics with this and saying, well, gee,
exactly what would the label look like, I think I have a lot of faith
both in the industry and in the consumers that together we can come up
and find appropriate labeling that can be used, that can intelligently
communicate the necessary information to consumers to use those products
on an OTC basis.

MODERATOR DeLAP: Okay. We\'ll move on to the second presentation. Oh,
sorry.

DR. FOX: Just a quick question. Will your written comments include a
thorough analysis of the argument that a sponsor has certain due process
and proprietary rights in maintaining its product Rx, if it so chooses?

MS. BACHRACH: Yes.

DR. FOX: Looking forward to it.

MODERATOR DeLAP: Okay. I believe we are now ready then for Mr. Donegan
and The Cosmetic, Toiletry and Fragrance Association. Tom?

MR. DONEGAN: Let me stake out my ground with a couple of products here,
and I\'ll come back to those. Those will be relevant very quickly.

I\'m Tom Donegan. I\'m General Counsel of The Cosmetic, Toiletry, and
Fragrance Association, and I will be joined shortly by Dr. Jim Leyden of
the University of Pennsylvania School of Medicine who is going to talk
about some of the sunscreen issues that we have here.

Before I start, I would like to congratulate FDA on holding this
hearing. One of my points is going to be openness in the OTC process,
and I think just this kind of dialogue and as many other dialogues as we
can have about the process and ways to change things and make them work
better is very important. May I have the next slide, please.

Michael Weintraub used to always like to ask at the beginning of
meetings on OTC drugs, well, what are the cosmetic people doing here?
Well, the first thing I want to do is explain that to you.

We are a trade association that was founded in 1894. We represent about
600 companies, 300 of whom manufacture products, and many of these
members manufacture not only cosmetics but drugs as well. In fact, many
of these products are regulated as both cosmetics and drugs, and have to
comply with both regulatory structures.

We are here to discuss not the switch issue but the monograph process,
the OTC Drug Review, which started in 1972, which we feel is very
important, particularly to our products. There are still many products
subject to ongoing monographs some 28 years later, and this provides a
way for people to market products in compliance with the monograph,
regardless of whether they have the resources to go through the NDA
process and to sponsor an NDA. Next slide, please.

One thing that strikes me as we look at this hearing and the subject
matter that you are covering is that the field of OTC drugs is getting
broader and broader from both ends. You\'re looking appropriately at Rx
to OTC switches which allow flexibility, that allow consumers to have
products that are available, and to have choice where the facts are
appropriate.

Well, also at the other end of the spectrum many drug products are now
being marketed in cosmetic vehicles, and so they are sold in cosmetic
settings in products that provide cosmetic benefits as well as drug
benefits. Our point is that greater flexibility should be allowed for
those products and the way that they are labeled through the monograph
process. Next slide.

What are cosmetic drugs? This gives you a list of the types of products
I\'m talking about. It\'s not all-inclusive, but we\'re talking about
sunscreens in cosmetic products, a foundation product that provides SPF
protection.

We\'re talking about antiperspirants which are drugs, because they are
an antiperspirant, and they are cosmetics because they are a deodorant
\-- these, by the way, are convenience sized packages, which I\'ll come
back to later on in another point \-- anti-dandruff shampoos, oral care
products, and a variety of other products. Next slide, please.

Why are they different? They are sold through different marketing
channels. For example, many cosmetic drugs are sold through department
stores, not a normal vehicle for many OTC drugs. In many cases, they are
purchased primarily for their cosmetic benefit, but they do provide
important drug benefits as a secondary benefit.

The broad consumer availability of these products provides, we believe
\-- and Dr. Leyden will talk about this more \-- an important public
health benefit, particularly for products like sunscreens, and they come
in small packages, convenience sizes which are essential for the
consumer to be able to use them in many different settings, at work,
while they are traveling, a variety of other settings. Next slide,
please.

Many of these products, not all but most of them, come to market through
the OTC Drug Review, which as you all know, started back in 1972, and we
are now in 2000, and we expect it to go for a while.

You\'re going to hear from many people during this hearing who were
there at the beginning of the OTC Review. I hope that there will be some
of us who will survive to see the end of the OTC Review, but quite
seriously, I raise the question, should it end or should that just be an
ongoing process where we are constantly revising and tweaking and
looking at new products, etcetera? It\'s provided an important function.
Next slide, please.

The problem with the monograph process \-- and I don\'t think it started
out this way or it certainly didn\'t start out with these intentions \--
is that it\'s far too slow. It\'s taken much too much time to come to
final conclusions on some of these products.

Typically, when you look at monographs like sunscreens or skin
protectants or others, it\'s been a stop and start process. It\'s a lot
of activity, and then years of seeming inactivity before it starts up
again.

I think there\'s a failure within FDA to distinguish between NDAs and
the monograph process. In fact, I\'ve been somewhat disturbed to hear
recently talked that the monograph process should be more like the NDA
process. I think quite the opposite. I think this needs to be an open
process where the agency holds itself open to learn as much as possible
about the product category and how it has evolved.

Evolution of the products is important here, particularly given the tim
frame that\'s been involved. Some of these product categories \-- and
again Dr. Leyden will talk about sunscreens \-- don\'t look anything at
all like they did back in 1972 or \'75 or whenever the process started.

There\'s a need during the ongoing monograph process to recognize new
ingredients, to recognize new product forms, and to take all of that
into account. Next slide, please.

I think the agency has found it difficult to update its expertise on
these over-the-counter drug products. I don\'t know whether that\'s
because of resources or lack of focus or what the issue may be, but the
agency should be on the cutting edge, certainly, of the science, and
they ought to also be up on formation technology, on testing methods, on
the whole variety of issues that have to be resolved in the context of a
monograph.

Our feeling is many times that\'s not the case, that the agency is
looking at a product category in 2000 through 1977 glasses, and you\'re
seeing a distorted picture. You\'re not really seeing what\'s out there.
You\'re not seeing what the consumer is using. You\'re not seeing the
products that the consumer needs.

One very good thing in the last few years that we had was a feedback
meeting on sunscreen formulation technology which, I think, is the kind
of meeting that needs to be held more often so that FDA can get up to
date on what\'s being sold, how it\'s being made, and what the new
product forms are that might benefit consumers. Next slide, please.

Another issue that needs more focus is international harmonization.
We\'re working in a global marketplace right now. There\'s no way around
it. It\'s not going to change. I think it\'s important that the agency
focus on ways to make the international marketing of products and the
availability of products across international boundaries more readily
available to consumers.

I just focus here on the material tim and extent barriers. The proposed
regulation that was issued earlier this year, I think, still poses
major, major hurdles to getting products into the U.S., to getting
foreign ingredients into the U.S.

Labeling harmonization is very important, when you look at whether
manufacturers can sell the same product across boundaries, and I think
there are things the agency could do to make that easier.

One of the reasons we\'re so concerned about this is our products, these
very products, are cosmetics in Europe and most of the world. They are
drugs in the United States.

So the regulatory hurdles here are much greater than they are in other
parts of the world, and although we are not necessarily arguing for a
statutory change in the system here, I think there are ways that the
agency can be more sensitive to that difference, and particularly with
labeling, to try to grant accommodations that don\'t pose unnecessary
barriers to international marketing. Next slide.

The solution here, I think, is increased resources, a focus on monograph
issues. As I said, I don\'t think any change in the laws is necessary,
but I think there\'s a lot of flexibility and leeway within FDA\'s
existing regulations to make this all work more smoothly.

I think FDA needs to adopt a policy encouraging more frequent
communication with interested parties throughout the rulemaking process,
and that\'s an important point. I want to stress that. Communication
with the interested parties \-- and I don\'t just mean the industry; I
mean consumers and the scientific community and others \-- is very
important to do all the things I\'m talking about in terms of updating
the agency\'s database, and a faster review and approval of new active
ingredients, both domestic and foreign. Next slide.

More outreach: I talked about international harmonization. I just want
to call attention to what\'s called the CHIC process, which is going on
now between FDA and European governments.

CFSA, the Center for Food Safety, has taken a major role in this to look
for ways to harmonize on labeling. I would encourage CDER to get
involved in that more than they have been in the past and to make that a
high priority.

It\'s called cosmetic harmonization, because we\'re talking about these
very products that are cosmetics in Europe and drugs here.

Finally, flexibility in the regulation of cosmetic drugs: If it isn\'t
used, it can\'t be effective. The cosmetics industry has been able to
develop ways to make these products usable on a day to day basis.
Sunscreens that are suitable for wearing to work, social events and that
sort of thing as well as the beach and outdoor events where we typically
think of using sunscreens \-- it\'s important that those products be
available to consumers. Next slide.

We\'re going to talk about two case studies, and I\'m going to skip over
the first one quickly, much to the relief of Dr. DeLap and Dr. Woodcock.
That\'s OTC drug labeling.

This is a rulemaking that was applied to all OTC drugs, a comprehensive
redo of the label. My only point here, because I want to give Dr. Leyden
time to speak on sunscreens, is that this is a classic example of how
one size fits all doesn\'t work for the OTC drug industry anymore,
because it is such a diverse group of products.

We need labeling rules that fit these kinds of products, small packages,
products that are marketed in different places, products that are
marketed with cosmetic attributes, as well as labels that are
appropriate for drugs that are in the middle and at the Rx end of the
spectrum.

At this point, I\'d like to turn it over to Dr. Jim Leyden of the
University of Pennsylvania.

DR. LEYDEN: Thank you, Tom. I see by the agenda my time is up. So if I
can answer any questions, I\'d be glad to.

The CTFA asked if I would be willing to say a few words about the
monograph process, and particular reference to these cosmetic drug
categories that you just heard about, and sunscreens in particular, and
I said I\'d be glad to.

I was one of those who was there at the beginning. Incidentally, if it
matters to anybody, I\'m not receiving any honorarium for my appearance
here today. I do feel that I\'ve been part of this process. I was
involved in giving seminars to many of those panels. I appeared many,
many times for several panels. In fact, several of them invited me to
the party that they had when their tenure was up.

The process has been long. It reminds me of my children. I have a son
who is 34 and a mergers and acquisitions lawyer, and a daughter who is
36 who is an epidemiologist at Berkeley, and it was a long, hard, costly
process getting them to where they are, but it was worth it.

I hope that, when the monograph process graduates in the new future,
that we can look back and say it was worth it with the same enthusiasm
that I have for my children, at least.

So if we can begin. The labeling process, as you just heard, is a
complex one. In the case of sunscreens, I think this is one area where
commerce and public health have come together. If there\'s one thing we
know for sure, it is that sun has acute and chronic adverse effects on
skin, and the introduction of sunscreens in everyday products, I think,
is an important public health step forward.

We know they can help prevent skin cancer, and we know also that they
probably can help prevent some of the what are more important to many
consumers, aging processes. I think prevention should be a priority for
the FDA in deciding these labeling issues.

When we started back in 1972, it was simple. We had two sunscreen
ingredients. We thought we knew everything there was, and we could just
prevent redness, then that would be enough. This evolving process that
is going to continue to evolve, as was just stressed, the need to be
flexible and to adapt as new information develops, I think, is an
important consideration.

We had just a couple of ingredients. We didn\'t UVA was important. We
thought it was, quote, \"safe.\" We now know it\'s anything but safe. It
plays a role in cancer. It particularly plays a role in the chronic
changes associated with what we call photo-damage or photo-aging.

We know a lot more about the mechanisms of skin cancer, the wave lengths
that are involved, which include both UVB and UVA. We have ways of
measuring protection. That\'s an evolving story that some of you are
more familiar with than others, and we have lots more than just
traditional products first designed for when one was going to be exposed
for prolonged periods of time. We have a whole variety of different
products.

We have a evolving formulation technology. The sunscreens are getting
better. They are lasting longer. People are learning how to make them
more stable so that you can use less and have it last longer. So it\'s a
very evolving process, and there are small units, as you just saw, lip
balm things.

In fact, this morning when I was getting ready \-- getting dressed, I
used a shampoo that was in a small bottle, an anti-dandruff shampoo. I
use an antiperspirant. I had some aspirin and Tylenol in small units,
and I had some sunscreens that were in small units.

I guess none of them would be available if the kind of label that is
being proposed and which has a lot of merit, I think, in many respects
for some of the drugs that are available and some of the drugs you are
going to be considering in the next couple of days.

These are more cosmetically oriented products, and I don\'t think the
need to have that kind of label which would have information that\'s of
no interest to just about anybody who would buy those products should
mean the end of convenient size products.

We have a much better understanding of what sunscreens can do. They can
do a lot more than just protect the acute adverse effect of sunburn. We
know they can play a role in preventing skin cancer and, certainly, in
preventing aging.

The aging changes, we\'ve learned, are what really attracts the public
to this concept. Telling people that it prevents cancer works. If
you\'ve had cancer or your mother had melanoma or your brother had
melanoma, that makes an impact on you as an individual. But on
populations \-- people are much more interested in wrinkling than they
are in cancer, because they think cancer is something someone else is
going to get, and everybody is going to get wrinkled and all the other
changes.

So we\'ve learned that\'s a very important, persuasive way of getting
people interested, and mothers then get their children interested. So
it\'s had benefits far beyond selling cosmetic products.

There are issues regarding how high SPF factors should be on labels.
Many people, probably the millions of people like me, if I play golf
with an SPF 30, I get burned. So I use an SPF 60, and I don\'t get
burned. Probably I\'m doing more benefit in terms of long term
protection as well as preventing that acute effect.

We now know that UVA is very important. There are people \-- I\'m also
one of those individuals who has a UVA photosensitivity, and better UVA,
truly broad spectrum UVA photo-protection is indicated.

I hope the FDA will take the position, at least in this category and
particularly with sunscreens, of encouraging products that help prevent
problems and encouraging innovation in the labeling to attract more
people to be protecting themselves in a better way as we learn more and
more about how to do this more effectively.

I think this has been really a major benefit to the public, this
increasing awareness and getting more and more people aware that they
can do things that protect them, not only from obvious exposure but from
the enormous amount of exposure we get on an incidental basis.

It\'s always interesting to talk to patients who say I don\'t go in the
sun. We say, well, do you run? Well, yeah, I run five miles every day.
Do you watch your children play? Yes, I do that. You know, do you sit
out, have lunch sometimes? Yes.

So incidental sun exposure is important, and protecting against it, I
think, is something that should be remembered.

Hopefully, the FDA in making these rules and regulations for labeling
for some of the more interesting drugs you\'re about to discuss over the
next two days or ones that are currently available won\'t come out with
regulations that will interfere, particularly with the sunscreen
cosmetic type product that has made, I think, a big difference, and that
for those of us who need high SPFs \-- and we know who we are \-- that
that be available; and that the anti-aging benefits be allowed to be
included in the labeling so that people who are more interested in that
will become increasingly more aware of not only those effects of UV but
also protect themselves from the biologically more important things such
as cancer.

Then finally, obviously, there\'s a very complex set of questions you
all are having to struggle with and come up with labeling and decisions
about what drugs should be available and how to protect people from
simultaneously using several drugs that have the same ingredient and
getting overdose effects.

In this area that seems to have somewhat fallen through the cracks a
little bit in the thinking of cosmetic products that contain active
drugs, I hope you will consider being more flexible, and particularly in
the area of sunscreens, realize the importance of these drugs in terms
of public health. Thank you. Now that my time is really up, if there are
any questions.

MODERATOR DeLAP: One of the areas that I have some concerns about has to
do with the labeling for sunscreen products. As these products are
intended to prevent certain kinds of short term and long term damage to
the skin, do we sometimes send the wrong message in labeling for
products and encourage people to do things that they shouldn\'t?

For example, when we see discussion of how many hours you can stay in
the sun if you use an SPF 30 product and you can normally stay in the
sun for X minutes, now you can stay in the sun for X hours, those kinds
of things that I do see and that do concern me.

DR. LEYDEN: Yes. I think that\'s a very, very good point. I think
recently the CTFA made a proposal of suggesting that on the label of
sunscreen products be something to the effect that the fact that this
makes it less dangerous to be in the sun doesn\'t mean that you should
think that you can stay out a much longer period of time and be safe.

I mean, I think the focus of saying it makes the sun less dangerous \--
I mean, nobody wants to live indoors. I want to play golf. If I played
better, I wouldn\'t play as long as I do, but I want to play golf, you
know, and not ad midnight.

So I think what we\'re really trying to do is find a compromise of
getting people to minimize the damage, and identifying people who are
much more \-- There are clearly people who are more vulnerable than
others, and implying that sunscreens make it safe to be outside, I
think, is a mistake.

I don\'t think the CTFA and their members see it that way. I think their
proposal of adding that kind of further understanding of what these
products do is a good one. I don\'t know if that\'s gone anywhere with
the agency or not, but I think their proposal is one that I would
support, and I think it fits in exactly with what you\'re saying.

DR. GANLEY: I just want to get a little clarification, because you mixed
two different types of issues here. One is the convenience size, which
actually has less labeling space, with these issues of conveying all the
information the consumer needs to know through labeling.

So there seems to be some disconnect there of how you can accomplish
both.

DR. LEYDEN: Well, I think having font size of the ingredients of a
certain size and certain other things would be very \-- might be
extremely appropriate for some of the other drugs you are discussing \--
is not so important in this.

I think what I was really trying to say in the few minutes there was
that, instead of having that kind of information, you want to have the
kind of information that people are interested in and can see and
attract them to the product; because the kinds of concerns you have for
some of these other drugs, I don\'t think, should be or are an issue
with sunscreen, particularly in cosmetic formulations.

I mean, people know what \-- They have a reason why they are buying it.
Some people, like my wife, likes to use cosmetic sunscreens rather than
beach products when she plays golf. She\'s much better than I am. She\'s
the club champion. So she likes to use a cosmetic formulation.

The people who are being enticed in the cosmetic world, many people are
now using sunscreens on a regular basis because they were attracted
because of the anti-aging possibilities and protection against
developing further in the way of wrinkling, which I don\'t think is
something that is currently likely to last on those products, as I
understand the proposals.

So I think that kind of information for that kind of category of product
would be more important than being able to see the font size of the
excipients and the active sunscreen, which the average consumer doesn\'t
really care about unless they are allergic to it, in which case they
will take the time to look at small print to see if a preservative or
whatever is in a given product, where the average consumer could care
less, because they don\'t even know what those things are.

So I don\'t think \-- Maybe I didn\'t have enough time to develop it.

MODERATOR DeLAP: Dr. Temple?

DR. TEMPLE: Well, I must say, I do feel I know you and your family much
better than before.

This is probably my unfamiliarity with it, but take a typical \-- I
don\'t know \-- cosmetic that happens to have a little blocker in it. Is
what you\'re saying, that should just become part of routine use. It
would be a better world if more people would use those to prevent sun
damage overall, and you don\'t need to give them a whole lot of drug
facts, because they\'re not using it to go out and lie on their deck for
many, many hours? I\'m not sure I\'m getting what the problem is.

DR. LEYDEN: Well, in large respect, yes. I mean, for example, we now
know \-- and I have some \-- If we had time, I could talk for hours on
this subject, as you know. We have examples of people who do not like
the outdoors, but whose job gets them in front of a window, for example,
on one side of their face for five or six hours, where they\'re getting
a lot of UVA.

I have pictures of 65 and 67-year-old women, one side of their face
completely caved in with wrinkles, and the other side smoother than
mine. That\'s clearly from indoor exposure of a large amount, you know,
five or six hours a day for many years.

There are lots of people who don\'t go out and deliberately sun, but get
a fair amount of exposure because they walk or run. They walk their dog.
They watch their children. They don\'t think of it as sunning.

DR. TEMPLE: So how do you want the package to convey that that\'s
different from now?

DR. LEYDEN: Well, I think any way that industry can figure out a way to
attract them to use the product, I would be for, and I wouldn\'t try and
tell them how to do it myself. I have some ideas.

DR. TEMPLE: So you think the specific language that\'s called for is too
limiting?

DR. LEYDEN: I think so, yes.

DR. GANLEY: I have another. This may be better answered by Tom, and it
deals with the regulation of products in Europe as cosmetics and
products in this country as drugs.

Are you suggesting there should be a separate category of drug/cosmetics
in this country or that we should adopt some of the regulations for
cosmetics that Europe has for cosmetics in this country?

MR. DONEGAN: What I\'m suggesting is that the regulations that you adopt
should be sensitive to the fact \-- to the way that these products are
marketed in other parts of the world, and it\'s not just Europe \-- and
it\'s actually most of the rest of the world \-- so that you\'re not
creating labeling requirements, for example, that are nowhere near the
same as those overseas and place a significant burden on manufacturers
who want to market those across international boundaries.

I\'m also saying that in cases where there are active ingredients that
are used in Europe, FDA needs to expedite the process to clear those
ingredients for use in the United States. That process has taken a long,
long time.

I think that\'s a response to the realities of the international
situation. I\'m not asking for a different class of products. That\'s
why I said that I don\'t think a change in the law is necessary. I think
the way that FDA operates within the laws and regulations that it has
need to more practically take into account the real world in terms of
international marketing and in terms of how consumers really use these
cosmetic drug products.

DR. GANLEY: To follow that up, I guess \-- and Dr. Leyden can probably
answer this also \-- is how should we allow a consumer to distinguish
between an anti-dandruff shampoo and a regular shampoo then, unless we
have some specific labeling that they can easily identify that there is
a difference here?

MR. DONEGAN: Well, we\'re not arguing that there shouldn\'t be drug
labeling on drug products. We\'ve never taken issue with the fact that
these products are drugs and that they should be appropriately labeled
for drugs.

What we\'re saying is that the same total comprehensive format should
not necessarily be required for these drugs, and we need to look on it
on a category by category basis and see if there are ways that we can
reduce the amount of labeling that\'s necessary for these.

I mean, we also just need to be very practical about the small package
issue in allowing people to market products in containers that will be
used as opposed to ones that are this big, that no one is going to carry
around with them. They\'re just not going to do it.

MODERATOR DeLAP: Dr. Kweder.

DR. KWEDER: I have a question for Dr. Leyden. Do you think that most
consumers have a general understanding of what is an appropriate
protectant level of sunscreen for them, say, in a cosmetic; and if so,
where do they get that information, from your perspective?

DR. LEYDEN; Well, I don\'t think anybody yet knows what the real answer
to that question is. Red-haired, blue-eyed individuals clearly are more
vulnerable than individuals who don\'t have blue eyes and red hair.
Those who have Celtic background are clearly more vulnerable, and there
are other factors in the case of melanoma.

So it\'s a very, very complex question. I think in the case of what
information people are getting from cosmetic products, it\'s mainly from
cosmetic companies and their representatives behind the counter and then
for those who deal through other ways, through brochures or other
information.

What they are being told is more is better. I don\'t think any of us are
against that. They\'re not being told use a 2. They\'re being told use
at least a 15, even if you\'re not going out, and if you\'re going to go
out, use higher. So I think what information they are getting is
something we can all be supportive of.

MODERATOR DeLAP: Okay. Well, thank you very much. I think, in the
interest of time, we need to move on. The next presentation is by
Francesco International, Steve Francesco, President and Founder.

MR. FRANCESCO: Good morning. First of all, I want to thank the FDA for
allowing me to speak at the forum. This is a historic forum and, as
you\'ll see, my company, which is a private company \-- we are not a
trade association or a lobbyist \-- has a great deal invested in the
subject of switch.

We do publishing. Many of you have seen our newsletter called SWITCH. I
believe the FDA has had a chance to review some of the issues that we
sent to them. We consult. We get involved in licensing and acquisition
of products involving switch areas, and we are involved in switch
process management.

SWITCH, the newsletter itself, is six years old, and it\'s quite unique
in that we cover the switch environment in the eight major markets
around the world. We cover the products, the processes, the problems,
and in many cases, the cultural issues.

We publish market impact studies. We have a product called the MAX
planning series, and we\'ll talk about one particular product in detail
called MAX the Molecule. We also, as I mentioned, do switch process
management. Next slide.

Our company is a niche company focusing on switch. We cover every aspect
of it in terms of molecules, public benefit, independent appraisals and
so on. We\'ve been influential in effecting switch policy in Canada, in
Israel, and in Mexico, and I might add that, if you can go to the next
slide, this company is a business, but it\'s also my hobby.

The principal mission is the responsible enhancement of self-medication,
and on a global basis we possess a huge amount of data on switching in a
number of markets. Our Website is RxtoOTCSwitch.com, as well as
Franint.com. Thank you.

The issue of switching is important to us, and I\'d like to expose you
to this chart here which you may or may not have seen. What this
represents is a global phenomenon in terms of the slow-down of switches
in the major markets.

Now there\'s a number of pieces of information embedded in this data. By
the way, the data focuses on molecule switches only. For example,
nicotine patches are grouped as one, as are H2s.

What you can see is that the pace of switching from \'98 and \'99 is
dramatically different than the previous years. You can see that, in
fact, in the U.S. and in the U.K., who are historically the leaders of
switch, the pace has slowed down considerably; whereas, quite
ironically, the switch champion for 1999 was France, a country which is
not really well known for its switching activity.

We like to look at this from a number of standpoints. One of the most
important things to remember is that embedded in these numbers are some
phenomenons for the switch industry. First of all, we have the vaginal
antifungals, which introduced a new concept called the initial medical
diagnosis.

We have a patch which five years ago nobody ever would have guessed a
patch would have been switchable. Of course, that patch is a nicotine
patch which, in fact, delivers a small dose of an addictive drug to
treat an addiction. Those ideas would not have been heard of five years
ago.

What you can also see in this market comparison is that most everyone,
not just the United States, is wrestling with the next step. What\'s the
next direction in terms of switching, if at all? Of course, many of them
are banging into the same problem of dealing with chronic therapy. Next
slide, please.

This is kind of, to be perfectly honest, a \"so what?\" slide, but I
thought I\'d give you some ideas of where some switches had taken place
outside the U.S. Penciclovir and Aciclovir for cold sores are available,
by and large, in Europe.

Allergy \-- and I know there\'s an awful lot of interest in the allergy
category at this meeting \-- In our market, coverage of about 22 markets
non-sedating antihistamines, at least one, is OTC in about 18 markets.
Multiple markets also have mild steroids.

You also have cultural factors in terms of switching. As some of you may
know, the morning-after pill has been switched in France. The
morning-after pill is in the process of switching in the U.K., and we
estimate that by 2002-2003 it will be throughout the European community
as an OTC. Next slide.

The switches in Europe are often referred to as, well, it can be
different because they have a third class of drugs. The third class of
drugs, as was mentioned earlier, is on the decline. At this moment, the
Netherlands, which is a unique country, in and of itself, is in the
process of ending pharmacy-only OTCs.

In the U.K. you might say that the third class of drugs is going through
a gradual meltdown. First of all, they are moving more and more drugs to
general sales list, which is the equivalent of being OTC in our markets.
Resale price maintenance, which was an artificial mechanism to maintain
profit, to establish guaranteed profits for local pharmacies, is under
attack and highly likely to go.

In most markets in Europe the third class of drugs is on the decline for
one major reason. The advice that you get from the pharmacist is
declining every day, because of economic pressures. The pharmacist is
behind the counter, counting the tablets, and so the concept of a third
class, which was originally quite noble in the Seventies and effective,
today is subsiding because of cost pressures.

So the point here is that, as we see the third class of drugs declining
in the European Community, as you do in Australia, what you are also
seeing is they are dealing with switch. So I want to make it clear that
some of the drugs we showed you earlier in terms of the antivirals, in
terms of the morning-after pill, are being reviewed in the context of a
declining role for the third class of drugs.

Now this is \-- My presentation, as you can see, is a little bit
different from the previous trade association presentations in that I
have a point of view which reflects our work on switch. Our personal
belief is that a number of issues here in the United States can be
adjusted through a market mechanism. By this, I refer to the dual status
of drugs.

My definition is a simultaneous Rx and OTC existence with the same brand
name and with a three to six-year patent protection OTC. As you know,
today most drugs in the United States are switched a year, two, maybe
three years before patent expiration. We call that a life cycle
extension exercise.

What we prefer to use as a strategy with our clients is not viewing it
as a life cycle exercise or viewing that as a dual status product. The
simultaneous Rx and OTC existence is most commonly seen as high dose/lot
dose. Sometimes in the case of allergy, it can be done via perennial
versus acute.

There\'s abundant international experience in this area to support dual
status in the U.K., in France, in Germany. It\'s very well known there.
Again, it must be perceived in the absence of a powerful third class of
drugs.

In the United States we have two very clear examples I\'d like to point
out. Imodium back in \'86 and \'92 was switched well before patent
expiration. You can see on the chart, at the last year \-- this is where
the prescription patent expired. Yet the franchise continued to grow and
meet consumer needs.

Another example is with Pepcid. Pepcid again switched well before patent
expired, the concept being developed of franchise on the prescription
side as well as in the OTC side. The way the growth of the curve shows,
there is business on both sides and not a great deal of suffering from a
sales standpoint; but as you can see, the consumer franchise opened up
opportunities.

In our view, dual status solves many, many problems. First of all, with
dual status reimbursement can remain. In the case recently of the H2
switching, at no point were the higher dose H2s de-reimbursed because a
lower dose was available OTC.

We believe that managed care will look at dual status and will find a
great deal of heat if they de-reimburse the prescription dosage because
of an OTC alternative. Yet with a lower dose available, those who don\'t
want to see an M.D., who don\'t want to go through the traditional
system, can buy.

If you have a problem with that idea, we need to quantify that. There\'s
a growing number of people in managed care who do not see the doctor,
and this is regardless whether it\'s allergy or osteoporosis. The
message of managed care is you\'d better take care of yourself. You\'d
better take care of yourself, because we won\'t and/or you better take
care of yourself because it\'s your responsibility.

The option to have reasonable drugs which allow consumers to take care
of themselves is very important, and we need to increase the pool for
that.

At the same time, as you\'ve seen from the previous charts, dual status
expands the market for the pharmaceutical industry, who are the owners
of the drugs, the developers, and the most knowledgeable.

Finally, again looking at stakeholders in context, managed care has
options. Depending on the diagnosis, depending on the drug alternative,
they can reimburse. At the same time, managed care is quite capable of
developing an OTC reimbursement budget, a budget of \$300-\$500. If you
want to buy your omeprazole, go right ahead.

From a pharmaceutical company\'s standpoint \-- and this, I point out,
comes from our modeling with MAX the Molecule \-- time and time again,
we find out that if addressed early enough and addressed objectively
enough, the numbers for the companies are pretty much better if you
pursue dual status as compared to a pure switch, which means a single
dose, as compared to staying Rx and ultimately dying what we call a
generic death.

What this hinges on is having two product forms. The debate today in the
non-sedating antihistamines often involves Claritin. It has one product
form. Therefore, it can\'t pursue dual status. We consider it a
structural flaw in the system.

If you go to the next chart, and we have a lot of information on this in
the newsletter and in other sources, we\'ve identified ten targets. We
believe it\'s important to provide a focus to this discussion. We\'ve
gone through our work, and we\'ve identified ten targets which we
believe should be considered as targets for dual status.

They include incontinence, asthma, hypercholesterolemia, hypertension
\-- that should say osteoarthritis, migraine, BPH, viral infections and
emergency contraception.

For perspective \-- and this is, obviously, one of the issues. For
perspective, many of the drugs out today in the nutritional area are
addressing these sectors, and yet, as we know \-- Let me put it this
way. As I believe, switch drugs are better researched, have an Rx
heritage, and in almost all circumstances, we believe, have a better
safety margin. Next.

In summary, I\'d like to expose you to this chart here. With our
clients, we get a little bit academic and explain to them the history of
OTC drugs. It\'s our point of view that we are now in the fourth stage
of evolution of Rx to OTC drugs, and it\'s a stage which requires use of
creativity at the time when you\'re dealing with more complex problems.

There is a great deal of a fear of change by many of the stakeholders.
I\'ve seen this week that even our journalists are being cynical and
skeptical about this process before it\'s even started.

What I\'d like to do is encourage this process to continue in an
environment where looking at the treatment of chronic therapy will be
viewed positively, and the people involved writing it and the people who
have the stakes in it give the process the benefit of the doubt.

A final recommendation is the following: We believe dual status as a
concept should have more structure around it. We believe it can solve a
number of problems without rocking the system too much.

For example, there\'s a need to review the international switch scene in
a number of areas and get up to speed as to what\'s being done out
there. There\'s innovative work on chronicity being looked at in
Germany, in Sweden and in the U.K.

We believe there are a number of significant questions for which we do
not have answers, and yet we don\'t really have a mechanism today to get
those answers. So as far as we are concerned, those ten categories that
I listed earlier, specific questions should be created and, on point C,
incentives should be provided to the pharmaceutical companies to answer
those questions.

Those questions will increase the body of knowledge significantly in
dealing with chronicity in this country. The incentives to the
pharmaceutical companies are designed to have those people who know the
drug, who know how to do the research, and who are incentivized to
answer the question.

We believe the questions should be identified and agreed to by the FDA,
and the answer has to be agreed to that it was answered. It\'s a
variation, in a sense, on Waxman-Hatch.

Finally \-- By the way, I know incentives to the pharmaceutical industry
are politically incorrect, but I happen to believe in them.

Finally, a number of ideas were expressed in the July summit of last
year and in other meetings. I believe the concept of opening up test
markets to deal with chronicity issues for OTC are vital, and I would
strongly encourage that they go in that direction. Last chart.

We are \-- In a sense, our company wears our heart on our sleeve. We
care about switch. We believe in it. We believe it has the possibilities
of significantly enhancing public health in this country. We have
products to do it, and we\'d like to see this forum advance positively.
And if everyone has in their heart the interest in improving public
health, I\'m confident that the outcome will be very positive. Thank
you.

MODERATOR DeLAP: Questions? Dr. Jenkins?

DR. JENKINS: Could you expand on what you meant when you said that the
Claritin situation was a flaw in the system?

MR. FRANCESCO: I should tell you a couple of things. First of all, I
switched Claritin in many markets. I ran the OTC Division
internationally for Schering-Plough for five and a half years. In my
view, with our recommendation \-- we\'re talking here about allergy.

What I\'d like to include as categories where there\'s incentives to
pursue dual status would be osteoporosis, hypertension and so on. In my
view, going back five, six, seven years when Claritin was going through
the review process, I believe incentives should have been provided to
get Schering-Plough to look for high dose/low dose. That would have made
a difference.

Today, if there were a high dose/low dose available with Claritin going
off patent, you can bet the low dose would be pursuing the consumer
franchise right now. And there\'s numerous precedents for that.

By the way, one other point on the dual status. The assumption there is
that the FDA does not force the switch. The assumption is that the
capitalist system, the system we have today, provides incentives for the
companies to pursue dual status and to pursue and answer questions which
will allow the product to get into the consumer segment.

MODERATOR DeLAP: Dr. Temple?

DR. TEMPLE: Well, as you pointed out, a number of, shall we call them,
devices have been used to maintain both Rx and OTC status, one of which
is dose, but another of which is specific indications. So it doesn\'t
seem out of the question to device one of those for some of the
non-sedating antihistamines.

MR. FRANCESCO: Claritin in the U.K. switched. The Rx indication was
perennial, and the OTC was acute.

DR. TEMPLE: That might seem a little silly, but it\'s possible.

MR. FRANCESCO: No, no, no. I totally agree. I totally agree.

MR. CAMPBELL: Could you elaborate a little further on the concept of
test market?

MR. FRANCESCO: One of the problems we\'re dealing with, with chronic
therapy is that you may have plenty of evidence when you do clinical
research to get the product into the prescription market. At that point
you have the learned intermediary involved. You don\'t have the
physician involved in the OTC side in a particular format. There are
other formats like initial medical diagnosis, you could. But in the
purest sense, you don\'t.

There are numerous companies in the United States that are experts at
identifying markets to test their products. They are as banal as
Pampers, and I spent a lot of my years working on Pampers. They are as
banal as underarm deodorants.

If we could identify a population that we feel safe should get exposed
to products under certain conditions \-- and I\'m specifically referring
to chronic drugs here; let\'s call it a third class of consumer. So
there will be a third class of drugs. Let\'s call it a third class of
consumer.

This is a group in Atlanta, Seattle, whatever, who have through proper
screening been exposed to \-- they\'ve been found to be okay to take
this drug. They\'re going to get certain types of labeling, certain
types of packaging, and it\'s going to be fairly strictly controlled.
Let\'s see how they respond to the drug.

Linked to that could be some of the bigger issues of monitoring and
compliance with OTC drugs. Let\'s create population samples. That\'s the
concept. I am by no means an expert on this today, but I think the idea
has a great deal of merit, and I think it will help address many of the
problems you\'re going to deal with in dealing with chronic therapy.

DR. GANLEY: Could you just expand a little bit on the answer you gave
regarding the FDA taking the initiative to bring products Rx to OTC
without the company really agreeing to it. It seems that, if it\'s in
the public interest and best for public health, that that should be
paramount rather than just based purely on economics.

MR. FRANCESCO: What is well established in markets outside the U.S. is
that the Board of Health has the ability to force a switch, and it\'s
based upon two reasons. One, it\'s written in their charter but, number
two, they are the insurance companies.

So that last year Sweden for the first time really, and I think perhaps
in history, forced a switch of omeprazole. It\'s a pharmacea product. It
was a Swedish product. Surprised us all. There are other areas where
drugs are being switched which are a little bit less controversial, vein
tonics in France.

So that governments outside the U.S. do have the power, clearly have the
power, but it\'s based upon the fact that it\'s cost driven. They are
trying to reduce reimbursement, since they are the insurance companies.

Here in the United States the system is a private insurance system. I
have a hard time seeing the initiative driven here on the basis of cost,
since you\'re not the insurance system. Therefore, it has to be driven
by something else.

My personal belief is in the capitalist system that we have today, if
you provide financial incentives to the pharmaceutical companies, they
will move. So in my perspective, rather than creating a whole series of
legislative proposals, ties up in court and so on and so forth, provide
a simple incentive.

For example, \$300 million goes into research before a product gets into
approval, generally speaking. The questions we deal with on switching
are much more banal, for the most part, by comparison, much simpler. A
cost could be \$15 million on top of the 30. So it becomes 315, but that
\$15 million gives you important information on what would happen if
that drug went into the consumer market, and particularly addressing
issues like monitoring and compliance, which are very big issues.

I think that they are prepared to do the research. My preference, if you
give them the tax incentive the first year of the prescription launch
\-- give it to them early. You saw my charts on net present value.
Pharmaceutical companies will say we\'ll get that break now. You run
that out. It\'s a lot of money.

I think that\'s going to be a better mechanism for getting switches done
properly and researched, rather than having a mandate from the
government. I do understand the frustration you feel of having certain
drugs you think should be switched. I prefer a market mechanism.

Not only do I prefer a market mechanism because of the system we have
today. I think the market mechanism will do a better job of getting
switches going, and it will increase the number dramatically.

If you take those ten categories I listed and you say there\'s four
products that are candidates, you now have 40 candidates for switch that
are going to be researched, and our body of knowledge in this area will
grow dramatically.

DR. WOODCOCK: And you\'re saying that the market mechanism would be to
formalize some type of dual system?

MR. FRANCESCO: I\'m not a lawyer, and this gets very tricky. The basic
concept is there\'s an agreement with the FDA that we want to know that
this drug being used by the consumer without doctor intervention is
working. They are complying with it, and it\'s having an effect.

There are ways of structuring that test market, if you will. If the
answer is, guess what, this works, then there\'s a reward. The point is
the research should be done early, because that feeds dual status, and
that allows the trigger down the road.

DR. WOODCOCK: What is the reward?

MR. FRANCESCO: The reward for the pharmaceutical company is a tax break.
It\'s a tax incentive. They spend \$15 million on research. They get a
\$30 million tax break the first year, but that product is ready.

I know this is politically incorrect, but that product is ready to be
switched much earlier, and companies have dealt with problems much
earlier, and it may reach the market five to six years earlier than just
before patent expiration.

MODERATOR DeLAP: Dr. Temple?

DR. TEMPLE: Could you talk a little bit, especially in relation to the
potential chronic uses, about something that\'s come up already today
and comes up all the time. That is the possibility that you encourage
people to use one out of a series of alternatives.

Just as an example, suppose low dose diuretics became available for the
treatment of hypertension. Low dose diuretics might not be the first
thing you should use. Maybe you should use an ACE inhibitor.

We, being doctors, tend to think of those as sophisticated decisions
that require our input. What\'s your view about questions like that?

MR. FRANCESCO: My view is I agree with you that there\'s a lot of
questions. The answer here is are we getting the answers that we need,
and are we getting them soon enough?

I hate to refer to this publication again, but we\'ve listed here about
25 questions where I believe we don\'t have decent answers. So your
question is very valid. We need a mechanism to get those answers, and
that\'s what I\'m talking about.

MODERATOR DeLAP: One more question from Dave Fox.

DR. FOX: Just curious about what your view is of three-year exclusivity
under Waxman-Hatch as an incentive for a sponsor to move
over-the-counter. Is that enough? Too little?

MR. FRANCESCO: I\'m not sure I heard the whole question. I\'m sorry.
Exclusivity in Waxman-Hatch?

DR. FOX: Yes. The potential to gain three years of market exclusivity on
the over-the-counter market if one does clinical studies that are
necessary to the switch as an incentive to encourage sponsors to pursue
a switch. What\'s your view of that? That\'s an incentive that already
exists in the statute, conveniently.

MR. FRANCESCO: The incentive to gain additional patent protection just
prior to patent expiration is a terrific incentive to a pharmaceutical
company to defend against generics. There\'s nothing inherently wrong
with that.

My question is: Is that going to affect the issues of chronicity? Is
that going to give you the information you need in dealing with
osteoporosis? Those kinds of problems have a much longer time frame to
solve. They cost a lot more money.

So that my feeling on the dual status proposal is that it should not at
all be linked with Waxman-Hatch. I think it should be a separate issue.
The other reason I don\'t think it should be linked with Waxman-Hatch is
Waxman-Hatch has a lot of other baggage to it. I would prefer to look at
this one as a clean, simple idea. Does that answer your question?

MODERATOR DeLAP: Thank you very much.

Rather than proceeding to the next presentation now, I think it would be
a good time to take a 15-minute break, but we will reconvene promptly at
10:45.

DR. TITUS: And we just want to announce that we have a second site. We
realize that the room is crowded, and you might want to go to our second
site, which is in Rockville. You can ask at the front desk for
direction.

(Whereupon, the foregoing matter went off the record at 10:31 a.m. and
went back on the record at 10:54 a.m.)

MODERATOR DeLAP: Okay. Again, if people can please be seated, we will
get underway.

We\'ll start up now with the presentation from the Consumers League, and
Linda Golodner and Brett Kay. I\'ll turn it over to Linda now. Thank
you.

MS. GOLODNER: Thank you very much. The National Consumers League is
pleased to present the consumer\'s viewpoint on over-the-counter drugs
and switch issues.

As everyone is aware, information, a lot of information, is available to
consumers through the media, through patient and consumer groups, at the
drugstore, from the doctor, and now through the Internet. It\'s not
neat. There\'s a lot of information. There\'s a heap of information
available, but consumers really need help in understanding that
information.

It doesn\'t help that we\'re now in a managed care system that often
does not encourage the communication of the health care professional
with the patient.

I know the FDA is very much aware of safety concerns, especially with
prescription drugs and over-the-counter drugs and dietary supplements
and foods interacting, and that there\'s not enough information for
consumers to make some choices when they are taking these products.

The FDA, I think, has been very strong in its position to make sure that
consumers do have information on a label, and is strong in their
position that information is in a large-sized type. Sometimes the only
information that a consumer has between the product, actually taking the
product and the \-- with the over-the-counter drugs is that information
on the label, and it must be in a size type. It must be available so
that they can read it.

It is particularly true with some of the over-the-counter drugs that are
considered now for switch. For instance, if a drug for osteoporosis or
for cardiovascular disease is over-the-counter, we want to make sure
that those people who would be taking it can read it.

We would also encourage that the FDA move closer to making sure that
information is available to consumers in languages other than English.

Who else is responsible for educating the consumer? Obviously, consumer
and patient groups do it, but the health care professionals are the ones
on the line who must be there to help consumers understand the drugs
that they are taking.

It is not only the responsibility of the health care professionals, but
those that manage the health care professionals in managed care
organizations, in drugstores, managers of food stores, managers of
discount stores that provide this product to make sure that there are
enough pharmacists there who can talk to consumers and can work in
reasonable hours so that they can actually have this communication with
consumers.

It\'s also important that there be greater communication between the
doctor and the patient.

The National Consumers League has done a couple of surveys in the last
month \-- and we will make the cross-tabs available to the FDA as part
of the record \-- that we want to share with you today.

Some of the things that we were concerned about are the great deal of
information that\'s available to consumers, how are they using it, are
consumers using OTCs appropriately; what OTCs do consumers want, and
what about statins and cardiovascular disease; and what\'s the consumer
responsibility, and where do consumers actually get their information
now when they do use an over-the-counter drug.

In the first survey, we commissioned Yankelovich Partners. They did a
random sample survey that\'s a plus or minus three margin of error.
These respondents were at least 18 years old, and these interviews were
done between May 15 and May 31 this year.

We asked, compared to five years ago, are you making decisions on your
own, and 58 percent of consumers said that, yes, that they are making
more decisions on their own. However, when we asked seniors, 52 percent
of them \-- that\'s about half seniors \-- are making more health
decisions on their own.

We asked consumers the first thing they do when facing a minor ailment,
and we listed some minor ailments like headaches or stomach aches. Half
of the people rely on their own self to make that decision. Twenty-two
percent said doctors and themselves. Ten percent rely only on the
doctor, and seven percent rely on a pharmacist and themselves. Some just
rely on the pharmacist.

We asked them, when you treat yourself, what is the preferred treatment?
Fifty-seven percent said an OTC. Some like to cure themselves naturally.
They want that headache to go away, and they just wait, and it actually
does go away. Sixteen percent, though, are using dietary supplements.

We asked them what resources they use to decide which OTC to take, and
we got \-- these were multiple answers. 66 percent depend on the label.
Others talk to their doctor, friends and relatives, the pharmacist.
Fifty-two percent also asked their pharmacist, and so on. Ten percent do
actually go to the Internet for some information, but I don\'t think
they \-- in some other questions we asked, they don\'t rely on it 100
percent.

We asked how often do you generally read the labels on OTCs. Always or
nearly every time, 66 percent. But if you combine the 66 percent and the
17 percent of \"most of the time,\" you end up with 83 percent always or
most of the time reading those labels. Of this, though, 75 percent of
seniors read the labels always or most of the time. We also found that
females are reading more labels than males.

We also asked how easy are the labels of OTCs to read and understand.
Very easy, 44 percent; somewhat easy, 31 percent. We found that a
combination of somewhat difficult and very difficult, 17 percent feel
that it is difficult to read. This is one in four people are having a
problem with reading the OTC label and understanding it, and this
increases with age.

We found that it\'s not only the 85-year-olds who are having trouble
reading those labels, but that 35 and above have more difficulty than
those that are younger.

We also asked how often do you read information inside the package.
Thirty-seven percent said always or nearly every time, and most of the
time, 21 percent. So there\'s a better information that consumers are
seeing inside the package, but they\'re not \-- Some of them read it.
However, when we asked \-- I don\'t have a slide on this \-- When we
asked about if they understood it, less people do understand that
information that\'s inside the package.

One interesting question we asked is how often, if ever, have you taken
more of an OTC med than was recommended on the label, such as taking
four pills when two pills are the recommended dose. Fourteen percent
said always or most of the time, that they do take more than is
recommended \-- the recommended dose. However, half of the people say
that they never do this.

We also asked if they had taken OTCs longer than recommended. As you
know, on several labels it says don\'t take for more than three days or
seven days. Nine percent of the people said always or most of the time
that they do take it longer than is recommended. However, 63 percent
said that they never do this.

We also asked how satisfied you are with the range of medications that
are over-the-counter. Twelve percent said they are extremely satisfied;
39 percent, very satisfied.

We asked whether OTCs are safer than prescription meds, and 25 percent
said that they think they are safer. The younger people, 18-34, 29
percent said that these are safer than prescription drugs.

WE also asked if you had to pay attention to the OTC labels \-- if you
don\'t have to pay attention to labels, and 89 percent agreed \--
disagreed with that. Ten percent felt that you don\'t have to pay
attention to them.

We also asked whether there are problems with OTCs interacting with
prescription medications, and 16 percent said, yes, there are no
problems with this. Seventy-eight percent, though, disagreed with this.

We also asked if you wished some of your prescription meds were OTC, and
65 percent said yes. Seventy-two percent of those were in the
over-\$75,000 a year category as annual income; 69 percent were of
younger age, 18-34.

We also asked what meds they would like over-the-counter, and we don\'t
have that information back, but I just did look at \-- I looked at the
raw material, and they are looking at non-sedating allergy drugs and
hypertension drugs as those that they would like to see
over-the-counter.

Now my colleague, Brett Kay, is going to make a presentation on a second
survey that we did.

MR. KAY: Thank you. We have data from this, and also we wanted to look
at some of the data previously that we\'ve done over the past couple of
years, which is leading up to why we\'re here today. Consumers are
concerned about OTCs. They are concerned about their health care.

Over several years now we\'ve had two different surveys over the past
two years that have said that consumers \-- 86 percent of consumers feel
that having an increased role in their own health care is positive.

Then when we focused more specifically on cardiovascular disease, which
is still the leading cause of death and disability in the United States,
the numbers are even stronger. Eighty-eight percent said they would like
to know as much as possible about lowering their risk of coronary heart
disease.

Sixty-four percent of Americans are confused about how to live a healthy
lifestyle, and are confused and overwhelmed by all the information out
there on how to lower their risk, what to do about diet and exercise.
They know there is something they should do, but they are not exactly
sure what to do because of some of the overload of information. I don\'t
think this comes as a great surprise to anyone.

Fifty-two percent did not know their cholesterol level, and that\'s over
the past couple of years, and that\'s consistent with data which I\'ll
show you also right now from the survey that we got \-- that we just
back the results the other day. Eighty-five percent cited their doctor
as the most reliable source of information about lowering their risk for
coronary heart disease.

Because of this continued confusion about coronary heart disease and
cholesterol, and because of the fact that it shows that consumers are
taking a much more active role in their decision making, we feel that it
is important to understand the consumer attitudes toward possible OTC,
specifically the cholesterol lowering medications. We wanted to see also
how a new OTC product really would be perceived and how consumers say
they would use such a product.

Let me get to some of the data on this. This survey was commissioned by
Opinion Research Corporation International. It was a random-digit dial
sample of 1,000, plus or minus 3.1 margin of error. The interviews were
conducted June 7-18.

The two screeners that we had originally were \-- they are 35 and older,
and we asked the question are you somewhat or very concerned about your
cholesterol level. Also, Lou Morris from SPC Communications helped to
design the survey and analysis for us with this.

The survey topics: Again, there\'s a sample description. We talked about
disease prevention, what activities people are doing, what information
they are getting, what they want, and then finally attitudes about
treatment in general and then specifically about cholesterol treatment,
and even more specifically about an OTC cholesterol treatment, whether
it\'s a good idea or a bad idea, and how they would use it.

Some of the sample demographics, as you see. Of the two columns, notice
the first column is the total, and this will be consistent for all the
slides you\'ll see, is the total weighted data. Then the second two
columns are one of the questions we asked was \-- and we use it as one
of the banners \-- is would you be personally interested in a low dose
over-the-counter cholesterol medication if it were made available? Would
you be interested or not interested?

So the first number you see there would be the interest in it, and
second would be not interested. Where you see an asterisk, there\'s a
statistically significant difference at the 95 percent confidence
interval. We have further data. I\'d be happy to talk about that later,
if you want.

When we pulled out for female, 56 percent of the total was female, the
majority 55+. It was 41 percent. Fifty-nine percent of our demographic
population had some or more college education, and an income of \$35,000
or more.

Some of the psychographic data \-- and this is consistent with previous
surveys that we have done and data that we have found: About 49 percent,
about half the population knows their cholesterol levels. Forty-one
percent believe their cholesterol level is high, and another third
believe that they are at risk because of their cholesterol levels.

Encouragingly, 81 percent have visited their doctor within the last
year. In our sample population, 91 percent had health insurance, and 89
percent had Rx drug coverage.

Some of the disease prevention activities: We asked what are people
doing to prevent disease, and again these are consistent with other
findings that we\'ve had throughout the past few years: 73 percent are
exercising; 67 percent are visiting the doctor.

People are taking an increasing amount of vitamins. They are also taking
prescription drugs, aspirin to prevent a heart attack. They are taking
OTC drugs. Then we asked about garlic, fish oil and other such
supplements that relate to heart disease or cholesterol lowering. Again,
nearly a third of the people are taking such a product.

Then we asked the question for disease prevention information: Where did
you get your information, and what do you look for? Sixty-nine percent
are looking at nutrition labels. They are starting to read the fat
content and things on the nutrition facts panels. They are talking to
their doctors. They are reading drug labels, and then about less than
half are getting it from magazine articles, newspapers.

On this recent survey, you\'ll notice 23 percent are looking to the
Internet. So that trend, I think, is starting to grow and probably will
continue to do so as it becomes a more mainstream media content channel.

Now we had some general attitudes regarding treatments in general,
especially for heart disease. What are some of the things that you do to
prevent or to get treatment, and how do you feel about it? Eighty-five
percent still feel that the doctor knows best.

People are concerned. Sixty-one percent are concerned that Rx drugs
cause too many side effects. They don\'t like \-- 60 percent don\'t like
to take them. Forty percent feel more comfortable taking an OTC drug
than an Rx drug. Again, 28 percent \-- as you saw previously it was 25
percent \-- feel OTCs are safer than an Rx, and 21 percent think that
it\'s more effective.

Now we asked specifically about cholesterol treatment attitudes, and
this is a combination of strongly and somewhat agree to questions.
Reducing cholesterol will add years to my life: 94 percent, as you can
see, think that this is a good thing. So at least the cholesterol
message is getting out there, and consumers are aware of it.

Then the second question also, that high cholesterol is a serious threat
to your health, also shows that this message is continuing to get out
there.

Some of the ones I thought are interesting: 75 percent, three-fourths of
the population, will seek advice of their doctor on a regular basis
about this. Then another 69 percent feel that their doctor gives them
advice, but they make their own decision, which is continuing to show
the trend of people taking more control over their own health care.

Fifty-one percent, again consistent, find information about cholesterol
confusing, which is consistent with our other findings from last year
and the year before.

We asked the question straight up, if a low-dose prescription \--
nonprescription cholesterol treatment were made available, would that be
a good idea or a bad idea? Overwhelmingly, by a two to one margin,
consumers said it was a good idea, and statistically, you can see in the
second column, 82 percent would be interested in such a product compared
to 41 percent not interested who said that. Obviously, in the bad idea
category, the numbers are reversed, which is at least consistent.

Then we sort of broke down why it would be a good idea and why it would
be a bad idea. Expense was cited as the number one reason; that it would
be more readily available. Under that we combined a lot of the
categories from the raw data into these, under readily available such as
they don\'t have to see a doctor, it\'s easier, it\'s less time
consuming, along those lines. They feel that it would help lower the
cholesterol.

For the bad idea, people feel that it\'s really important, 44 percent,
that they need to consult their doctor before something like this, and
also people are concerned that they wouldn\'t know how to take it
properly.

Now this goes to some of the attitudes and actual use, and I think this
is some of the important data around what would people actually do if
this were made available. I know there are a lot of concerns of would
people continue to see their doctor, would people continue to have
follow-ups and check-ups.

Ninety-one percent, an overwhelming majority, said that they would still
talk to their doctor if this drug were available and they were using it.
Again, 83 percent would talk to their pharmacist, which is good.

Fifteen percent wouldn\'t have to watch what they eat, and 11 percent
said they would see their doctor. So you\'re talking about really a very
few people would really neglect the doctor\'s health advice, which I
think is encouraging to see.

Again now, if directed on a label to see the doctor prior to use on the
package label, what would people do? Eighty-seven percent said they
would only use it if the doctor said it\'s okay, and 86 percent would
consult it before the doctor.

So again, people have a strong desire to continue the doctor-patient
relationship and follow up with the labeling.

I\'m just going to go through this next one quickly to the confidence
question. Confident I can use it correctly was the question we asked. Do
you feel that you could use this properly? Seventy-six percent, if you
combine somewhat and very confident, three-fourths again of the
population feel confident that they could use this correctly.

So our conclusions: People are already taking some actions. They are
concerned, as you saw \-- Unfortunately, I breezed through it quickly
\-- people are taking supplements and garlic and these other products
already. They are concerned about it. They are trying to exercise. They
are watching their diet.

Consumers have \-- There\'s a solid belief in consultation and
visitation to the doctor. They think it\'s overwhelmingly a good idea if
this medicine were made available, and from that consumers will still
talk to their doctors. They will consult with pharmacists, and few
people will avoid cholesterol checks and doctor visits.

Finally, our recommendations: If such a product were made available, our
recommendations \-- Let me stress this. We are not advocating a position
on a low-dose OTC cholesterol medication, but we are recommending that,
if a product does switch into a nonprescription status, that there be
clear label directions about warning, that it be easy to read and
understand, that there be a large-size type so people can follow it,
that package inserts and other materials should be easy to understand
and read, that they should see their doctor before taking this product,
and that it should state that clearly on the label, as well as it should
state clearly on the label that it\'s important for regular doctor
visits, continued check-ups.

Finally, it\'s important to know your cholesterol test, to have a
cholesterol test regularly, and important to know the numbers. Know the
warnings, precautions, side effects, who should take this medicine, who
should not, is it appropriate for you, and there should be an emphasis
on interactions, food-to-drug, drug-to-drug, and dietary
supplement-to-drug, as that\'s an increasing market.

Finally, we feel that there should be an ongoing consumer education
campaign that the FDA and manufacturers and consumers and everyone
should support since coronary heart disease and cholesterol are still
major causes of death and disability in the United States. Thank you.

MODERATOR DeLAP: Russell, you have a question?

MR. CAMPBELL: I have a question for Linda Golodner. We were told earlier
by James Leyden that consumers aren\'t especially interested in some of
the stuff on the small packages. Can you comment on that?

MS. GOLODNER: I\'m sorry?

MR. CAMPBELL: Like cosmetics \-- like sunscreen in cosmetics, small
packages.

MR. KAY: Are you talking about the ingredients?

MR. CAMPBELL: Yes, the labeling.

MR. KAY: About labeling? I think that this shows that consumers are
interested. It may be that they don\'t want to read every single
ingredient on the back of a suntan product, for instance, but I think
that they are concerned when it comes to questions of safety, of
precautions, side effects, clear labeling directions.

I think that the data we\'ve had over the past couple of years has
stated clearly that consumers want that information and, in our opinion,
need that information.

MR. CAMPBELL: And what about print size for small packages?

MS. GOLODNER: Print size \-- I don\'t think there should be any
exception for print size. I think manufacturers can be innovative in
packaging so that the print size can be large enough to read.

This is your only measure of safety. If that\'s the only thing that
you\'ve got is the label, you\'ve got to be able to read it. I also
wanted to point out that I think that consumers are more and more
looking at labels probably because of the food labels that are available
now that provide health information to consumers.

If that information is clear and available on over-the-counter drugs,
dietary supplements and other products, consumers will read it.

MR. CAMPBELL: Thank you.

DR. WOODCOCK: Bob, I have a question here. I\'d like to know, to what
extent do you think that self-reporting is accurate in your surveys
about reading the labels?

MS. GOLODNER: It\'s hard to tell. I think probably in doing some mall
intercept or, you know, personal interviews and trying to find out if a
consumer comprehends what\'s on the label would be a better survey
method.

Obviously, some people will say they\'re reading the labels when they
are not, and knowing data about those people who can\'t read or have
difficulty reading, we don\'t know how much they are able to comprehend
on the label.

DR. WOODCOCK: Thanks.

MODERATOR DeLAP: In the instance where there are multiple products
available for a similar indication, do you have information that would
speak to consumers\' confidence in their ability to select among the
different competing products?

MR. KAY: We didn\'t ask that specific question. Basically, it was a
general, if such a product were available. So we don\'t have data that
would answer that question directly.

I think that some of the issues about labeling, if it were clear, if it
were easy to read, would help some of that. If consumers can look at two
things and compare them evenly and equally, I think it will make it a
lot easier for consumers to make those choices appropriately.

MODERATOR DeLAP: Dr. Kweder.

DR. KWEDER: I had a question, and you might have said this. I\'m sorry
if I missed it. In your surveys was there a \-- did you identify people
and screen them out if they \-- Did you ask them if they could read,
what their reading level was, and also whether English was their first
language? Was it only English \-- primarily English speakers who
answered the survey?

MS. GOLODNER: It would be English speakers who answered the survey, and
we did not ask them skill or reading level.

MR. KAY: More than half the survey population, at least in the one I was
discussing, has some or more college education. So that would assume
there is. I can get you \-- I have the cross-tabs. I can give you, you
know, below high school or whatever, but we didn\'t ask could they read.

MODERATOR DeLAP: Well, if there are no further questions, we\'ll need to
keep moving. Thank you very much.

The next speaker on the agenda is Kaiser Permanente, Anthony Barrueta,
counsel, Government Relations.s

MR. BARRUETA: Good morning. My name is Tony Barrueta. I\'m counsel in
the Government Relations Department at Kaiser Permanente.

The reason that we felt it was important to register our interest in
this subject today is primarily because of the unique nature of our
organization. We\'re the largest nonprofit HMO in the country.

We serve approximately 8.6 million members internally through our own
organization. There are 10,000 Permanente physicians who treat those
patients. As a pharmacy provider, we have hundreds of pharmacies in our
own facilities. In terms of prescription drugs, we purchase about \$1.6
billion a year in prescription drugs. More than 90 percent of our
members have a prescription drug benefit.

This issue is particularly interesting to us in an environment when the
prescription drug benefit is increasing in cost at a range of \-- for
Kaiser Permanente it\'s 17-18 percent a year. For many other third party
payers and those who subsidize prescription drug benefits, they are
seeing increases in prescription drug costs in the range of 25 and 30
percent a year.

In fact, we see a number of public programs that are experiencing
increases in that range, and this is a very troubling phenomenon, I
think, because it starts to raise questions about the extent to which
what have become very broad prescription drug benefits will continue to
be affordable.

The physicians within our organization, when they look out at the
pharmacopoeia that is available for treating their patients, they see
certain market anomalies that exist, and they have to question whether
consumers are really getting good value for money in terms of the money
that\'s being put forward either in terms of the premiums that they pay
us to provide a prescription drug benefit or paying out of pocket for
particular drugs.

You\'ve got my full statement. So in the interest of time, what I\'d
like to do is sort of give you our conclusions, the main concerns that
we have, and see if you have any questions.

When it comes to considering prescription to over-the-counter switches
for currently prescribed drugs, we really believe that the fundamental
concerns need to be prioritized in the interests of patients and
consumers, not necessarily in the interests of the product sponsors.

I think that the discussion so far today has really flushed this out as
an important question that needs to addressed by policy makers, not
necessarily FDA alone but policy makers in general.

The first concern really has to be clinical safety. Our sense is that
the current standards that FDA applies in looking at clinical safety
seem to be pretty good. They seem to be pretty well focused on making
sure that patients are not going to be harmed because a drug becomes
available over-the-counter.

Second, the FDA really ought to be considering whether maximizing access
to drugs through OTC status will be a substantial improvement in public
health, both in terms of their ability to get access to the therapies in
a timely fashion, in a continuous fashion, but also that the quality of
care isn\'t impaired.

To the extent that certain therapies are considered to be moved
over-the-counter, the specific questions in specific cases really need
to be asked about whether there is something about prescription drugs
that brings people to their physician providers and whether we are going
to be losing something in particular areas.

I think there\'s going to be different answers to those questions in all
cases, but it is a question that really needs to be asked on an
indication by indication and possibly on a drug by drug basis.

Third, the economic interests of consumers and patients, both
individually as patients and collectively as consumers who ultimately
foot the bill for health care financing, whether as premium payers, as
taxpayers to the state and Federal government, as workers who receive
health insurance in exchange for lower wages, are really able to have
this process work in their interest, to the extent that there doesn\'t
appear to us to be in Federal law any specific property interest of the
product sponsors in the question of whether or not a drug is prescribed
versus over-the-counter.

We would really caution the FDA in designing a new process which may
very well be in order for considering how to decide whether a drug
should be OTC or Rx. Great caution should be made in designing that
process to assure that it doesn\'t create a property interest that
doesn\'t currently exist.

In terms of a little bit of specific information on a couple of specific
therapies, I will say that it is the situation of the non-sedating
antihistamines or the less sedating antihistamines that has been driving
a tremendous amount of provider interest within our organization.

Within Kaiser Permanente, less sedating antihistamines represent the
third largest class of drug expenditures; and when you have a situation
where it seems to be relatively accepted that allergic rhinitis,
allergies, are the type of drug that really naturally could be
considered to be over-the-counter.

There are older drugs that are available over-the-counter at this point.
The key question, it seems, really ought to be the relative safety, the
relative efficacy of the current Rx drugs as opposed to what\'s already
over-the-counter.

Certainly, the absolute safeties need to be questioned, but we have had
situations where the product sponsors of the current Rx drugs are
effectively promoting those drugs as having safety advantages because of
the side effect profiles of some of the OTC drugs. So it really ought to
be focused on the relative safety and efficacy.

We did survey physicians within our organization, and our drug
information staff in Oakland and Downey, California, did review patient
profiles. They went through the computer systems to try to identify
patients who were taking less sedating antihistamines exclusively. They
were treatment naive to any other therapy, and we came up with something
along the order of 6,000 patients.

Within that patient population, there were approximately 12 cases that
were identified where it was possible that there could be \-- It didn\'t
certainly mean that there was an adverse drug reaction, but there was
information that made it a possibility.

That strikes us as being a fairly low incidence of adverse drug
reactions. Informal surveys of our chiefs of allergy around northern
California indicated that there was a high level of comfort about these
drugs.

What I think this type of information really suggests is that FDA ought
to be looking to the physicians in the community to get a sense of
whether there are therapies that are available that ought to be moved
over-the-counter.

Now one question that I think is appropriately raised by consumers when
an organization that is a third party payer and finances prescription
drugs \-- they want to know, are you just trying to do this so that you
don\'t have to pay for them anymore, which is an absolutely legitimate
question; because it goes to the consumer\'s economic interest in
whether or not a drug is prescribed or Rx.

To talk about this, it really requires talking a little bit about the
marketplace dynamics that are out there. One of the earlier slides we
saw showed that there was a decline in recent years in the number of
drugs being switched from prescription status to OTC status.

Well, during this same period there\'s been a massive expansion in
prescription drug coverage. So that in 1990 only about 25 percent of
people \-- 30 percent of people had some form of prescription drug
coverage. Today 75 percent of people have prescription drug coverage.

It seems quite obvious, if you\'re a product sponsor looking at a market
like that where the benefits basically cover prescription drugs but not
OTC drugs, that you\'re going to want to get the benefit of that
potential subsidy and continue for a longer period perhaps having that
drug be prescription status, moving it to over-the-counter status when
you\'re facing a looming generic coming onto the market and using your
brand in order to increase your profitability in the future.

There\'s nothing wrong with a manufacturer seeking to do that to pursue
their economic interests. Our concern is really that the economic
interests here have to be balanced. The consumer\'s interest needs to be
balanced, and not only the consumer\'s interest whether or not they are
going to be going from having a co-pay of five dollars to paying out of
pocket \$20 or \$25 for an OTC drug, if the benefit is lost.

The consumer interest is also the ultimate premiums that get paid in
terms of the prescription drugs and whether it makes sense for these
types of costs to be individualized by making people pay out of pocket
at the point of service or whether they should be part of a prepaid drug
benefit. Ultimately, those are questions that really ought to be worked
out between the consumers and the third party payers who are managing
their drug benefits.

As it exists today, the way the process seems to work, I don\'t think
because of legal mandate but simply we\'ve fallen into this approach,
that it\'s really the manufacturers who are the ones who are driving
this process. That\'s something that probably needs to be reexamined.

Happy to take any questions that you might have.

MODERATOR DeLAP: I think I heard a comment in your presentation that you
weren\'t advocating additional property rights for providers of drugs as
part of this process. But I would ask if you think that there is some
way that the incentives that are available could better stimulate the
kind of behavior that you think would be optimal for the consumer.

MR. BARRUETA: Well, I think in terms of providing financial incentives,
I really wonder whether there aren\'t already adequate financial
incentives for manufacturers to seek to maximize the profitability of
the products that they currently have.

I think the real challenge for FDA and for the public as a whole is to
find processes that are really consumer focused, to find ways for FDA to
tap into the information that is available in the community so that
there is another access to the types of safety information that really
needs to be looked at before something can be comfortably moved
over-the-counter.

I think, as FDA develops processes in this area, we certainly look
forward to working together with FDA so that our databases are
potentially made available. I know that other third party payers, other
pharmacy benefit managers keep track of this kind of information, and
it\'s the kind of information that exists today. It\'s not really being
used in a way that can help to support the efforts that FDA, I think,
ought to be pursuing.

DR. WOODCOCK: Does Kaiser know anything about the other costs of having
some product, say, be prescription versus OTC, because from a consumer
point of view or patient point of view, there are costs other than the
out-of-pocket expenses. There\'s perhaps time lost off of work, having
to go to the doctor\'s. For Kaiser you bear the cost of the doctor
visits and the processing. Have you ever looked at any of that?

MR. BARRUETA: We haven\'t looked at that systematically. There are a
number of studies that have been done for other purposes in terms of,
particularly, pharmaco-economics studies that are currently being done
to essentially support the pricing of existing Rx drugs which are trying
to identify those types of costs.

Kaiser has participated in some of those studies to try to identify the
extent to which lost time at work, the cost of coming into the facility,
the cost to the organization, a visit to the physician. Those are things
that are studied in other areas, and a properly designed study could
certainly be applied in this case as well. But I\'m not aware of any as
it relates, really, to OTCs versus prescription drugs.

DR. MURPHY: In your database, the information you collect \-- or is
there another approach to this? \-- do you have a mechanism to collect
what products patients call you about that are OTC that they want
information or clarification, particularly relevant to the prior
speaker\'s statements that patients will call their doctors.

Do you have any way of addressing that or gathering that information?

MR. BARRUETA: Not systematically in the current database. I think that
in the next several years, as we develop the clinical information
systems, the electronic medical record which is being rolled out within
Kaiser Permanente from kind of the far west coast in Hawaii east \-- I
don\'t think it\'s going to get here for a number of years yet, but once
that is done, each of those interactions between the physician and the
patient potentially will be put into a system that could be studied to
try to identify those types of questions.

For now, the best, I think, we can do is informally surveying the
physician experts and trying to get a sense from them what types of
questions are coming back and the magnitude of those questions.

DR. MURPHY: Let me just go down that path, since you said you survey
physicians. It sounds like you\'re proposing, when you say ask the
doctors which, of course, we always include the doctors in our
discussions \-- are you saying that you think that there should be a
development of a list of products that physicians feel would be to
provide the public help if they went OTC?

I\'m asking what you meant by that process.

MR. BARRUETA: Oh, I think \--

DR. MURPHY: In addition to what we are doing already.

MR. BARRUETA: Yes. The sense that I have is, once there\'s a drug
that\'s identified or an indication that\'s identified as potentially
being subject to OTC, there ought to be significant outreach to
physicians on the front lines, in addition to the experts who work on
your advisory committees.

We haven\'t considered whether physicians ought to sit down and try to
come up with a list that they think ought to move everything OTC or
potentially look at OTC.

DR. HOUN: I had a question on your statement about making sure that, if
the product goes OTC and you have greater access, that the quality of
care not be impaired with decreased physician interaction.

Is this something your physicians were saying, and what was the basis
for those kinds of statements? Was there an experience existing?

MR. BARRUETA: No. It\'s an interesting question. One of the things that
we again informally surveyed the physicians within the organization was
the question of the statins. There really is a panoply and a wide
variety of opinion among our physicians on that subject.

There are some who think in some cases, particularly at higher doses,
it\'s very important that the patient be continually seen, as some of
the drugs are currently labeled. The question, I think, that has to be
asked is, is there another way to make sure that whatever the optimal
amount of physician-patient interaction happens still happens, even if
the drug is made over-the-counter.

So in terms of the quality of care question, it\'s trying to look at
specifically and make sure that it doesn\'t create a problem if you have
a situation where the patient no longer has to come to the physician for
the prescription.

MODERATOR DeLAP: It\'s been my observation that certain categories seem
to come to the fore at different times and for different reasons. I
think I am very interested, though, if you have any ideas as to how we
can more routinely be obtaining physician input, consumer input, on
these kinds of issues rather than, you know, the current pattern where
certain things seem to come to the fore for different reasons.

MR. BARRUETA: I think one way to do that potentially is for FDA to
enhance its communications with some of the pharmacy and therapeutics
committees that exist within health plans, within PBMs. Those tend to be
the experts within the payer community who have really substantial
contacts out into the expert community, the people who they really rely
on for expert opinion on what\'s the best way to manage a drug benefit.

That could be one source of information that you could reach out to. I
know that the physicians that we have, both in our regional pharmacy and
therapeutics committees, the local pharmacy and therapeutics committees,
and also the chiefs of service are very interested in these questions,
and we\'re always happy to throw those questions out to them as they
come forward.

MODERATOR DeLAP: Okay. If there are no further questions, thank you very
much.

The next on the agenda is Buchanan and Ingersoll, Attorneys at Law,
Robert Pinco and Mary Johnson.

MR. PINCO: Good morning. My name is Robert Pinco. I was former Director
of the OTC Review, and I was Executive Secretary of the Commissioner\'s
Steering Committee for OTC Drugs.

I mentioned that, because I want to go back to what happened in the very
beginning of this process and talk about where we\'ve come from there.
This was a process that in the FDA had a very high priority. The
Commissioner did have a special steering committee that dealt with this
issue.

It was focused on at a very high level, so that we could find a way to
regulate over 400,000 products. The reason this review came about was
there was a perceived failure of litigation as a regulatory model.

In the early days, in the Sixties and so on earlier, they had brought
actions against companies, but there was a limit to what the General
Counsel\'s office could do and what they could achieve, and as fast as
they got products off the market, the products changed and it was not an
efficient mechanism to work with.

So what they went to, which I think showed a great deal of foresight by
a gentleman by the name of Peter Hutt, was to go to a legislative
approach, and I think it worked exceedingly well. This was an approach
that was legislative rather than adversarial, and its purpose was really
to get people talking.

They also instituted a moratorium. The moratorium, basically, was this:
If you will modify your products while we\'re doing this review process,
we won\'t bother you; we\'ll let you do it. It was an encouragement to
industry to do things that they wanted them to do.

As long as it was consistent with the safety and efficacy requirements
of what the expert panels were coming up with, this was encouraged. What
this all did was to support a healthy and innovative industry. That was
what I was told when I joined the agency. I think it was very important
during the time that I was there.

I\'m not sure if that\'s the case today. I think the mechanisms are such
that it\'s not really working.

The legislative approach, I think, was successful because it was a
win-win proposition. It was built on a dialogue between FDA and
consumers, industry and scientists and other government agencies. Senior
agency management, particularly people like Charles Edwards and
Commissioner Schmidt, Mac Schmidt, were directly involved in policy.
This resulted in very rapid change.

One of the first lessons that Peter Hutt taught me was, if you\'re going
to do something, telegraph it to the industry, give them time, give them
notice and time to make a change, and you\'ll get the change pretty
quickly, and you won\'t have to litigate for years with these fancy law
firms that charge a lot of money and make people like me very wealthy.

The best example of that is zirconium. When we thought zirconium was a
problem, it was in antiperspirants. We could have litigated this issue
with the major law firms in Washington. I bet you we would still be
litigating the issue.

What I did was something that was a little extra-legal. We went to a
couple of the major companies who had very, very important products in
this marketplace, and we said we\'re going to ban this product, this
ingredient. Now we know this would kill your market; if I got arthritis
of the signing hands for about six weeks, would we be hearing from you?

I get a call about four weeks later from the President\'s office of this
very large company, and he says we just want to announce to you that
zirconium is no longer in our antiperspirant products. So in six weeks
we had gotten exactly what the agency wanted.

Now I think it was because of the dialogue and because they knew that we
could move quickly within the agency, if we had to move. I think what
the industry wanted out of this is that they got respect. This was an
industry that had had a history way, way back of being involved with
snake oils, and they wanted some respect, and they were willing to be
regulated to get that respect.

It also stimulated innovation. It\'s scientific research. It promoted
quality products. Companies usually rushed to modify their products,
sometimes too quickly from the agency\'s point of view, to get their
products to meet the standards that were being evolved by the expert
panels.

The ultimate winner in all of this was the public. New products were out
there. Better products were out there, and we had a very healthy
industry.

In the Eighties I think we lost that focus. There was a phasing out of
personnel in the development of the OTC program. The interest in the
senior management waned and then disappeared. A new breed of Center
office and division directors with backgrounds in only new drugs came
along.

Basically, it was the NDA way or the wrong way. The result was a shift
in interest, and the only focus more recently has been Rx to OTC
switches. I don\'t want to suggest that that\'s a bad thing, because it
is important to consider that issue, but it\'s not the only issue.

Now maybe these changes were due to a number of factors, maybe the
generic drug issues and things that were going on, maybe PDUFA and the
user fees were the focus over on prescription drugs, maybe even the
early successes of the review. Some people thought, well, we\'re
finished with the review; we\'ll just go on to do other things.

Unfortunately, with the limited staffing and the downsizing persons with
institutional knowledge were no longer present. They retired or were
removed. There were limited resources. The focus is really going to the
user fees areas.

Something that certainly wasn\'t the agency\'s fault was that the agency
review, the governmental review, increased. When I was at the agency,
sometimes six to ten levels of review were all that were needed to get
an item in the [Federal]{.underline} [Register]{.underline}.

Somebody explained to me that more recently they looked at the numbers,
and it\'s like 40 levels of review. It\'s not something you can control,
but it is a fact of life.

Then what we began to see is agency long delays in addressing industry
petitions and completing rulemaking. The law says you\'re supposed to
respond in six months, and that\'s honored in the breech. There\'s a
sunscreen example. There\'s a petition that\'s 20 years old now.

Foreign marketing petitions that I know is finally coming to fruition is
ten years old. That\'s a long time. One of the most frustrating things,
I will tell you as a person representing industry, is to have somebody
from FDA call me up on a petition that has been sitting, going nowhere,
and ask me if I want to withdraw it because it hasn\'t been moved and
because the data is outdated.

It becomes a little bit on the outrageous side, and that\'s exactly what
we\'ve gotten. Also I\'ve begun to see that the relationship has become
far more adversarial than collaborative. The whole purpose of the
legislative approach was to get away from the adversarial approach, to
get a dialogue between industry, science, and consumers and the agency.
That seems to have been disappearing.

My personal experience in going to some feedback meetings on sunscreens
and seeing some letters where people have asked for meetings with the
agency, only basically to be told to go away or to start filing new data
as though they hadn\'t been dealing with the agency for ten or 15 years
is really very, very frustrating on the part of people who have to deal
with this.

I don\'t know what the reticence to meet with industry is and to deal
with these issues, but that\'s what FDA is supposed to do. They are
supposed to regulate this industry, and I got to tell you, it\'s very
frustrating, and it\'s caused a number of companies and others to go the
Hill to force the issue, and that\'s not the way, I believe, to work
with the agency.

I think the industry would like to \-- I don\'t speak for all of the
industry; I just speak from my views \-- would like to have an
arrangement where they do speak with the agency and have a running
dialogue so they can understand what\'s wrong.

Where you don\'t get response in this, as we did in the phytomedicine
petitions to the agency, then when DSHEA came along what happens is a
good portion of the people who wanted to come to FDA\'s OTC review
process said to heck with them, I\'ll go to DSHEA.

Now as I understand it, that\'s a \$21 billion industry that you don\'t
regulate, and you could have regulated it. That\'s what frustrates me
the most. This could have been yours, and they wanted to come to you.
They wanted to get the imprimatur of the FDA, but it took so long that
they just went the easier route.

It\'s unfortunate, but most of those people are no longer interested in
coming back to do the OTC review process.

One of the things, I think, I want to talk about quickly is that the
statute distinguishes between old and new drug. It\'s not a
one-size-fits-all approach. You need to deal with new drugs and old
drugs in a slightly different way.

Remember, the old drugs have been around for a very long time. You\'ve
got experience with them. If you try to do that in an NDA framework, it
causes all kinds of problems. You ask for all kinds of data that you
don\'t need. The problem then is that it makes people want to move away
from that process.

The OTC review was not created by statute. If you will look, you\'ll
never find anything in the statute to tell you to use it. It was really
done as a regulatory mechanism for flexibility.

What I would like to see happen is that in addressing the 400,000
products, not just Rx to OTC, that we begin to look at some of the
issues.

Sunscreens are a critical need which Tom Donegan spoke about and Dr.
Leyden. It\'s a perfect exercise in frustration where we\'ve seen the
number of sunscreens drop by one-third in the United States from the
ANPR to the final, while at the same time in Europe, which is where a
lot of our products are being developed, the numbers are constantly
increasing.

They are getting better ingredients, and if you go to Australia where
they\'ve combined the best of U.S. and the best of Europe, they\'ve
reduced the incidence of the epidemic of sunscreen cancers dramatically.

We need to do that. We need to have mechanisms that work. These
mechanisms just don\'t work.

MS. JOHNSON: I think Bob\'s clearly laid out some of our concerns with
regard to the OTC monograph process. What I wanted to talk about is just
to address two ways that the process could be improved.

One has to do with the broadening of the eligibility criteria to
encompass foreign marketed products. That, of course, is well underway.
The other has to do with the timeliness of the review process.

With regard to the proposed foreign marketing rulemaking, we think this
is a significant step in the right direction. It certainly is in line
with world harmonization efforts such as those with regard to ICH, the
International Conference on Harmonization. However, as has been noted in
industry comments, the proposed standards really need to be commensurate
with the types of products being regulated.

These are not intended \-- This mechanism is not intended for new drugs,
but it\'s supposed to address older drug products. As Bob mentioned,
with the availability of DSHEA, it\'s unlikely that oral products will
be reviewed under this proposed mechanism.

In contrast, though, topical products such as sunscreens are very likely
candidates for the expanded eligibility program, because in particular,
products like sunscreens are really ill suited to the NDA mechanism. As
was brought out earlier, they are marketed in a variety of sizes and
formulations, and from an economic standpoint it doesn\'t make sense to
move forward with NDA supplements to get changes and modifications
cleared for these formulations.

I think also it was noted in the comments to the proposed rulemaking
that industry feels that the criteria at this point are overly
burdensome. Several comments, for example, mentioned concern regarding
the lack of interim marketing or at-risk marketing as a mechanism.

This is already a mechanism in place for products that are marketed in
the U.S. and reviewed under the monograph system.

The second issue I wanted to talk about was the timeliness of the
review. As Bob has mentioned, and others, the agency response time on
OTC drug petitions through the monograph process has been extremely
slow. One, in particular, has pended for 20 years, but others anywhere
from five to 20 years.

This is difficult to rationalize, and I think it\'s led a very
frustrated industry to seek attention to these matters through other
means, such as through lobbying efforts on the Hill.

The decision making process on these petitions needs to take place
within a reasonable time frame. Understandably, the agency has limited
resources available.

One idea that was brought to the attention of the agency in 1998 was the
concept of using a third party review program. This is a concept that\'s
already in place in the Center for Devices. It\'s a voluntary program,
and the goal is to use it in order to expedite the review time.

The nuts and bolts of such proposal would include, basically,
accrediting \-- FDA would accredit outside organizations to conduct the
initial review of petitions for eligibility. The industry would again
pay for the initial review, and recommendations would be made to FDA by
the accredited parties. At that point, of course, FDA would make the
final determination with regard to safety and efficacy.

So we feel this is a relatively simple mechanism that has already been
tested in the device area and should be explored in this area. Thank
you.

MR. PINCO: Well, one of the very nice signs that you are rethinking this
issue, obviously, is this meeting here today, and I hope that this is a
sign that some of these issues are going to be considered.

I would like you to consider the following: We need mechanisms to make
this process work. The OTC review is over. I don\'t want to go back \--
harken back to old times again. That\'s not what I would like to see.
What I\'d like to see is rethinking of a new direction and new
approaches.

Those new approaches need to address three categories: The foreign
marketed products, as we go into internationalization; modifications to
existing products, because there are a lot of them that are changing;
and, of course, the Rx to OTC switches. They are important.

Unless those things are happening, we\'re going to see that this
industry is going to stagnate, and in the case of the sunscreens, for
example, you\'re going to see that people will make business decisions
to develop new products or not to develop new products, because they
can\'t get them through the U.S. system. That, I think, is really
unfortunate.

A major loser in all of this scenario, obviously, is going to be the
American public. So I would like to see something to establish
mechanisms that are usable, and that we look at, more or less, the big
picture.

Obviously, the number of people here in this room and in the other room,
I guess, if we were to see them, shows that there\'s great interest in
all of this. I would like you to take out of that perhaps that we really
do want to see this mechanism become viable and not become a backwater,
as I believe it has become more recently. Thank you very much.

MODERATOR DeLAP: Thank you, and I think again, as you just said, I think
with the number of people that you have in this room from the agency is
a measure of our interest in trying to see ways that we can improve
processes and continue to serve the public health.

Questions from the panel?

DR. GANLEY: Yes. I just had a question or a few questions probably. I
think one of the interesting things you brought up is the OTC review
process, and that has become a cumbersome process.

What has changed from the 1980s on to now that has made it cumbersome? I
mean, you had given the example of resources. I\'m not familiar with
what resources were available, but the number of rules that are in the
final monograph stage still are significant and has to be addressed
somehow. But you really haven\'t provided any concrete examples of how
to do that.

I\'m not sure if just meeting with industry or individuals about this
pushes the process forward.

MR. PINCO: I agree with you. One of the things, I guess, that struck me
\-- and of course, no one ever likes to believe that they made mistakes
or didn\'t do things in the proper way \-- I think the three-step
process was overkill.

It was intended \-- It had good intentions in the very beginning, and in
the system where you have six or eight levels of clearance to get
[Federal]{.underline} [Register]{.underline} documents out, clearly that
was \-- it made sense there.

Now if you have 40 \-- I don\'t know if I\'m right or not, but 40 levels
of clearance through HHS and OMB and all the other things you have to
do, you\'ve got a mechanism, but you have to find other mechanisms to
deal with it. That\'s why it\'s important to try to find the ways to
streamline some of these things as much as possible, to cut down the
levels of review, the re-review, to look for mechanisms by which the
industry can get products to the marketplace.

For example, we suggested interim marketing. Once you\'ve decided that a
product is out there and it\'s perfectly safe, why do we do the rest of
the process. That\'s the way the whole OTC review process worked.

That\'s why there was no pressure. We told people, you can be on the
market until we finish the final monographs. Now if they\'re not on the
market and years go by, there\'s great pressure for them to do something
to get their product to the marketplace. They can\'t wait ten or 20
years.

So that\'s one mechanism that you could deal with. The pilot mechanism
that Mary mentioned is a mechanism to review things. If you don\'t have
the people, use this process. It speeds up the effort. It makes it work
better.

The foreign marketing approach is an attempt \-- I think, is a good
attempt to try to deal with the international harmonization issue. It
doesn\'t go nearly far enough. It requires much too much in the way of
the kinds of requirements that you need, considering the kinds of
products. We\'re only talking about topicals now, because the orals all
have gone the route of DSHEA.

So it may be mechanisms to find ways to harmonize with the approaches
taken in Europe, which has, in the process of forming the European
Union, found ways to speed things up and make their processes work much
better than we have. I could go on, but I don\'t know that you want me
to continue.

DR. GANLEY: Well, I guess the other thing is that I think that what some
of us have a concern about is that, in providing feedback prior to
finalizing a rule or a monograph, is that we don\'t necessary have input
from all the stakeholders.

Certainly, industry has a motivation to be involved in the process, but
oftentimes the consumers aren\'t involved in that process or academia is
not involved in that process unless they are, you know, individuals that
are sponsored by industry.

So I think that\'s a concern that I have, regarding your comments about
providing some type of input back to industry during the rulemaking
process where we don\'t always have all the stakeholders involved.

MR. PINCO: Well, part of it this is not \-- We\'re not talking about
what we call an [ex]{.underline} [parte]{.underline} kind of an
arrangement where you go and have a side conversation with somebody, and
nobody else inputs.

These are public meetings, and I don\'t think the industry cares if
other people show up to these things. We\'re not getting private
licenses in the monograph system. There you do want a private meeting,
and you don\'t want it public.

These are situations in which they have questions. They\'re not sure how
you\'re reacting to what they have submitted. They have concerns about
what else you think you want because, as I said to you before, if you
will tell industry what you need or what you like or don\'t like,
you\'ll find rather than fight, they will switch. It\'s in their
interest to do so.

If you do that in a consistent way, you\'ll find that the industry is
very cooperative. I couldn\'t believe how cooperative they were. The
example I gave you was zirconium. I was very pleasantly surprised. I had
people in the old Bureau of Drugs tell me that I had done something
really terrible by having the side conversation with them, but I got
what we wanted, what the agency wanted. I thought that was in the public
interest.

So I guess I would say that it is not something that you\'re violating
any law and, if anybody is interested, they can come into those
meetings. I think what we need is a way to have a dialogue to know what
you\'re thinking and whether we\'re off track with where the agency is
at any particular point in time.

That would really help in developing some kind of a dialogue, a
continuing dialogue, with the industry, not just the major trade
associations but individual companies or individuals.

DR. MURPHY: Could I go back to the Australia example and ask you to
summarize for us what were the elements that you thought \-- you
mentioned them as taking from two systems, and it made the process work
in Australia. Could you summarize for us what the important elements
were that you thought were extracted from the different systems to make
it work?

MR. PINCO: Well, I can\'t tell you I have all the data. But what I
understand is what happened here is that the Australians, who are,
obviously, linked to the Brits historically, picked up from the European
Union all of the new UVA sunscreens that were being evolved. They have a
lot more going through their process.

They\'ve got a very streamlined system that works. Even though they are
cosmetics, it\'s a preclearance mechanism that they have. They then
realized they had a very serious problem of skin cancer epidemic, worse
than ours. It was increasing at a very rapid rate.

So they undertook, as I understand, a very, very complicated campaign of
consumer education, physician \-- discussions with physicians and get
them to speak to the public in general, and then also expansion of these
sunscreens.

What it does is it allows the industry is they can bring more
ingredients into mix and match and to get the best product they can get
out on the market, and the competition will take care of the rest.

Here in the United States, none of those sunscreens have been made
available. So what we ended up doing is we took sunscreens that were
around in the 1970s and we decreased the number of those products, while
at the same time the rest of the world was getting all of these new and
better sunscreens.

We have not solved our problem, and that has been communicated to the
agency by American Academy of Dermatology and a number of others, and
it\'s very frustrating to see that even now after all these years with
the sunscreen monograph finalized, we still haven\'t dealt with this
issue.

MODERATOR DeLAP: I think we will need to move on. I would encourage you,
if there are things that you think we could learn from that Australian
experience that we haven\'t already heard from you about, please go
ahead and submit them to the docket, and we\'ll certainly look at them.

MR. PINCO: I\'d be happy to. Thank you.

MODERATOR DeLAP: Thank you. The next speaker on the agenda is David
Steinberg of Steinberg and Associates.

MR. STEINBERG: Thank you. In the interest of time, I am not going to be
being redundant and cover some of the issues that other people have
already covered. I will not be following my written notes, because it\'s
just being redundant.

Since 1995 I have written a column for [Cosmetics and
Toiletries]{.underline} magazine on international personal care
regulations, and on their behalf is why I\'m here today.

Tom Donegan described this group of over-the-counter drugs as being
cosmetic drugs. They are sold frequently for their cosmetic properties,
even though they do have drug actions. The last speaker also addressed
some of the issues.

These drugs are unique in two other factors. One is that they do not
have dose restrictions. These products are sold with the basic
directions, \"apply as frequently as needed.\" You don\'t overdose on
lip balms. You don\'t overdose on sunscreens. You apply it as often as
it\'s needed.

The second reason that these are different is the reason for me being
here. These drugs are basically produced and discovered by chemical
companies who invent the raw material. They then try to market this not
to a single marketer of a finished drug but to sell it to every producer
of sunscreens or antiperspirants or anti-dandruff shampoos.

These are chemicals as opposed to being drugs which go through an NDA
process. In fact, when you talk to a chemical company who has invented a
new UVA filter and you try to explain that to sell this in the United
States you basically have to become a drug manufacturer, a retail drug
manufacturer, they throw up their hands.

We need a simple way to add new chemical drugs like this to the
monographs for these limited purposes. They are drugs that have no dose
dependency.

Now since the start of the process, if we look at the different
categories, we have not added any new skin protectants. We have not
added any new antiperspirants. We have not added any new anti-dandruff
agents to the monograph. We\'ve added one new UV filter, and that took
close to 20 years to do.

The OTC system has been great for the consumer in terms of competition,
but we\'ve stifled innovation to the new actives for this narrow
purpose.

In April I attended the World Conference on Cosmetic Regulations in
Malta. Speaker after speaker got up and criticized the FDA. They called
the FDA old-fashioned. They called the FDA out of step with reality.

I didn\'t understand this. There were over 75 different regulatory
agencies present from 75 different countries, and they kept saying that
there\'s something wrong with the FDA, and they kept on pointing to the
European Union\'s method of regulations as being the way for the future.

I just didn\'t understand this, because I find the European regulations
to be extremely onerous. They are much more complicated and much more
difficult than in the United States.

They have these products that I call the drugs without dose
restrictions. They are all cosmetics, but they are not like nail polish
or lipsticks. You can\'t just go into the marketplace. You must get a
preapproval for the active ingredient, and they set up an independent
organization called the SCCNFP which stands for the Scientific
Committee, Cosmetics and Non-Food Products, to evaluate and approve
these new actives.

Was this an easy process? No. In fact, it almost was funnier than our
process in the time it took. In 1978 the FDA put octomethoxycinimate as
a safe and effective Category I sunscreen. This is the standard for the
European Union\'s SPF testing, and yet this was not approved until a
couple of years ago.

Why was it left in regulatory limbo for 18-20 years? For the same
reasons that we have problems. They do not have a transparent system for
approving new OTC actives like UV filters, anti-dandruff agents.

Finally, about three years ago they published a model submission. You
fill out this form. You do these tests, and we can make a decision. Wow.
No sooner was this document published that within two years all their
provisionally approved UV filters finally were permanently approved. All
the provisional preservatives were finally permanently approved.

It works. Now after this came out we\'ve had six new sunscreens that
went from being never used to being permanently approved, because the
manufacturer of the UV filter knew what was asked of him. Run all these
tests, we can make a decision as to whether they are safe.

All these sunscreens, incidentally, would have marketplaces in the
United States, and also they all would be considered new drugs by the
FDA.

As the FDA requires drugs to be safe and effective, the efficacy of
these products is not a question. The monographs have defined the
efficacy. It is the final formulation that you run SPF on. It\'s the
final formulation that you run antiperspirant testing on. It is the
question of safety that we must address.

Now it is really easy for everyone to get up and to criticize the FDA,
like they did in Malta, because we don\'t have a simple system. However,
I think it\'s much more productive if we have a suggestion on how to do
this, and that is my purpose.

We have a mechanism right now in the United States called the Cosmetic
Ingredient Review, independent. They review the safety. They set up the
parameters and, by the way, the FDA sits on this panel. They happen to
be the biggest voice at the Cosmetic Ingredient Review. If the FDA says
time out, everyone stops and listens.

So why not have these products shifted away? Take it form your valuable
time. Let you concentrate on all the drugs that other people are
interested here. Take these cosmetic drugs. Shift over the safety
responsibility, the preclearance to the Cosmetic Ingredient Review. Then
bring it back to the agency for a final review, and let\'s move on.

I will tell you this, that if the FDA adopted this simple, transparent,
simple and easy to follow, cost effective system for approving these new
actives, that at the next World Harmonization meeting in Japan in 2002 I
won\'t have to listen to speaker after speaker say that the FDA is out
of step. Everyone will be saying why don\'t we harmonize with the U.S.
methodologies. Thank you.

MODERATOR DeLAP: Okay. So if I can summarize one thing that I thought
was central to your talk, you\'re suggesting that certain categories of
products that are regulated as cosmetics in Europe, nonetheless have
some preclearance requirements, and we could have a new mechanism in
place that would consider these products separately as cosmetic drug
products and incorporate some preclearance kinds of testing that would
not be an option under our current cosmetic regulations.

MR. STEINBERG: That\'s correct. Yes.

MODERATOR DeLAP: Any other questions or comments from the committee?

DR. GANLEY: I guess one of the things that comes to mind: If you have a
new ingredient that\'s not marketed OTC anywhere in the world, in the
U.S. it would require an NDA.

MR. STEINBERG: Yes.

DR. GANLEY: Assuming \-- If we assume the foreign marketing document
eventually gets published this year, are you saying that there should be
another mechanism where, if there\'s a new active ingredient, a new
process for these things to come into the U.S. market in the monograph
rather than going the NDA route?

MR. STEINBERG: Yes. Absolutely. I don\'t remember the last time I went
to my doctor and asked for a prescription for suntan or sunscreen or an
antiperspirant or for lip balm. In fact, the problem that exists in
regulations throughout the world is that the regulators come up with
legal definitions which don\'t reflect consumer reality.

You can go to 100 consumers on the street there and tell them that their
anti-dandruff shampoo is a drug. They\'re not going to believe you.
They\'re not going to believe you that sunscreens are drugs. They\'re
not going to believe you that lip balms are drugs.

We can put all the labels, we can put all the advertising in the world,
and they still consider them cosmetics, and laws are not going to change
consumer perception. So let\'s deal with it. Let\'s stop worrying about
it.

DR. GANLEY: Well, I think the one difficulty with that is that we\'re
saying that sunscreens prevent skin cancer. So I wouldn\'t necessarily
characterize it purely as a cosmetic, if we\'re making some disease
prevention claim on it, necessarily.

I guess the other issue would be to address the point about new active
ingredients is the safety reporting. I think that would be an issue that
would need to be addressed, because we really don\'t have a good handle
on the safety or what is happening with some products out there that are
marketed under a monograph.

You know, we hear about them sometimes, but not all the time. So should
there \-- If there is going to be a mechanism in place to allow new
actives into the monograph that have not been marketed in the world in
any other OTC market, does there have to be some change in the reporting
of safety for these types of products that would contain these new
actives?

MR. STEINBERG: Let me answer it this way. There were some questions by
the previous speaker and comments on Australia, and I\'m quite familiar
with the regulations there. I\'ve been involved with it.

They require mandatory adverse reaction finding. This has to be
submitted once a year in order to get your license approved to be a
manufacturer of these types of drugs, and sunscreens in Australia are
regulated as drugs. They are not cosmetics.

They have a mandatory \-- When they come up to get their license renewed
each year, they must submit documentation on all adverse reactions that
are found to their products. So it\'s doable.

MODERATOR DeLAP: Okay. Well, thank you very much. Next on the agenda,
the American Pharmaceutical Association, Rebecca Chater, RPh.

MS. CHATER: Good morning. Thank you for the opportunity to present the
views of the American Pharmaceutical Association, the national
professional society of pharmacists.

I am Rebecca Chater, a community pharmacist with Kerr Drug in North
Carolina. My practice experience is broad, including long term care,
pharmacy management, academia, and clinical practice. In addition to
having a great interest in public health within the context of my
pharmacy background, my Master\'s degree is also in public health.

I am a past member of the APA board of trustees, and APA\'s more than
53,000 members are pharmacists providing care in a variety of practice
settings such as community, hospital, long term care, and hospice
settings, as well as pharmaceutical scientists and pharmacy students.

In each of these settings, pharmacists help consumers manage and improve
their medication use, including the appropriate selection and use of
over-the-counter products.

An important component of the discussions today is the site where the
majority of our members practice, the pharmacy. Most OTC products are
purchased at a pharmacy. This positions pharmacists well to interact
with consumers at the point of decision making and purchase.

The pharmacist fulfills an essential role in the use of medications,
helping consumers make their medications work. While the FDA ensures the
safety and effectiveness and availability of available products,
manufacturers ensure the production of quality, contaminant-free
products, and physicians and other prescribers diagnose and direct
consumer interaction within today\'s health care system, pharmacists
work with consumers to make the best use of the powerful technology we
know as medications, whether classified as prescription medications,
over-the-counter products or dietary supplements.

In my practice and in community pharmacies across the country,
pharmacists serve as a bridge between consumers\' self-care activities
and interaction with the formal health care system. For example, we
monitor interactions between OTC products, dietary supplements, and
prescription medications, and for the development of adverse effects.

My comments today are based on the perspective of a pharmacist as a
medication use manager. APHA has long supported activities and programs
designed to assure the appropriate use of OTC medications for
consumers\' health care.

Examples include publishing the [Handbook of Nonprescription
Drugs]{.underline} for more than 25 years, conducting consumer hotlines
for access to pharmacist\'s consultation about OTC products, and
participation in the Partnership For Self-Care, an initiative designed
to help consumers use OTC medications safely and effectively.

The APHA House of Delegates has advocated for appropriate labeling of
OTC drug products since 1978. APHA believes an important component of
the pharmacist\'s professional responsibility includes providing
consultation to support drug selection, dosing, and use of prescription
and nonprescription medications and dietary supplements.

My comments today will focus on four of the many questions posed in the
April 27 announcement of this meeting. Specifically, I will discuss the
criteria FDA should consider in rendering decisions on OTC availability
of drug products; a recommendation for assuring consumer understanding
of OTC products through pharmacist directed research; risks posed by
consumer confusion regarding brand name line extensions; and the current
structure for marketing OTC products.

Regarding criteria: The number of products shifting from prescription
only to OCT status has increased markedly over the past several years,
providing consumers with many more choices for self-care. These
products, however, are available in a myriad of environments, including
environments that do not provide the consumer with convenient direct
access to a health care professional.

This lack of access to a pharmacist places greater responsibility on the
consumer for the interpretation and the understanding of drug labeling
and appropriate use of medications. As such, the decisions determining
what products should be available in this environment must be carefully
considered.

The question of whether a product should be switched from prescription
to OTC status must involve more than the traditional review of the
clinical information and research information demonstrating the safety
and effectiveness of the product.

While such information represents the core information for considering a
transition to OTC status, APHA recommends that the FDA criteria include
an assessment of the environments surrounding the use of the product in
question, as well as the environment of the disease or the symptom at
issue.

The product switch question must be animated by a comparative review of
existing therapies in the self-care market, the degree of treatment
sought in the existing self-care system, and the risks and benefits of
increasing access to the product at issue. Let me explain.

A review of existing therapies in the self-care market is important to
explore what products are being used for self-care in the current
environment. If existing alternatives for self-care are less safe due to
potential for interactions with other therapy or risk of negative side
effects, the relative safety of the product in question for transition
may increase, making transition to OTC status favorable. If, however, a
broad array of safe and effective products with minimal side effects is
available for self-care, transition would be less favorable.

If existing alternatives for self-care are limited to dietary
supplements, other problems may exist. Numerous studies have documented
problems with product content and relief of the active ingredient in
dietary supplement products, and consumers in this scenario are limited
to products whose content may not match the claims on the label. Again,
the relative safety of the product in question for transition may
increase.

Another component of a comparative analysis should be a review of the
degree to which consumers are choosing self-care treatment for the
particular disease or condition at issue. Assessment of the use of
self-care treatment, such as OTC products, dietary supplements or other
alternative therapies, could provide valuable information for the
consumer\'s interest in self-care treatment for the condition at issue.

Such an assessment may provide information about how consumers use those
products, including whether consumers seek health care advice when
symptoms persist after using the available self-care treatment.

The risks and benefits associated with increasing access to the product
must also be evaluated in this comparative analysis. Specifically, the
FDA process should evaluate the use of the product in the
prescription-only environment to assess prescribing patterns, etcetera,
that may be consistent with increasing consumer driven use of the
product.

The provision of the product by pharmacists under the purview of
collaborative practice agreements, for example, may support the expanded
availability of the product. Generally, a collaborative practice
agreement is authorized by state law and allows pharmacists and
physicians to develop a protocol detailing conditions under which a
pharmacist will initiate or modify a patient\'s drug therapy.

Regarding assuring consumer understanding of OTC products: Consumer
understanding of a proposed OTC product labeling is essential to support
the transition from prescription only to over-the-counter status.

APHA supports methods to assess consumer understanding of proposed
labeling that involves the site where most OTC products are purchased,
the pharmacy, and the health care professional most accessible to
respond to questions about OTC products, the pharmacist.

In a recent multi-center clinical trial, pharmacists acted as principal
investigators to evaluate compliance and persistence by consumers
self-selecting to receive a product being considered for transition to
OTC status. In this study data was gathered at more than 50 pharmacies,
gathered at a site where most OTC products are expected to be purchased,
and overseen by the health care professional most likely to help
consumers choose a product and answer questions about how to use the
product most appropriately.

Studies such as this provide valuable information to support transition
from prescription-only to OTC status. Pharmacists, if widely utilized in
Phase IV and post-marketing surveillance clinical trials such as the one
I\'ve just described, can play a valuable role in assessing and
influencing through pharmaceutical care, where appropriate, medication
use in the uncontrolled real world setting of self-care and health care.

In this system, pharmacists will ultimately provide contributions to our
knowledge base regarding the effectiveness of various medications in the
population at large.

Regarding risks posed by consumer confusion resulting from brand name
line extensions: AS APHA has expressed to the FDA many times,
pharmacists continue to have significant concerns about the presence and
proliferation of the use of the same brand name or minor variations of
the same brand name to identify products with similar active
ingredients.

Just as Kleenex is now a universal name for facial tissues, consumers
and health care professionals correlate product brand names with active
ingredients of OTC medications. Consumers, and perhaps even some health
professionals, may also assume that a consistent brand name on an
over-the-counter drug product refers to consistent active ingredients.

This is not the current situation, given the trend toward
over-the-counter brand name line extensions. The APHA is concerned that
this practice may cause significant confusion.

Recently, I was made aware of a cough and cold product where a
children\'s suspension formulation is significantly different from the
pediatric drop formulation. The parent, directed by her pediatrician to
use the brand name product but with no specific direction as to which of
that brand product to choose, presented at the pharmacy trying to choose
among the products where different formulations \-- many different
formulations of active ingredients existed.

Interaction with the pharmacist helped this parent resolve the
situation. But one must ask how many times this situation is repeated,
and how much confusion could be prevented by avoiding or limiting the
use of similar brand names for products with different active
ingredients.

When choosing or recommending OTC therapy, consumers and health
professionals are likely to see only the prominent brand name and assume
that this conveys active ingredient consistency. Consideration of the
risks of confusion with brand name line extensions must be a component
of FDA\'s review of consumer understanding.

Reviewing product names and brand name line extensions fits within the
concept I previously discussed, the comparative review in order to
assess transition from prescription to OTC status. A brand name,
considered in isolation, may appear clear and understandable, but when
placed on a pharmacy shelf with five or 15 other products with similar
names, clarity is lost or, more concerning, the clarity may be lost when
consumers try to recall their OTC therapy when consulting with a
pharmacist about appropriate medication use.

Without being able to accurately identify the active ingredients in a
product, checks for drug interactions or other potential problems are
severely limited.

Finally, I will address the agency\'s question about the adequacy of the
marketing structure for OTC products in the United States.

Generally, FDA\'s existing structure for marketing both prescription and
OTC products could be improved by an expanded recognition of the role of
the pharmacist in ensuring appropriate medication use.

We are each aware of the steadily mounting evidence of morbidity and
mortality attributable to underuse or misuse of prescription
pharmaceuticals. This evidence has recently spilled over from its
historical confinement in the pages of medical journals to play out in
the lay media.

The media, with the public not far behind, are demanding more
accountability of manufacturers, physicians and pharmacists. With
prescription medications, part of the problem is the fact that health
professionals are, unfortunately, being pushed by economic pressures
into spending less time with each patient.

With OTC products, consumers must navigate the self-care system without
the assistance of a health care provider unless they choose to ask for
assistance. These marketplace trends make it difficult for providers,
pharmacists \-- prescribers, pharmacists and consumers alike to remain
fully alert to the risks of every drug they prescribe and dispense and,
in the consumer situation, purchase and use.

The FDA could help this situation considerably by enhancing the use of
the pharmacist in managing medication use. Pharmacist consultation can
be valuable in ensuring appropriate medication use, reducing adverse
events, and ensuring consumer persistence and compliance with therapy.

Additionally, pharmacists can be valuable sources of information about
medication use in real life, providing additional information about the
use of prescription and OTC medications and dietary supplements.

As I described earlier, pharmacists\' participation in research
activities and in the community pharmacy can provide valuable
information about consumer comprehension of labeling and the
appropriateness of medication use, without the traditional health care
professional intervention involved in the prescription medication use
system.

Should the agency be presented with a situation where the
appropriateness of OTC classification is questionable, however, the use
of a system of marketing products through pharmacists should be
considered. Such availability would expand access beyond the traditional
system, while maintaining health professional interaction.

Additionally, data gathered from the experience of expanded access
through pharmacists could be used to support the transition from
prescription to full OTC availability.

It is important to recognize that APHA is not asserting that every
product considered for switch to OTC status must flow into a transition
class. Rather, APHA is recommending an alternative distribution system
for use when the data are insufficient to support a transition to full
OTC status, but expanded access to the product is necessary to support
quality self-care.

Over-the-counter medications are a valuable part of consumer self-care
and our health care system. The FDA must assure that OTC products are
accompanied by labeling to support appropriate use and coordination with
the health care delivery system.

The believe that over-the-counter drug products are helpful is true, but
the belief that they are risk free is dangerous. The FDA\'s hearing
today about the agency\'s approach to regulating OTC products is a vital
step in assuring quality OTC products for consumers\' use in self-care
and pharmacists\' interaction as a bridge between self-care and health
care.

Thank you for your consideration of the views of America\'s pharmacists,
and I would be happy to entertain any questions you may have.

MODERATOR DeLAP: Thank you. Questions? Dr. Jenkins?

DR. JENKINS: One of the points you made at the end of your talk seems to
suggest that you are in favor of a third mechanism, the so called
behind-the-counter availability of products. Yet we heard earlier about
other views that that system doesn\'t work and that other countries are
moving away from that system, and there\'s GAO report that did not seem
to favor that system.

Can you comment on your thoughts about those other comments?

MS. CHATER: As a community pharmacist, I do firmly believe that there is
clearly a role for pharmacist activity in this area. I think that a
pharmacist is very well positioned to address the individual patient
needs and balance that with the value, the use of a particular
medication. So I am in favor.

DR. JENKINS: Could you maybe give some examples of \-- Part of the
questions we had in the [Federal]{.underline} [Register]{.underline}
notice were particular drugs, classes or illnesses that might be
appropriate. Could you give some examples of where you think that
behind-the-counter would be an appropriate mechanism to move things
over-the-counter, such as asthma, hypercholesterolemia, chronic
conditions?

MS. CHATER: Well, there are a variety of examples I could offer, but for
example, if a pharmacist is aware of a patient\'s medical history, there
are products available that could cause concern in an absolute OTC
switch, but would be appropriate for that individual patient.

For example, if there is a collaborative practice arrangement in place,
a pharmacist with a previously arranged relationship with a physician
could be able to assess that patient\'s needs and address those
appropriately.

DR. JENKINS: Just one final question: Can you clarify? Do you practice
in an independent pharmacy or a chain pharmacy, and can you correlate
how you think that impacts on the ability to do these counseling
sessions and some of the interactions with patients that you are
suggesting pharmacists can do?

MS. CHATER: Yes. I practice in a regional chain. Kerr Drug is a regional
chain in North and South Carolina of about 150 pharmacies.

Heretofore, we have made substantial efforts in evaluating processes
such as work flow, building efficiencies into our dispensing process to
allow our pharmacists more time to provide direct care with patients.
That is a system for us that is working and growing.

We actually have pharmaceutical care centers within some of our stores
where that direct patient care is provided in the setting that\'s a
little bit less hurried and more beneficial to the patient than has been
in the past.

By the way, we find that patients remark consistently that receiving
care in an environment like that is a very non-threatening way to
receive care, and patients seem to be very, very much in favor of the
services that we are providing.

MODERATOR DeLAP: Okay. Well, thank you very much, and we\'ll move on
then to the National Community Pharmacists Association, Doug Hoey, Vice
President.

MR. HOEY: Good afternoon. My name is Douglas Hoey, and this is my
colleague, Boyd Ennis. We are pharmacists on the staff of the National
Community Pharmacists Association, and on behalf of NCPA we would like
to thank the FDA for allowing us to comment on this issue that is so
important to public safety.

NCPA represents the 25,000 independent community pharmacies in the
United States and the 60,000 community pharmacists who practice in those
pharmacies.

The FDA posed several questions for feedback in the April 27
[Federal]{.underline} [Register]{.underline} announcing this hearing. My
comments today will address three of these areas mentioned: Public
safety; a potential solution; and initiating product switches from Rx to
OTC status. NCPA will also file more written comments and supporting
documents prior to the August 25 deadline.

All of us here have patient safety as our highest priority. Patient
medication safety is perhaps more complex than ever before, because
there are more medications, both prescription and OTC, available to
consumers than ever before.

At the same time, patients have access to more information and are more
interested in being involved with their own health care decisions
affecting them and their family than ever before.

Although the FDA\'s recent regulation providing easier to read labeling
will help patients better understand the actions and side effects of
medications they are taking, in the pharmacy I still see a considerable
amount of confusion that sometimes exists when it comes to taking OTC
medications.

Illiteracy and difficulty reading English contributes to the confusion.
According to information from the National Institute for Literacy,
nearly one-third of Americans need a stronger foundation of basic
reading skills.

This lack of universal understanding about medications becomes even more
important as the FDA begins to consider medications used for chronic
conditions for which patients have no immediate symptoms. For example,
the class of drugs featured in yesterday\'s USA Today, today\'s New York
Times, yesterday\'s evening news, on the morning shows this morning,
interact with drugs from at least 15 categories of medications,
including some OTC vitamins and some OTC products that are currently on
the market.

I mention those news stories only to raise the awareness of the
potential for drug or food interactions. These potential interactions
make it imperative that ready and accessible expert health care advice
be available to patients to provide information about their medicine and
help them to make a rational selection of care.

One of the questions we would like to address is: How can FDA be assured
of consumer understanding?

Consumers need both oral and written information to ensure understanding
about the medications they wish to take. Pharmacists are an excellent
source of this information. According to a 1999 FDA survey, 87 percent
of patients are receiving written information about their medications
from pharmacists.

With the explosion of Direct to Consumer advertising, it seems more
appropriate than ever that access to a medicine expert, the pharmacist,
could provide more safe and effective care. Additionally, pharmacists
were voted the most trusted professional in the United States in Gallup
poll surveys for 11 straight years, and are the most accessible health
care professional.

Pharmacists have a minimum of six years education. If a patient comes to
the pharmacy where they also pick up their prescription medicine, the
pharmacist has the advantage of having the patient profile readily
available. This knowledge and information allows the pharmacist to
assist the patient in making a rational selection for their condition.
It also helps to eliminate the risk of duplicate therapies or therapies
that conflict with a regimen the patient is already taking.

NCPA supports a transitional category of prescription drugs. This method
seems to offer the best of all worlds by offering a bridge between the
prescription and OTC categories.

Prescription drugs in a transitional category provides the FDA with the
ability to assess the use and safety of the drug in an environment
similar to OTC status, but one that would provide the safety elements of
the patient conferring with a licensed health care professional.

The transitional category we are suggesting would be for an interim
period of, say, three or four years, during which time the public health
experience with the drug as an OTC candidate could be evaluated. This
extra time allows the agency the flexibility to assess the drug and
allow it to go OTC or, if safety concerns warrant, return the drug to Rx
status, as it did with Metaproterenol in 1983.

To add to the FDA\'s collection of data, perhaps a reporting mechanism
specific to this transitional category might be initiated.

Approaches similar to the transitional category have already been
successfully implemented in other countries. Many countries in Europe
have employed a third category of medications for years. At a symposium
on Capitol Hill in 1991, a panel of pharmacy leaders from Australia,
Canada, Great Britain, and the Netherlands described how a transitional
category of drugs has worked in their countries.

Robert Davies, the Executive Director of the Pharmacy Guild of
Australia, said: \"We believe our system of graduated drug control
provides the greatest flexibility in balancing conflicting interests of
protecting public health and providing drugs at a reasonable level of
convenience.\"

Furthermore, an additional category of drugs has been in place in U.S.
pharmacies for decades. The Controlled Substance Act allows for a fifth
schedule of controlled drugs or a C-5 category. Drugs like Robitussin
AC, Donnagel PG, and terpin hydrate with codeine, are sold only under a
pharmacist\'s supervision or by prescription.

The advantages of this transitional category of prescription to OTC
status could be: Drugs that might be abused could be identified and
controlled; reduced medication errors, duplicate therapies, or
inappropriate therapies; enhanced compliance, particularly for
medications taken for chronic conditions; and it also allows the FDA the
ability to further evaluate patient safety and provide flexibility in
recalling the drug, if necessary.

Who should initiate product category switches? Regarding this issue, we
would make the following observation: There should be a formal mechanism
where representatives from the manufacturer, health care professionals,
FDA, and consumers can review prescription products on an ongoing basis
to determine their potential for OTC status.

If the OTC Advisory Committee has the proper composition, structure, and
authority to do this, they may be an appropriate group to perform this
function. If it is not the appropriate group, then another committee
could be formed that could be a link between public and private
interests.

Again, NCPA appreciates the opportunity to discuss the importance of
patient access and patient safety, as these potent medications are
contemplated to be considered for OTC status. We hope the FDA will
strongly consider this concept of a transitional category to act as a
safety link between prescription and OTC status. Thank you. Can I answer
any questions?

MODERATOR DeLAP: Questions? Well, I guess you covered it all in your
comments. Thank you very much.

We\'ll move on to \-- We have two more sessions, and then it will be
lunch break. The next is Becton, Dickinson and Company, Anna Longwell,
Director of Corporate Regulatory Affairs.

MS. LONGWELL: Well, most of you probably haven\'t heard of it. It\'s a
publicly traded New York Stock Exchange medical supply company, and
it\'s got a global market with about 50 percent U.S. sales, and it
serves both the consumer and the hospital supply.

Our diabetes care segment of our business, for example, provides first
aid alcohol wipes to consumers in a panoply of diabetes care products.
We are also a hospital supply company who supplies a great deal of
business-to-business antimicrobials, skin preps, surgical scrubs,
etcetera. So that\'s our interest in OTCs.

We have monograph products. We have NDA products, and we have NDA
prescription products that could be switched. So we\'ve got the whole
thing.

In terms of criteria for OTC availability, we\'d like the FDA to
consider the intended user. We are dealing now with the fact that we
have two very different sets of customers, our consumers who are going
into Long\'s and buying things, and our professional users.

The risk assessment is different for each of those and needs to be
considered differently. In fact, in the tfm for antimicrobial products,
you will see that they are broken out separately.

A common practice with cosmetics is to define quite differently those
cosmetics that are intended for professional users as opposed to those
cosmetics that are intended simply for everybody who is just buying them
at the cosmetic counter.

With nonprescription IVD devices, there is a standard that is applied
differently to products that are designed for professionals and products
that are designed for consumers. Why don\'t we do this for these
products?

Okay. The other issue was consideration of public health risks in
prescription to OTC switch. I have to say that I really think that, if
FDA is going to proceed with consideration of public health risks in
determination of product safety, they are going to have to take [Brown
and Williamson]{.underline} into account in some way.

This is \-- Nobody wants to expand on a Supreme Court decision that\'s
so fresh the ink is hardly dried, but certainly, this was a component in
the Supreme Court decision, and it was germane to the decision made, and
it was a majority. However, I do think that public health is, in public
opinion, part of the health consideration. That is, I think the American
public expects public health to be considered in any public health \--
in any health safety determination, and BD agrees with that.

We think it is a necessary component of the decision whether a product
is safe. However, our concern is that FDA itself probably may not have
the statutory authority and doesn\'t really have the expertise that
other parts of the government have in determining public health issues.

Public health assessments have to be done by experts, and it\'s a
different discipline than product evaluation. It really is. It requires
a different panoply of expertise. So our concern is more with FDA
expertise, and we believe that FDA will have to go back, look at the
Supreme Court decision, and decide what its impact is on their ability,
statutory ability, to use public health as a consideration.

Okay. We\'ve been through this already. The criteria for OTC
availability \-- I just wanted to add a new one, which I think was added
by the cosmetic people, too. Consider the intended user. Risk
assessments are different.

There was another question about home IVDs and comprehension, and I did
want to point out that DCLD, CDRH in general is dealing with educational
efforts. However, they could do more. I realize nobody is here from
there at the moment, but there is an international organization that\'s
looking at criteria for home IVDs that are the kinds of IVDs that would
be used to generate information that\'s used almost immediately to take
a dose of a drug with a low therapeutic index.

These are products that really do require more concerted regulatory and
standards making input. The current demands for the labeling is that it
be understandable at the seventh grade level, and that is a demand now.
But \-- Yes?

DR. KWEDER: I\'m sorry. At the risk of sounding ignorant, I have no idea
what IVD stands for. Could you \--

MS. LONGWELL: Oh, I beg your pardon.

DR. KWEDER: I\'m sure there are many in the audience who don\'t either.

MS. LONGWELL: I\'m sorry. [In]{.underline} [vitro]{.underline}
diagnostics. There was a question about home [in]{.underline}
[vitro]{.underline} diagnostics that FDA had put into their set of
questions, and it\'s true that there is a concern about especially the
home [in]{.underline} [vitro]{.underline} diagnostics that produce a
value that a consumer will use immediately to self-administer a drug
with a narrow therapeutic index.

So that there is one area of IVDs that is even of international concern,
but we believe that DCLD is part of the agency that should be dealing
with this, and not ODE.

I\'m sorry. I thought everybody here was totally familiar with all of
the initials in the world. Okay.

On this, this is one area where I think FDA, because individual
companies really can\'t do the kind of comparative analysis that perhaps
an overbranching organization could, if there really are therapies for
the same condition, certainly a consumer cannot go read the labels of
the OTCs and decide, oh, well, maybe I should be talking to my doctor
about the prescription drugs that are available. This is impossible.

That\'s why I think that\'s where FDA should be looking at educating
consumers better about the different therapies. The other thing is
perhaps some of the professional Websites could do it, too. Individual
manufacturers can describe their product very well. It\'s a little more
difficult to develop comparative tables, and it\'s not something that
everybody wants to do anyway.

Okay. You\'re marketing OTCs. We have global marketing experience. We
kind of like \-- Unlike the rest of the members of our manufacturing
community, we kind of like the idea of the third class of OTC.

It makes more products OTC. It is a different risk/benefit. Our
disadvantages are we think FDA now has two classes, the professional use
and the consumer use. They\'re treating them as one at the moment.
We\'re worried that, because it\'s so onerous to maintain the regulatory
structure to keep two or three separate regulatory categories intact,
that FDA would probably have difficulty managing another regulatory
paradigm.

On Rx to OTC, we\'d like to see more transparent procedures, and I think
you\'ve already heard that from the industry. So I don\'t think that
I\'m going to go into it very much, except to say that we\'d like to see
internal guidance, too.

That is to say, if you are going to take \-- for two things. If you are
going to take an Rx to OTC switch and consider maybe turning that into a
petition to amend a monograph, we\'d like to see internal guidance on
that. We would also like to see internal guidance on criteria for FDA
initiated switches.

FDA has been very good about producing internal guidances that are
available to everybody. We would just like to see a few more of them.

This is something nobody has talked about yet. Maybe it\'s kind of a hot
topic, but we really think some of these products have been made for a
long time. Notwithstanding that we want to put in new APIs, we have some
products that we have been cooking now for at least 15 years, almost
exactly the same way.

We think that parametric release is something that could be done with
the well characterized process, given rationales for validation of
vendor\'s C of A\'s and review and acceptance of non-USP standard
methods. Once again, this is being done in other branches of FDA. Why
can\'t it be done here?

There are both U.S. and international methods that may very well be
acceptable without extensive validation in the quality assurance lab.

Okay, monograph: My only comment is it really is kind of a disgrace. I
will say that I don\'t think, you know, it\'s all FDA\'s fault, but
Congress insisted in FDAMA, please finish the sunscreen monograph. They
didn\'t just say please either. It\'s still not really finished. I mean,
technically it is on the books. It\'s a final reg, but effectivity means
something.

No regulation is better than something that\'s unenforceable or too
vague, it\'s true. But my advice is to just give a timeline and stick to
it. Try to do \-- It\'s an embarrassment to the industry as well, I
think, as to the agency.

My last point is that OTCs are important to U.S. health. People have
said this already. I think, and perhaps some people here would agree
with me, that it\'s often seen as a regulatory step-child. Prescription
drugs are getting more expensive. We know that. Self-medication is
getting more popular.

I\'m from Silicon Valley. I teach food and drug law at the Santa Clara
School of Law, and I will say that this is going to be a very big issue.
You people should be spending more time looking at your Website,
improving it, making it more user friendly, looking at those quack
med.com sites that are out there that are giving out advice that is
totally hopeless.

Perhaps you ought to consider links to some of the reputable
professional organizations and what they are saying about drug use,
especially OTC use. This is just the quality of the information on the
Internet. It ranges from excellent to, you know, why isn\'t somebody
coming after these guys.

Anyway, BD wants to thank FDA for holding the meeting and for paying
more attention to this important subject. I hope that this is going to
be the beginning of a concerted effort to improve the monograph process
and to spend more time making the process as it exists more transparent
and more rapid. Thank you. I\'ll answer any questions you have, if you
have any.

MODERATOR DeLAP: Well, thank you for your comments. You\'ve obviously
put a lot of thought into this, and I appreciate it. Do we have
questions? Well, if not, we\'ll move on to the American College of
Obstetricians and Gynecologists, Dr. Michael Greene.

DR. GREENE: Thank you. I will be brief. I notice there are fewer
questions as we get closer to lunch.

My name is Dr. Michael Greene. I am a Fellow of the American College of
Obstetricians and Gynecologists, and I\'m appearing today on behalf of
the College to present the College\'s concerns regarding reclassifying
prescription drugs to over-the-counter status.

My relationship to the College is as a member and an unpaid volunteer in
this assignment today. My day job is Director of Maternal-Fetal
Medicine, Massachusetts General Hospital and Associate Professor of
Obstetrics/Gynecology and Reproductive Biology at Harvard Medical
School.

My other paid position is as an associate editor of [The New England
Journal of Medicine]{.underline}. I also serve as Chair of the FDA\'s
Advisory Committee on Reproductive and Neurologic Drugs.

I will not speak today either in favor of or in opposition to any
specific product or products. I have no financial interests or potential
conflicts to disclose to the agency.

The College thanks the agency for the opportunity to be heard on this
issue. The College\'s mission is to improve the health care of women. We
pursue that mission through a combination of education and advocacy.

Prior to the epidemic of thalidomide babies in the 1950s and Sixties,
there was little public or professional awareness or concern about human
teratogenic risks. This disaster coupled with the heart wrenching
photographs from Japan of the devastating effects of methyl mercury
poisoning in Mitamota Bay raised both the lay and professional
consciousness about the vulnerability of the developing human fetus.

The 1960s saw the development of the Goldenthal guidelines requiring
specific and detailed animal reproductive safety testing for new
compounds which were designed to prevent another thalidomide epidemic.
Women were advised to avoid any and all unnecessary drug and
environmental exposures during pregnancy, and to check with their
doctors prior to taking any medications.

This educational campaign seemed to be successful. Hypervitaminosis A
was one of the original experimental animal teratogens in the 1950s.
Thus, when the potent synthetic congener Vitamin A, isotretinoin, was
introduced, it was anticipated that it would have the potential to be a
dangerous human teratogen.

It was hoped that the general education of both physicians and patients
regarding potential teratogenic risks and the manufacturer\'s extensive
efforts to avoid exposures in pregnant women would prevent fetal
injuries. Unfortunately, it was not long after the introduction of
isotretinoin that reports of severe consequences of fetal exposures
began to pour into the manufacturer and the Food and Drug
Administration.

There are several reasons why women remain vulnerable to teratogenic
exposures. First, it is generally acknowledged that 50 percent of all
pregnancies in the United States are unplanned. Some pregnancies
represent failures of appropriate and conscientiously applied
contraceptive measures. More commonly, however, they result from failure
to take appropriate contraceptive measures.

In many of these cases, women may not even recognize that they are
pregnant until they are well into the first trimester. By that time,
much of the critical period of organogenesis has passed. Many potential
teratogenic exposures occur under these circumstances.

The potential for adverse fetal consequences of drug exposure also
extends well beyond the first trimester, as we have learned with the
angiotensin converting enzyme inhibitors. Dr. Allan Mitchell of the
Sloan Epidemiology Unit at Boston University has studied the
epidemiology of drug exposures during pregnancy quite extensively.

He has shown that, when women are questioned regarding drug use during
pregnancy, they frequently fail to report the use of over-the-counter
preparations. When questioned in more detail about this, they frequently
respond that they \"did not consider over-the-counter preparations to be
drugs.\"

Similarly, women will frequently be reticent to take prescription drugs
due to safety concerns, yet take over-the-counter drugs without a second
thought. This casual regard for over-the-counter drugs makes it all the
more important that they be safe for use during pregnancy.

Drug safety during pregnancy goes beyond concerns about teratogenicity
and developmental toxicity. The liver and kidneys are both more
sensitive to toxins when pregnant. This lesson was learned when pregnant
women suffered fatty degeneration of the liver and renal failure when
given large doses intravenous tetracycline to treat pyelonephritis in
the 1950s.

Although of less consequence, women still occasionally develop
enterohepatic cholestasis due to exposure to erythromycin estilate. On
March 30 of this year I participated as an FDA panel member in a public
meeting regarding safety issues surrounding dietary supplement use
during pregnancy which were raised by the Dietary Supplements Health and
Education Act, DSHEA.

During that meeting, a public panel member presented the results of her
research among consumers, the lay public. She found that consumers were
generally not aware of the individual components and active ingredients
in most products. She found that most women assumed that, if a product
\-- in this case, dietary supplements \-- was available for sale
over-the-counter, it was safe for any and everyone.

When challenged, women responded that they were confident that if a
product was not safe for everyone, including pregnant women, quote,
\"they wold not permit it to be sold over-the-counter.\" The FDA is
\"they.\"

The irony in that case was that the restrictions of DSHEA specifically
prevented the FDA from regulating the sale of those products. In the
case of over-the-counter preparations, the FDA has the ability to
regulate these products.

The general assumptions of the safety of over-the-counter preparations
and the degree of confidence placed in the FDA to safeguard the public
safety places a heavy burden of responsibility upon the agency. As you
are also aware, the agency cannot count upon the assistance of a, quote,
\"learned intermediary\" to help consumers assess the relative safety
risks and therapeutic benefits of a drug purchased over the counter in a
supermarket.

Although consumers are ready to accept the idea that over-the-counter
remedies may not be perfectly effective, they are not prepared to accept
the idea that they are not safe.

The American College of Obstetricians and Gynecologists urges the FDA to
make a rigorous assessment of reproductive toxicity safety in its
broadest sense a routine and mandatory requirement for drugs being
considered for over-the-counter sale. The burden of proof of safety must
be high.

American women expect the FDA to protect them and their fetuses from
risks due to over-the-counter drugs. We trust that you will not let them
down. Thank you.

MODERATOR DeLAP: Thank you for your very eloquent comments. Do we have
questions?

DR. HOUN: In looking at safety for pregnant women, it\'s hard to do
controlled studies. So are you saying looking at epidemiologic data to
make that assessment?

DR. GREENE: I think you\'re absolutely correct and, as we all know, when
a drug is introduced the number of persons that have been exposed to it
is relatively small, and usually pregnant women have been systematically
excluded from that small number.

So there is frequently very little information, controlled or
scientifically useful information, to base these decisions upon. I
suppose we would have to advocate that any and all available information
that could be useful to address the issue be reviewed.

DR. KWEDER: To follow up on that, Dr. Greene, you made the comment that
the liver and kidney have unique sensitivities in the pregnant woman. Do
you think that those considerations should be factored into the kinds of
data that might be considered in assessing an Rx to OTC switch?

DR. GREENE: Absolutely, and that\'s what I meant by a broader assessment
of reproductive toxicity, not just looking narrowly at fetal or
developmental effects.

MODERATOR DeLAP: If there are no further questions, thank you very much.

We do have one or two announcements that I will let Dr. Titus make.

DR. TITUS: While we can\'t invite all of you to lunch, the panel and DAC
members have reserved seats in the cafeteria so that you can get a quick
lunch, because we are coming back and reconvening at two o\'clock.

We have an announcement for Susan Winkler. There is a FAX at the desk
for you, at our desk out in the hall.

MODERATOR DeLAP: See you at two.

(Whereupon, the foregoing matter went off the record at 1:09 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(2:08 p.m.)

MODERATOR DeLAP: Okay. We are going to start with a couple of
announcements from Dr. Titus.

DR. TITUS: Many of you have been asking us how soon the information from
the meeting, the transcript, gets posted. In approximately two weeks
after the meeting, it will get posted, and we\'ve provided at the table
out front this yellow flier which is your way to access how to find it
on docket.

Then the second thing we want you to be thinking about is tomorrow
afternoon, assuming that we stay on schedule, from 2:30 to whenever the
meeting ends, we have an open public hearing scheduled. We are
encouraging you to fill out a form that we also have left at the table
indicating if you are interested in participating in the open public
hearing tomorrow.

Our first priority is to listen to people from whom we haven\'t heard,
obviously, but we will also consider people who have presented today if
they want to add more things. So we\'re encouraging you to fill out the
form and indicate what you would speak to us about, and you should plan
on at most something along the lines of five minutes. The sooner you
turn them in, the easier it would be for us to figure out what was going
to happen tomorrow afternoon.

We will post a list probably sometime after lunch tomorrow indicating
who is speaking at the final open public hearing session.

MODERATOR DeLAP: Very well. Our first speaker for the afternoon session
is Dr. Sidney Wolfe, representing the Public Citizen\'s Health Research
Group. Dr. Wolfe.

DR. WOLFE: The speaker after me needs to catch a plane. So I have \-- I
wouldn\'t call it gracious, because that\'s not the adjective to
describe it. I\'m switching places with her.

MODERATOR DeLAP: Thank you, Dr. Wolfe. So then the first speaker is Dr.
Chao of MedImpact.

DR. CHAO: Good afternoon. First of all, I want to thank Dr. Wolfe for
his graciously letting me speak before him so that I can catch a flight,
and also thank you, Dr. Titus.

Good afternoon, everyone. It\'s always a challenge to be the first
speaker after lunch. So I will keep my remarks very brief so that you
can fall asleep on the next speaker. That serves Dr. Wolfe right for
letting me speak first, I guess.

I\'m Schumarry Chao. I am here on behalf of MedImpact, which is a
pharmacy management company who also deals with information from the
pharmacy data in looking and managing care.

My other day job is as the clinical professor of emergency medicine and
the clinical professor in pharmaco-economics in the School of Pharmacy
at University of Southern California. On a voluntary basis, I\'m on the
Board of Emergency Medicine in terms of Board of Examiners, as well as
on the Board of Health Care Policy at the University of Southern
California in the School of Public Administration.

My remarks today really are to raise the concerns that I see with the
potential of the conversion of prescription drugs en masse to the
over-the-counter status. As the medical officer and the Chief Medical
Officer at MedImpact, I oversee the medical aspects of pharmacy benefit
management and clinical interventions for millions of members and
consumers.

As a prescription benefit manager, we adjudicate claims real time. In
that role, we capture complete longitudinal drug history on each of our
members regarding how many \-- regardless of how many different
physicians prescribe medications for that patient and regardless of how
many pharmacies that patient may access in the dispensing of that
medication.

This information is invaluable in that at the time of prescribing and
dispensing, the physician and pharmacies are able to be alerted to drug
interactions so that we can prevent the medical problems that can result
from the adverse reactions.

For example, combinations of certain allergy medications and antibiotics
or antifungals can have serious implications on the cardiovascular
system. In addition, for example, medications which are very efficacious
in the treatment of asthma can have serious conflicts if the patient
happens to be a hypertensive.

According to our data, physicians or pharmacists have been able to avoid
an adverse event in about 15 percent of the time due to our
intervention. If these therapeutic classes are converted to OTCs, we
will no longer be able to capture that information, nor will we have the
opportunity to be able to intervene real time to prevent these adverse
reactions.

As we are all familiar with the recent results which were released by
the National Institute of Health regarding the number of iatrogenic
deaths per year, up to 100,000, and the majority of which are due to
drug adverse reactions, I think that with the conversion en masse to
OTCs we can only see those numbers increase logarithmically.

In addition to the alerts of drug interactions, the longitudinal drug
history also provides physicians with information on patient compliance,
which is key in the management of chronic diseases, as well as that it
also alerts the doctor as to other patient diagnoses which the doctor
may not have been aware of, if he\'s only treating that patient for a
specific one particular complaint.

According to our data, up to 30 percent of the time physicians act on
that information to better manage the patient, thereby alerting the
patient of the importance of compliance or changing their therapies
based on their knowledge of other diagnoses. Again, with the conversion
to the OTCs, that opportunity will be lost.

Finally, the aggregation of the pharmacy claims data, which to date is
still the best clinical data that we really have, with other pieces of
data, including medical claims data, lab, etcetera, really provides us
with the best opportunity to the future \-- for the future of evidence
based managed care.

Analysis of this data can provide insights as to the relative efficacy
and cost effectiveness of alternative therapies on major disease states.
As you can see, I\'m a typical doctor. I can\'t read my own handwriting.
This opportunity also will be lost in the event that we actually lose
access to that claims data.

Now as an emergency physician for the past 25 years, and also as one of
the key architects of the emergency medical system in L.A. County in the
1970s, I\'ve always been a strong advocate of having appropriate
population access to the appropriate care based on medical necessity,
not based on ability to pay.

It is ironic today that in Congress we are having a debate in terms of
promoting access to affordable drugs on the Hill with the expansion of
prescription benefits for Medicare at the same time as we are looking at
conversion of these drugs, the prescription drugs, on major therapeutic
classes to OTCs. We are, in essence, changing the benefit design to 100
percent co-pay for the patient, and we are basically looking at
allocating drugs and access to these drugs based on ability to pay, not
based on medical necessity.

From my perspective, that raises some really serious concerns. As a
physician, if we are looking that we think that this is the best line of
therapy \-- and often drugs are the first line of therapy, because of
their cost effectiveness as well as of their noninvasive nature.

Now if we actually lower that access because we are fooling ourselves,
saying that we are opening up access, but if the patient can\'t afford
to buy their drugs, they basically have no access. One is they will be
denied that access to care.

Secondly, in all likelihood, health care costs will go up, because we
will be shifting to second and third line of therapies, because those
therapies are really covered by insurance.

Lastly, I\'ll reserve my comments as a practicing physician. In the
emergency room, if I were to ask a patient what drugs they are on, in
all likelihood they would even forget to mention that they were on OTCs.
The reason for that is most consumers perceive OTCs as innocuous. They
are harmless. They are totally safe. Otherwise, they wouldn\'t be so
openly accessible.

They don\'t even bother to mention that. Now when we don\'t have the
physician oversight because of lack of prescription, in addition, based
on the 1992 report by the GAO office, we also find that the OTCs have
much less oversight from the FDA than prescription drugs.

So as we take a look at this whole issue from all the different
perspectives of a pharmacy manager, as an academician and a researcher,
as a health care policy adviser and as a practicing physician, I raise
the concerns that conversion to OTCs of major therapeutic classes will
have negative impact on patient care.

Access to commonly accepted first lines of therapy only on the basis of
ability to pay, which is what this really means, with no means really
for clinical monitoring nor intervention go against the very principle
of managing care, which is to promote access to the appropriate care for
the appropriate patient. Thank you.

MODERATOR DeLAP: Well, thank you very much. I think we did have some
discussion this morning about the ramifications of changing availability
and what that meant as far as adverse experience reporting.

I think that is an issue that we have to consider. The reporting, of
course, is quite different for an NDA kind of drug than for a drug
that\'s marketed under a monograph. And even when products are marketed
OTC under an NDA, I think we have to be secure that we are still getting
the adverse experience reporting that we need to get.

In that regard, your comment about having the claims data to try and
make associations and epistudies and that sort of thing is something
that, I guess, you lose if you go into the OTC setting, even with an NDA
drug.

Are there other comments or thoughts from the panel? Dr. Temple?

DR. TEMPLE: You made a number of points about how there were
disadvantages to self-care, that you can\'t monitor for interactions,
and you can\'t get a history of allergy and all the kinds of things.
That\'s certainly true, and you can imagine that we\'ve put those
elements into discussions of this.

One of the arguments that people have used strongly for the availability
of certain chronic medicines, notably antihypertensives or lipid
lowering drugs, is that the current system, for better or worse, fails
to treat a large fraction of people who need treatment. And while
recognizing the disadvantages you cite, they say that\'s worth \-- that
makes it all worth it, because so many more people could be treated this
way.

Do you have any response to that line of argument?

DR. CHAO: I guess I\'m a little puzzled in terms of that line of
argument. They would have a larger number of people because they would
have open access. Is that the argument?

DR. TEMPLE: I think the idea is that the promotion would be so
unbelievable that everybody would now know, whereas now the companies
are helpless and can\'t promote their products.

DR. CHAO: Well, I think that anyone who thinks the pharmaceutical
companies have been, you know, slouching in the area of directed
consumer marketing hasn\'t been watching TV very often, because in my
perception it doesn\'t seem to matter whether it\'s an over-the-counter
or a prescription drug in terms of the raising of awareness of the
consumers to particular drug classes and their benefits to those
consumers. However, I think as you raise the issue of access, I totally
am supporting access.

The question that I raise is the appropriate access and the monitoring
of that, because there is a perception, as I mentioned before, that with
the advertising people are looking at it in the same category of a
number of other consumer products where consumers can really choose at
will as to whatever they find sexy on the ads, that they would then go
and access those type of products.

You know, if drugs are innocuous, they wouldn\'t have any therapeutic
effects. If by having therapeutic effects they are not innocuous and,
therefore, really do have downsides as well as upsides, and I think
that, regardless of all of the things that we\'re talking about of
Internet and the patient education, patients are a long ways away from
knowing enough about this to be able to self-medicate appropriately as
to not create as much the downside as much as the upside.

In fact, as I showed in my data, even physicians who, hopefully, through
medical school and medical training would have more knowledge, we are
intervening in up to 15 percent of the time, because they are not able
to keep in their head all of the drug interactions.

To be able think that individual consumers accessing information ad lib,
whether it\'s on the Web or on TV or on radio, especially given that
OTCs are not as heavily regulated in their advertising as prescription
drugs, I think that we are really setting ourselves up for a major
disaster.

MODERATOR DeLAP: Well, thanks very much for your comments, and I guess
we can let you go and get your plane then, and we can \--

DR. CHAO: Thanks again, Dr. Wolfe. I think they are still awake.

MODERATOR DeLAP: We can hear from the long awaited Dr. Wolfe.

DR. WOLFE: We have been watching this process for 29 years or whatever
of the switching slowly of certain drugs from prescription to
over-the-counter status, and in many of the instances, such as the
analgesics, we have thought it was a good idea.

Really, only twice prior to now have we attempted to intervene to stop
switches, in one case a drug that had already been switched. In other
words, it was pending to be switched.

I will mention those in the context of some principles that we have used
over the years and will continue to use when we review possible switches
from prescription to over-the-counter status. I think that these are
principles that could be helpful to other people. They are principles
that, I\'m sure, a lot of other people have thought about as well.

The first is the ease or possibility of self-diagnosis, the presence or
absence of symptoms which can accurately make the diagnosis \-- pain,
itching, cold, allergy, and so forth. Related to this is the question of
self-diagnosis of other medical conditions which might counter-indicate
the use of the drug. That will come up, and I\'ll mention it briefly in
the case of the cholesterol lowering drugs.

An example where we intervened in a problem in this category was back in
the early Eighties, 1983, I think, where the FDA had decided to switch
from prescription to over-the-counter status an asthma drug,
metaproterenol, brand name Metapril, and we believed that this was
dangerous, because it is not possible for someone to accurately make the
diagnosis on their own of asthma.

My chief of medicine, Dr. Ramilkamp, taught us that all that wheezes is
not asthma. Someone who may be wheezing may have heart failure or, as
Dr. Chao mentioned, hypertension, and what may be good for treating
asthma may be fatal for treating someone who actually has heart failure
as the basis of their wheezing.

The second principle is self-limited or chronic condition. It\'s
related, in a way, to the first principle, because if you have a symptom
that you recognize, you treat it and it goes away. It\'s a self-limited
disease or, in some cases, you may have disease that may go away on its
own, such as a cold.

This is important in terms of the duration of treatment and the
evolution of both the change in the course of the disease and the
occurrences of adverse reactions or interactions which may requite
physician monitoring. A long term use such as for diabetes or
hypertension or cholesterol lowering is more likely to get into the
problem of interactions or adverse reactions than something you use for
a shorter period of time.

Third, benefit/risk ration and its evaluation: Because the continued
benefit/risk evaluation by the patient without any input from the
physician is troublesome in a number of areas, you may actually wind up
altering the ratio of benefit to risk. What might appear to be a good
ratio initially may turn out to be bad. The patient may not be aware of
the development of adverse effects or interactions and so forth.

So that this whole constant need to evaluate the benefit/risk ratio for
chronic diseases, which I believe a physician or a nurse practitioner
needs to be involved in, is something that, I think, for many of these
kinds of conditions is beyond what a patient can do.

Fourth, low potential for harm which may result from abuse under
conditions of widespread availability: This is a quote from the Code of
Federal Regulations that has to do with part of the definition of what
an over-the-counter drug is.

The abuse here does not mean drug abuse as in street abuse. It refers to
the kind of abuse that occurs when a patient generally believing that
over-the-counter drugs are safer than prescription ones \-- I think
that\'s something that\'s been well established and in general is true
\-- may say, quote, \"if one pill does so much good, two or three will
do even better; so I\'ll take more than one.\"

Despite the introduction of most OTC versions of drugs at doses lower
than the prescription form, this restriction can be easily overcome
because of the history of patients increasing their dose. Related to
this is the question of whether the potential for harm is such that the
use of the drug without the involvement of the physician or other
learned intermediary such as a pharmacist is not appropriate.

The switch of drugs with a low margin of safety, ones where doubling of
dose may significantly increase the toxicity, should be generally
opposed.

Fifth, number of adverse reactions of interactions and the ease of
detecting them: If there are numerous adverse reactions or interactions,
as Dr. Chao referred to, which may not be fully known to the patient or
the physician, there\'s even more cause for concern than the already
troublesome situation involving only prescription drugs, and in this
case the physician who is prescribing prescription drugs, but the
patient is possibly, unbeknownst to the physician, taking
over-the-counter drugs.

If the detection of the adverse reaction is hampered by the absence of
signs which the patient can detect, such as abnormal laboratory tests
which are an early signal of liver toxicity, the frequent absence of the
physician\'s involvement because the drug is available OTC may be
dangerous.

Six, long term data from prescription use to assess likelihood of
problems with OTC use: Needless to say, if the drug has been available
for a long time on a prescription basis, we\'re going to know more about
it, and drugs that have only been around for a few years, probably just
on that basis alone, should not be switched.

Seven, toxicity compared with other drugs in the class: If there are
other drugs in the class, how does the safety and benefit/risk ratio
compare to these? A good example of this was the rumors started by, I\'m
sure, partly the pharmaceutical company involved of the possible switch
of Pyroxycam or Feldene from prescription to over-the-counter status.

There is little question from a large number of case controlled studies
that the gastrointestinal toxicity with this drug is significantly more
than with Ibuprofen or with Naprosyn or with other already switched
analgesics or drugs for treating arthritis.

So that, even within a class where it may make sense to switch some
members, it doesn\'t make sense to switch others.

I\'m just going to finish the few minutes I have left with specific
concerns about switching cholesterol lowering drugs, partly in
anticipation of the hearing next month; but I will give much more detail
on why we are opposed then, but because I think that it\'s a good way of
looking at a number of the other classes.

We go back to some of these same principles: Ease or possibility of
self-diagnosis. Given that the indications for these drugs in the OTC
status would be a total cholesterol level between 200 and 240, an LDL of
over 130 milligrams per dl, and the absence of established
cardiovascular disease or diabetes, it is highly unlikely that this
combination of evidence plus other information that should be there will
be present before the OTC purchase of Mevacor or Prevacol.

Since the indication for these drugs varies as a function of other risk
factors, this overly simplified indication by total and LDL cholesterol
is, at the least, misleading. The National Cholesterol Education Program
guidelines state, for example, that those without established
cardiovascular disease or only one other risk factor, such as smoking or
hypertension, should start cholesterol lowering drugs only if their LDL
is over 190, not 130. Even with two other risk factors, the
recommendation is 160 or over.

This is in contrast to the company\'s proposed recommendations of
starting drugs for levels of over 130, as announced in the notice of the
July meeting.

In addition to the problem of accurate ascertainment of cholesterol
levels, the warning against use in people with established
cardiovascular disease or diabetes belies the fact that many people with
these diseases have not yet been diagnosed. Thus, self-diagnosis of
these conditions is not a reality unless the patient had previously had
a heart attack or angina or symptoms of diabetes that led to a
diagnosis.

Self-limited or chronic condition: Because of the implications of an
increased risk of cardiovascular disease associated with elevated
cholesterol levels, the use of these drugs could well be on a chronic
basis or forever. In addition to the need for a physician evaluation
initially, medical follow-up is also necessary for the detection of
either an evolution into cardiovascular disease and/or the occurrence of
adverse reactions or interactions with other drugs which may require
physician monitoring.

Finally on this issue, number of adverse drug reactions or interactions
and ease of detecting them: An additional problem with Mevacor and
Pravacol concerns the impossibility of self-diagnosis of an early sign
of liver toxicity, namely the presence of elevated liver enzymes in a
blood test.

At the earliest stages this is completely asymptomatic and can only be
detected with regular monitoring under the supervision of a physician or
other health professional such as a nurse practitioner. The current
physician labeling for Mevacor states, quote, \"Persistent increases to
more than three times the upper limit of normal in serum transaminases,
a liver function test, occur in 1.9 percent of adult patients who
receive Lovastatin for at least one year.\"

It goes on to say that usually, but not always, these go back to normal.
Because of this, labeling further states, quote, \"It is recommended
that liver function tests be performed before the initiation of
treatment, at six and 12 weeks after initiation of therapy or elevation
of dose, and periodically.\"

There is a similar warning on the labeling for Pravacol. The need for
this kind of surveillance is not consistent with a switch to OTC status
of these or any similar drugs.

Common to the concerns of switching cholesterol lowering drugs, diabetes
drugs and drugs for hypertension are many of the same kinds of concepts.
All are used to treat lab values, cholesterol, blood sugar, elevated
blood pressure, and diseases for which there are not necessarily any
symptoms and which are chronic conditions for which therapy will likely
have to continue for a very long time.

There is no way of titrating the dose of the drug without repeat tests
and evaluation of results. Medical check-ups are needed periodically for
determining if the drug is working and for assessing other aspects of
the disease progression or the evolution of adverse reactions.

For these reasons, we strongly oppose the switching of these drugs from
prescription to over-the-counter status.

MODERATOR DeLAP: Thank you, Dr. Wolfe. Do we have questions? Dr. Temple?

DR. TEMPLE: Actually, so let me ask you the same question. It\'s been
observed that a large fraction of people with hypertension are not
treated by the current system, however it is, and the similar phenomenon
exists for people with treatable lipid abnormalities, not people who
shouldn\'t be treated.

Do you have any sympathy for the idea that OTC availability would change
that in a favorable way?

DR. WOLFE: Well, two answers to that. First of all, there is little
question that our colleagues in medicine have not done as good a job as
they should in detecting a lot of these diseases and, when appropriate,
treating them and should not be left off the hook. And I think much more
needs to be done along those lines.

On the other hand, it is likely that the benefit/risk ratio for people
who are recruited through the massive advertising that you correctly
project if these things are switched is going to be much different and
not as favorable as for \-- not always, but in a number of instances,
there are people who are going to get recruited with some of these low
borderline values that are going to be getting a risk without any proven
benefit. Namely, the proven benefit of treating very low levels of
cholesterol or whatever else is just not there.

So I think that to essentially put a larger number of people at risk and
deprive them, in a way, of evaluation because many of them are going to
be doing this on themselves, I think, is a big public step \-- public
health step backwards. I think this is a wake-up call to really remedy
the situation within the confines of the health care system as opposed
to just making more things.

I mean, I would have some of the same answers to the dangerous
proliferation of herbal and dietary supplements which are being used to
treat some of these same conditions. I mean, we essentially have a lot
of people out there who have or may have chronic medical conditions, and
I think it is no more sensible to switch drugs that really need a proper
medical context from prescription to over-the-counter than it is to have
to labor, as we all do, under the confines of this regressive 1994 law
that puts all sorts of other things on the market for people who didn\'t
have a chance to go to their doctor. I think they are both dangerous
kinds of moves.

MODERATOR DeLAP: Dr. Murphy?

DR. MURPHY: Dr. Wolfe, since no one wants to put FDA in charge of
reforming the health care system, and we have heard that \--

DR. WOLFE: I am in that group.

DR. MURPHY: I know. \-- and we understand that that may be part of some
of the concerns here, in your discussion would it make any difference if
there was a third process, as was discussed this morning, both pros and
cons, of the pharmacist interaction after some initial requirement of a
physician visit?

DR. WOLFE: I have spoken a number of times about the so called third
class of drugs. This country is in the minority, the distinct minority,
as opposed to majority in terms of not having this kind of availability.
This is an extra intervention of a learned intermediary, pharmacists in
this case.

I think that that might help for some of these switches. I\'m not sure
that, for the issue of hypertension or diabetes or cholesterol, that
would be appropriate. But certainly as a third alternative between
prescription and over-the-counter status for some kinds of drugs, I
think that might make sense.

It certainly worked out well in a number of countries where it\'s been
tried. I attended probably six years ago, seven years ago, an
international meeting in Washington where representatives from a number
of countries that had already used the third class of drugs talked about
how effective it had been and so forth.

So I think the idea is good. I think, again, on a case by case basis it
might be applicable to some of these classes of drugs. It might not be
to others.

MODERATOR DeLAP: Dr. Jenkins?

DR. JENKINS: One of the questions we asked for feedback for in the
[Federal]{.underline} [Register]{.underline} notice was about what role
the agency should take in initiating switches in situations where the
sponsors have not initiated such a switch.

Can you give some thoughts about how you would feel about that in the
context of diseases or classes of drugs that are already recognized as
over-the-counter appropriate drugs \-- for example, treatment of
allergies, antihistamines, decongestants, etcetera? What would be your
thoughts?

DR. WOLFE: Well, the image of the pharmaceutical industry kicking and
screaming to prevent a drug from being switched from prescription to
over-the-counter status is an amusing image, because one of the cases
that\'s been presented is one where the company doesn\'t want it
switched, but the insurer \-- the insurance industry does, because it
will relieve them of having to pay bills for prescription drugs and dump
the cost onto patients.

So the motivation is important. I think, though, in the context of
over-the-counter switches by antihistamines, there was a time when
serious consideration was being given to switching terfenadine or
Seldane to over-the-counter, same with Hismanol, and I think that the
principle of waiting a significant amount of time \-- I would argue ten
years after a drug has been on the market \-- so that the chance of
surprises is lower as opposed to higher, would be important.

I mean, I remember \-- this is probably 30 years ago, whatever \-- when
chlorfeneuramine maleate, a drug I used to use and still use to treat
people with allergies because you can use a much, much lower dose, get
rid of the sedation for at least a number of people. Physicians these
days don\'t bother doing that, because they\'ve got all these other
\"non-sedating\" drugs around.

I think that the idea of waiting long enough so that you are relatively
sure that there\'s not going to be any problem and then doing it does
make some sense. I mean, in other respects \-- allergy, because it is
capable of self-diagnosis \-- it is relatively short treatment for at
least a lot of people. There aren\'t a lot of people who are taking
these drugs around the year.

So I think that makes sense. I don\'t know legally what one can do with
a drug that is still on patent to force a company to make an
over-the-counter switch. They have legal liability and things like that.
I think it\'s an interesting issue to look into.

MODERATOR DeLAP: Other questions for Dr. Wolfe? If not, thank you very
much.

We\'ll move on to PEGUS Research, Dr. David Bradford.

DR. BRADFORD: Good afternoon. The colleague stumbling for the on/off
switch here is the President of our esteemed company, Dave McCammon. I
might mention that, contrary to what you may think, the main goal of
PEGUS Research is not the hiring of researchers named Dave.

More germane to the point of the discussion today, PEGUS Research is a
pharmaco-epidemiology research group that\'s been involved in a number
of OTC switch studies. My purpose here today will be to discuss some of
the design considerations that we take into account in those trials in
suggesting some alterations in the strategy that the FDA uses for
considering the suitability of a drug for an OTC switch.

Let me start by making my key point, which is that it is my belief that
the interests of public health are better served by at least
supplementing, if not, more ambitiously, supplanting entirely the time
and extent of use criterion for assessing safety with data from
appropriately designed active safety trials.

Let me start by making a few assumptions explicit, at least for today\'s
discussion. For this discussion, which assumes that the key question in
an OTC switch is safety, I will assume that, first of all, standard
comparative trials have already demonstrated efficacy for the switch
candidate in the proposed OTC dose for the proposed OTC indications;
secondly, that the safety of the drug in prescription use has already
been well characterized.

This is actually not a necessary assumption, but for simplification of
today\'s discussion, I propose that as a second assumption.

Finally, that the basic question in an OTC switch that must be answered
is the question of whether removing physician involvement in the drug
use process, which involves diagnosis in some form, prescription of the
drug, and monitoring drug use and outcome, results in an unacceptable
increase in public health risk.

Implicit in this question is the issue of comparative risk of OTC use
versus prescription use. If indeed the issue of comparative risk is
fundamental to the switch decision, a method for determining risk under
OTC conditions is required. However, the time and extent of use
criterion that has traditionally been employed relies heavily on various
kinds of passive surveillance such as MedWatch and reports in the
medical literature which are not particularly useful nor ever really
intended for estimating risk.

Here are some of the main reasons why. First of all, the numerator in
this proposed risk estimate using passive surveillance sources is
significantly flawed. There are almost certainly biases in the data of
unknown extent and type resulting from the fact that it is voluntary
reporting and that the voluntary reporting comes from a wide variety of
sources, and there is almost certainly considerable underreporting,
although the degree of underreporting is, of course, not well known.

Therefore, the data which form these rate estimates, the numerator for a
rate estimate, are inadequate. So we have a bad numerator. We have an
almost nonexistent denominator as point number two.

The most usual substitute for a use denominator is sales figures, but
there is essentially no information available about the amount or
conditions of use for the persons for whom an adverse event is reported.

Thirdly, the amount of information is quite severely restricted in these
passive surveillance systems, and there is almost no capacity to query
the data to find out more about the relationship between the use of the
drug and the reported adverse drug event.

Finally, the data that are collected in these systems are cases of
prescription rather than OTC use and, given the very substantial
difference in the nature of the usage patterns between prescription and
OTC use, that difference turns out to be a potentially very significant
one.

So in summary of this section then, while passive surveillance is a cost
effective means of detecting the possibility of very rare adverse
events, its epidemiologic shortcomings are of such a fundamental nature
that simply accumulating more data in the system fails to increase the
value of the information for assessing either adverse event rates or the
nature of the causal connection between drug use and the adverse event.

Where passive surveillance then fails, active surveillance can succeed
very well, provided it is designed correctly. I will next sketch the
research design principles which I believe will produce the best data to
answer the switch question that I outlined earlier.

The overarching principle is that subjects should be evaluated in a
setting that\'s as similar to the actual conditions of OTC use as
possible. Points 2 through 8 really are just elaborations,
particularizations of this broad general principle.

First of all, subjects should self-select into the trial, and if the
trial is designed to have an active comparator, subjects should be
allowed to self-select into the treatment arm of their own choice.

Thirdly, it should be an all-comer study. That is, all subjects who
self-select into the trial should be allowed to participate.

Next, the study must be an open-label study to reflect the patterns of
use and selection and decisions about use that take place when a
consumer makes the decision to use an OTC drug.

Assessment of drug use and outcome, which is not \-- should be
unobtrusive. This is not a particularly big problem in standard
randomized blinded trials, but in these kinds of trials it\'s important
that the measurement of the process doesn\'t influence the process
itself.

The sixth point is that the studies should be relatively large. We
propose that they should be able to detect roughly one order of
magnitude more sensitively the occurrence of rare adverse events, and we
suggest somewhere on the order of one in a thousand to three in 10,000.

Point number seven is that subject recruitment and enrollment procedures
should be as simple and realistic as possible to produce a sample that
is truly representative of OTC subjects.

Finally, recruitment and enrollment should be done in sites where people
go to obtain their OTC medications, a point which has been raised in
earlier discussions today.

Let me just add a note in passing about randomized blinded trials. These
studies, of course, are the sine qua non of efficacy evaluation. We
don\'t have anything better nor is there anything better likely to
emerge. However, they are the wrong tool for assessing safety in actual
use, especially OTC use, as they impose constraints on the subject
sample and conditions of use which are entirely uncharacteristic of the
self-selection and use patterns consumers engage in who seek OTC
treatment.

In summary then, let me conclude with these points. Properly designed
safety trials can provide important information which is directly
relevant to this fundamental question of drug safety in OTC use.

Active surveillance studies can provide true adverse event rate
estimates relatively quickly. Therefore, decisions about a potential
switch can be made much more quickly and efficiently and with greater
accuracy.

Finally, active surveillance may be particularly useful for drugs that
have a relatively low prescription use rate where it would require a
large amount of time for data to accumulate in a passive surveillance
systems for those that are being proposed for a direct-to-OTC sale and
for those that are on a fast track for OTC approval.

So in conclusion, I believe that OTC switches based on properly
designed, active surveillance studies will provide better switch
decisions in a more timely fashion than can be done using the data from
passive surveillance.

That concludes my presentation. Thank you.

MODERATOR DeLAP: Dr. Woodcock?

DR. WOODCOCK: I just want to make sure I understand your ideas. The
study design you outlined, it seemed, would be useful for determining if
inappropriate people self-select, if people are incapable of diagnosing
their condition, if people are failing to seek medical care for
deterioration of their self-diagnosed condition.

Are those the type of adverse events you are talking about? Are you
actually talking about the known kind of adverse events?

DR. BRADFORD: Actually, both of those are very easily handled in this
kind of design. Data are collected about the nature of the enrollment
population, including those who are presented with a decision about
enrollment and then choose not to participate in the trial. That is, to
not use the drug. But these trials also include specific methods of
following up on use and outcome in order to find out what the
consequences of use were and to correlate that with the way the drug was
used.

DR. WOODCOCK: Are you contemplating there\'s something \-- Is that what
you\'re calling active surveillance or are you calling active
surveillance a wide variety of things of which that was an example?

DR. BRADFORD: I\'m just contrasting active surveillance with the sort of
passive surveillance that comes as a consequence of data accumulating in
a spontaneous reporting system.

DR. WOODCOCK: Okay. Thanks.

MODERATOR DeLAP: Dr. Temple?

DR. TEMPLE: It would actually be helpful if you could indicate without
giving anything away an example of where you would use this and what
kinds of things you would be looking for.

I ask that, because my worry would be that in selecting one of a class
of drugs, people might select differently, depending on their past
history, and you might be misled. Just for example, if you wanted to
compare a sedating and a non-sedating antihistamine, people who have
trouble with sedation probably would choose one, and people who didn\'t
might choose the other, and they might be fundamentally different with
respect to their likelihood of having car wrecks and stuff like that \--
you know, all the problems that come up when you don\'t randomize.

So the other reason I ask is that even a good sized study of 20,000
would be detecting sort of relatively common risks, not the sort of odd,
bad torsade de pointe or something like that.

So when \-- Can you say a little more precisely when you might use this?

DR. BRADFORD: Sure. The usual constraints that are \-- The cost
constraints that are associated with studies of this type would probably
limit them to 20,000 or less, although certainly there are instances of
studies that go up into the 40-80,000 range. Those indeed will detect
probably at best something on the order of one in 10,000, which is a
pretty reasonable goal for a study like this to accomplish.

If I understand the other part of your question, it has to do with the
nature of the actual process of evaluation itself. I think it would not
inappropriate to mention our experience in the assessment in the safety
of Denavir, which was considered by the Advisory Committee some months
ago.

One of the interesting things about that trial was that, although the
demographic profile of subjects was quite different from the population
demographics, it matched almost identically the information that was
obtained about cold sore sufferers themselves.

So we were able, on the basis of the enrollment criteria that we used,
to gather a sample that looked like it was very representative of the
potential target population.

Now with respect to the question of sedating versus non-sedating
antihistamines, one of the crucial elements of that is how do people
self-select? So one of the possibilities in a trial of this kind where
you allow people to self-select and the conditions is determining what
it is that \-- how those populations differ from each other, what the
characteristics of each population is.

DR. TEMPLE: Okay. I\'m still a little \-- I understand you\'re sort of
making sure everybody reports actively, so you get a complete
enumeration of everything that happened to them. I guess that\'s more
important than the comparative aspect of it.

DR. BRADFORD: Yes. The safety assessment, we would argue, is
fundamentally a noncomparative kind of activity.

MODERATOR DeLAP: Dr. Jenkins.

DR. JENKINS: This is a very interesting study design that you proposed.
As you know, the devil is always in the details. I was interested in
your item number 3 where you say that all subjects who self-select into
the trial should be allowed to participate.

Can you comment on how you would actually deal with someone who
self-selects who is clearly, obviously contraindicated for use of the
drug, say a woman who is obviously pregnant self-selects to use the drug
even though the drug label says not to use if you are pregnant. Would
you still enroll that patient into the study, and how do you deal with
the ethics of that?

DR. BRADFORD: Yes. Our argument is that any drug that is being proposed
for a true OTC switch \-- that is, an OTC switch in the environment that
we operate in here in the U.S. \-- for whom there is no learned
intermediary to, in fact, intervene needs to be allowed into the trial,
because under OTC conditions that person would be able to purchase the
project, even in spite of recommendations against its purchase.

So one of the issues that\'s important to understand is, when they
self-select into the trial, do they in fact actually use the drug. Under
what circumstances do they use it, and what is the outcome of use for
those subjects who would be free to use it if, in fact, it were approved
for OTC sale.

Now there may be some intermediate studies that need to be done if the
safety of the drug is still in question, but for most of these drugs the
safety issues have been reasonably well resolved, at least to the point
of being able to make the case for an OTC switch.

DR. JENKINS: Can you clarify if what you just described is a
hypothetical or have you actually applied that to a study situation?
I\'m just thinking that most people would have ethical concerns with
that type of study design, and I\'m thinking that most sponsors would
have serious liability concerns about enrolling patients into such
trials.

DR. BRADFORD: Well, it is important to make sure that these are
adequately reviewed by ethics committees and also approved by the FDA.
But it seems to me that the FDA is in much better decision to make a
decision about the suitability of a switch if they have that kind of
information available to them.

So rather than taking a drug to market for which there is no data of
that sort available at all, it seems like a very sensible thing for the
agency to require that kind of information.

DR. JENKINS: Do you have experience actually applying this model in a
successful trial?

DR. BRADFORD: We have had the experience in two of about six trials. In
the other instances, some of these considerations have prevented the
sponsor from wanting to continue in that regard.

We would encourage the FDA to consider the need to have that kind of
information, though, available.

MODERATOR DeLAP: Well, it\'s been a conundrum, I think, for the agency
over the years. How do you know about things like safety of use in
pregnancy, which you know happens for these products that are in the OTC
marketplace. How do you know that, if you don\'t study it, and yet how
do you study it?

So it\'s a real puzzle, and I\'m always interested in different views on
the subject.

If there are no other questions, we\'ll continue. Thank you very much.
Next we have Amy Alhna for the National Women\'s Health Network.

MS. ALHNA: Thank you. I\'m speaking today on behalf of the National
Women\'s Health Network, which is a nonprofit women\'s health advocacy
organization. We are supported by more than 10,000 individual and 300
organizational members, and we accept no financial support from
pharmaceutical companies or medical device manufacturers.

In the 25 years since the Network was founded, we have spoken at a
number of FDA meetings that have been called to consider whether
specific drugs should be made available over-the-counter, and sometimes
we\'ve supported the shift, and sometimes we have opposed it.

Just as we know the agency is striving for a consistent set of standards
to use in making these determinations, we have also tried to be
consistent in the positions that we have taken.

My comments today will address a number of specific types of products,
as well as some of the more general issues relating to consumer
understanding and to the structure of the regulatory system. I\'m going
to start with talking about the specific products.

The Network is strongly committed to the development of topical
microbicides which women will be able to use to protect themselves
against STD and HIV infection. We believe that, in order for microbicide
products to be used widely and effectively, there will have to be some
that are available without prescription.

There\'s currently a range of products in development, some of which are
likely to be appropriate for over-the-counter distribution, and others
may need to start as prescription products. While the safety standard
for OTC distribution should not vary from product to product, some
microbicides will be able to meet that standard more easily and/or more
quickly than others.

Those products which have already been approved for other uses and,
therefore, have an established safety record are likely to be able to
demonstrate sufficient safety for OTC distribution more easily than
products which are entirely new. Based on our understanding of the
microbicides in development, we are suggesting that the FDA might
consider these products in four tiers: First, products with an
established safety record in vaginal or rectal use, which is the area
where they will be used; second, products with an established safety
record in contact with other mucosal tissue; and third, products with an
established safety record in topical use on non-mucosal tissue; finally,
new chemical entities that don\'t have an established safety record.

I know that you will hear more about each of the products that I\'m
going to talk about tomorrow. So I\'m going to keep my comments brief.

The second product I want to talk about is oral contraceptive pills.
While the Network would like to see more OTC contraceptive options made
available to women, we oppose the OTC distribution of oral contraceptive
pills for continuing, regular contraception.

We believe that prescription status for regular oral contraceptives is
necessary to maintain effective use of this method and to protect the
health of women who choose to use it. Experience in Sweden and other
countries has demonstrated that when the pill is distributed with no
counseling and no opportunity for dialogue about the method, effective
use declines.

In addition, we have concerns about the health impact of OTC
distribution of the pill without a prescription requirement. There will
be no opportunity for a health care provider to screen out users who
should not be taking the pill over the long term, and the opportunity
for preventive health care and disease detection will be lost, which is
a particular concern when it comes to women of color and to low income
women who are already likely to have decreased access to such health
services.

If a third alternative between the current prescription status and OTC
distribution were available in the United States such as distribution by
pharmacists from behind the counter, the Network would support
distribution of oral contraceptives in that way. In the interest of
time, I should just say here that we support the establishment of such
an alternative.

The final product I want to talk about is emergency contraceptive pills,
\"morning after\" pills. It\'s already been mentioned a couple of times
today. The Network believes that the medical and economic issues raised
by emergency contraceptive pills are different from those associated
with the ongoing use of oral contraceptives.

Recognizing that there are communities where even pharmacist
distribution will not resolve the barriers that currently prevent women
from having timely access to the method, the Network would support
over-the-counter distribution of emergency contraceptive pills under the
following conditions.

We believe there must be appropriate label warnings to protect the
health of women with contraindications to the use of emergency
contraceptive pills. We would like to see there continuing to be a
prescription option to ensure that OTC availability doesn\'t raise new
barriers to access for those women who do have insurance coverage of
prescription contraceptive options, and finally that, as with any other
OTC product, women have to have access to clear, complete and accurate
information about the product.

Package inserts for emergency contraception products should be available
in multiple languages, should employ techniques for women who cannot
read such as using pictorial representations as appropriate.

Now I\'m going to move on to talking about consumer understanding. One
of the underlying principles that guides the Network\'s work is that
informed consumers can make good health care decisions for themselves.
The definition of an informed consumer, however, is critically important
to the realization of this principle.

We need to trust people with complete information rather than
withholding details that commercial sponsors or health care
professionals may fear will complicate or bias the consumer\'s decision.
The FDA needs to ensure that consumers have access to unbiased
information about the products that the agency regulates. Here, I think
it\'s especially important to say that advertisements paid for by
commercial sponsors which are designed to sell a product are not
adequate information sources for consumers.

The need to ensure consumer access to unbiased and complete information
is greatest where the advertising campaigns are the most intense and the
budgets highest. That is in the area of OTC drug products, although
direct consumer advertising of prescription products is certainly making
a run for it.

The only source of information that the vast majority of consumers have
about a drug other than an advertisement is the information that\'s
included on or in the product package. The information on the product
label and in the patient package inserts must be carefully reviewed and
assessed by the FDA to determine that it\'s complete, accurate, and
easily understood by potential users of the product.

The Network supports the use of a standardized label format for OTC
products with consistent categories and placement to make it easier for
consumers to find the important information on a product label, and to
make it possible for consumers to learn how to find the information they
need easily.

One of the specific questions the FDA raised in this context of consumer
understanding in the notice for the hearing is whether a prevention
claim can encourage ill advised behavior.

Taken in the context of microbicides, for example, we understand the
agency to be asking whether the availability of products that claim to
prevent or reduce the risk of transmission of sexually transmitted
disease will lead to an increased willingness on the part of consumers
to risk exposure to disease.

The Network feels strongly that a product which offers partial
protection and does not entirely eliminate risk can be used safely, as
long as clear information about risk and protection is conveyed to the
consumer. In fact, in the field of contraception there are research
models which demonstrate that a less efficacious product used more
consistently can actually increase the level of infective protection.

Products which are easier to use consistently than condoms, such as
microbicides, therefore, may actually be more effective in preventing
the spread of STDs, even if they have a lower theoretical efficacy rate
than condoms.

Furthermore, we believe that this question reflects a tendency in this
country to equate morality with health. We believe the association is
inappropriate and unfounded. There is no scientifically valid evidence
that prevention claims lead to increased risky behavior, much less to an
increased incidence of disease.

The Network feels strongly that, if clear information can be conveyed to
consumers regarding a product which offers partial protection and does
not entirely eliminate risk, then consumers can make responsible and
informed decisions about their behavior based on that information.

Thank you again for the opportunity to speak today and to provide you
with our comments. I\'ll take questions, if there are any.

MODERATOR DeLAP: Thank you. Well, it looks like you did a very good job
of covering all the bases.

MS. ALHNA: Thanks.

MODERATOR DeLAP: Thank you. Our next speaker will be representing the
Pharmaceutical Research and Manufacturers of America, Russell Bantham,
Deputy General Counsel.

MR. BANTHAM: Thank you, Dr. DeLap. My name is Russ Bantham. I\'m General
Counsel for the Pharmaceutical Research and Manufacturers of America.
PhRMA represents the country\'s leading research based pharmaceutical
and biotechnology companies which are devoted to inventing medicines
that allow patients to lead longer, healthier and more productive lives.

Our members this year will invest over \$26 billion in research and
development. With the announcement earlier this week regarding the human
genome project, that \$26 billion investment is even more important.

Prescription drugs discovered and developed by PhRMA members are the
source of virtually all major new OTC products today. PhRMA, therefore,
has a vital interest in the subjects being considered by FDA today at
this hearing. I will focus my testimony on the matters of greatest
interest to PhRMA and will file more detailed post-hearing comments in
accordance with the notice.

The principal issues that I want to address today concern the role of
the sponsor in initiating an Rx to OTC switch and the criteria to be
applied by FDA in reviewing switch applications.

The questions presented in the hearing notice suggest that FDA is
considering whether it may decide to switch a drug from prescription to
nonprescription status without the participation or even over the
objection of the holder of the approved NDA for the drug for
prescription use.

In our view, this would be both unlawful and contrary to the goal of
protecting public health. Under our regulatory system FDA reviews
applications submitted by sponsors for uses they have presented in their
proposed labeling. It\'s not within the FDA\'s authority to force a
manufacturer fundamentally to change the conditions of use of its
product from prescription to nonprescription status.

The switch of a drug would alter the terms of an approved NDA for a
prescription drug by removing the Rx legend and changing the labeling
from a physician package insert to consumer oriented directions. Under
Section 505(e) of the Food, Drug and Cosmetic Act, FDA cannot make such
changes over the objection of the sponsor without following the notice
and hearing process that protects the rights of the NDA holder.

FDA cannot use rulemaking to circumvent this process. There is a
procedure in 503(b) of the Act which has been referenced earlier dating
back to 1951 for the issuance of so called switch regulations, but as
also was mentioned, this process hasn\'t been used since 1971 before the
institution of the OTC drug review and before the Hatch-Waxman
amendments in 1984.

The switch regulation procedure was never used, and certainly can\'t be
used over the objection of a sponsor, to avoid the sponsor\'s hearing
rights under 505(e). As a matter of both administrative law and
procedural due process, FDA could not switch a drug through informal
rulemaking without the consent of the holder of the approved NDA that
would be changed through the switch.

Forced switches would also violate a sponsor\'s proprietary rights and
their own safety and efficacy data. Any switch will be based in
substantial part on the demonstrated safety and effectiveness of the
underlying prescription drug.

The full reports of studies that provide proof of safety and substantial
evidence of effectiveness reside in the sponsor\'s NDA. They cannot be
relied on by the agency to support regulations or approvals that would
allow anyone else to manufacture and sell the drug for either
prescription or nonprescription use except to the limited extent
provided by the Hatch-Waxman amendments.

The current system under which switches are initiated by NDA sponsors
through the submission of new applications or supplements serves the
public health well. Extensive prescription use, as Dr. Wolfe noted, is
an essential part of the full characterization of a drug\'s clinical
profile.

Moreover, manufacturers have the most comprehensive and detailed
knowledge of their drugs, including information bearing on whether a
drug is a suitable switch candidate. Taking all of this information into
account, manufacturers are in the best position to decide when to begin
the switch process and thereby avoid premature switches that could put
some members of the public at risk.

In addition to poorly serving consumers, a forced switch approach would
unfairly force manufacturers to bear product liability risks associated
with OTC use, even if they believe that a drug should remain available
only by prescription.

The manufacturers are also in the best position to invest in developing
the additional data needed to support a switch. Any switch today
requires extensive data in addition to what\'s in the NDA for
prescription use.

Switches proposed on the basis of conclusory assertions by third parties
that are not privy to all of the data on the drug and who are unwilling
or unable to fund the necessary studies to support the switch should be
summarily rejected.

Several of the questions in the hearing notice concern the criteria to
be used by FDA in evaluating applications to switch drugs from
prescription to nonprescription status. We believe that FDA should apply
the same approach to these applications that it does to any other NDA.
That is to evaluate each switch application on the individual merits
based on the statutory criteria of safety, effectiveness and proper
labeling.

Thus, for example, nothing in the Act authorizes FDA to declare an
indication or a disease state to be exclusively prescription or
nonprescription. The question must be addressed in the context of each
drug intended to treat or prevent the disease based on its particular
risk/benefit profile and labeling.

There is nothing at all incongruous about the simultaneous availability
of both prescription and nonprescription drugs for the same conditions.
This is true today across a wide variety of disease states. Moreover, it
promotes sound public health policy by providing consumers the options
of both self-treatment, where that is appropriate, and consultation with
a physician and treatment with a prescription drug, where that is
appropriate.

It wouldn\'t make sense to declare a disease off limits to prescription
drug therapy and thereby discourage both consumers from consulting with
their physicians and manufacturers from investing in the development of
new products.

As another example, any suggestion that FDA take into account the
relative economics of prescription and nonprescription distribution must
be rejected. FDA\'s relevant statutory authority relates exclusively to
drug safety, effectiveness and labeling. The agency has no authority to
consider prices or related matters as part of the approval process.

FDA certainly should not allow its agenda to be dictated by insurers
that are motivated to request switches in order to shift costs from
their own prescription drug benefit programs onto consumers. Any change
in policy to allow FDA or third parties to initiate switches would
unnecessarily encumber the drug development process, chilling many areas
of research and development and complicating the already difficult
considerations that underlie the decision to proceed with drug
development.

In conclusion, we commend FDA for holding this hearing on this important
subject of Rx to OTC switches and other aspects of nonprescription drug
regulation. FDA should retain its existing policy of making switch
decisions through the evaluation of NDAs and supplements filed by
manufacturers, based on an individual assessment of the safety and
effectiveness data and proposed labeling for each specific switch
candidate.

This is the approach \-- This approach is the one that FDA must follow
in accordance with the law. It also protects and ensures the safety of
consumers.

Consumers should have the widest possible array of treatment options,
both prescription and OTC, in an environment that is conducive to
investment in drug research and development, because only through
continued research and development will consumers have more treatment
options, both prescription and OTC, in the future. Thank you very much.

MODERATOR DeLAP: Thank you. Dr. Woodcock.

DR. WOODCOCK: Yes. I would like to comment and then ask you a question,
because I\'ve heard a recurring theme that people feel we are asking
should we be making relative \-- comparative, I guess, decisions, and
it\'s been pointed out numerous times during the course of today, we
don\'t have the authority to do that.

I would like to point out that the concept of safety \-- It has also
been pointed out that, really, no pharmaceutical is absolutely safe.
There is no absolute safety of an active drug. Therefore, concept of
safety for a drug is really a contextual one. It depends on the context.

For example, products that were considered safe in 1900 would be
considered, many of them, to have terrible side effects and be
unacceptable as treatments today in the year 2000. Therefore, the
concept of safety has some contextual quality to it, and it can\'t be
\-- It\'s not a stand-alone assessment, in my opinion. I\'d like you to
comment on that.

MR. BANTHAM: I agree with that, but I think that\'s FDA\'s most
important job, to do that balancing of risk and benefit.

DR. WOODCOCK: Okay. But part of that context then for any pharmaceutical
does have to do with the available armamentarium, not just drugs but
other treatments. Therefore, arsenic which used to be used for certain
treatments really wouldn\'t be acceptable nowadays. You see what I mean?

MR. BANTHAM: I do.

DR. WOODCOCK: Okay. Just so that\'s clear to everyone, we are not really
saying, oh, you\'re going to compare all these drugs, you know, their
effectiveness, to one another and so forth and so on. There is a context
in which drugs are made available, and we all hope through research and
development that, as time progresses, the armamentarium will become
overall safer for everyone.

MR. BANTHAM: That\'s correct.

MODERATOR DeLAP: The thing I like to say is that we like consumers to
have choices about drugs, but we want to make sure those are good
choices. There is no point in having a drug out there if it\'s outlived
its usefulness.

For example \-- I\'m not speaking in the context of any particular drug
or class right now, but as the years go by and as we get better drugs
that do a little better job and effectiveness and may be safer, there
may be times that come when there is a drug that\'s outlived its
usefulness, and we\'ll have to say there is no good reason that a
consumer should choose this drug. So why do we offer it as a choice in
the marketplace?

Dr. Temple?

DR. TEMPLE: I think someone answered that before. If a drug has outlived
its usefulness and is too toxic, whether it\'s Rx or OTC, we would
follow the usual procedures and get rid of it.

I guess I want to probe a little further the idea that we should have
little to no role in suggesting that certain drugs might be usefully
available over-the-counter.

Dr. Wolfe suggested it takes ten years. That would be one answer. I
think we thought three or four is usually enough, and I guess a usual
answer we get is about one year before the drug goes off patent. Now
these are various ways of making that decision, and apart from the
question of what process we would have to follow if we wanted to do that
\-- and I guess I also want to note that I don\'t know anybody who ever
contemplated taking one of these making a monograph drug. I think we
were talking of \-- In our wildest dreams, we\'ve been thinking of
asking for a supplement, you know.

How far do you want to push this? Don\'t you think it\'s worth
discussing whether something now prescription might have an advantage or
might also need to be available, along with other drugs that are
available in the OTC market?

To say no seems to sort of fly in the face of some of the arguments
about why it would be so good to have, say, lipid lowering drugs
over-the-counter. That\'s an argument about what should be widely
available so people can use it. You can make the same argument in
reverse for drugs that lack certain side effects that other OTC drugs
have.

How far are you pushing that or are you just wanting to say the company
should be involved; we shouldn\'t be high-handed?

MR. BANTHAM: No, but I think the difficult is answering the question in
the abstract. You can have an interesting philosophical discussion, when
is the appropriate time, and people have different views, depending on
their personal opinions or wherever they are coming from in the health
care system.

I think that\'s why you have to take it drug by drug and look at the
weight of the evidence and using FDA\'s traditional benefit/risk
calculus, they are in the best position to make that judgment.

The real question is who initiates the process. It seems to me, you just
can\'t have a process that\'s totally open. The system that we have is
the system where the sponsor initiates the switch process. That seems to
us to be the best system. It\'s working.

There isn\'t a real reason to change that, and there are a lot of good
reasons why that system that we have that\'s embodied in the law is one
that should continue.

There are, obviously, people who have different points of view, and
forums like this are opportunities to get those points of view out. But
when you get down to making judgments, it\'s really difficult to
generalize. You really have to \-- You can\'t look category by category,
because within categories there are different drugs that have different
safety and effectiveness profiles.

The process allows for the petition to be filed, the data supporting
that, the labeling supporting that. FDA then goes through the review
process and makes a judgment on behalf of the public, and that system
seems to be a very good one.

DR. TEMPLE: Well, I mean, from time to time we\'ve suggested to
companies that it was time for an efficacy supplement for something or
other, because we were aware of a cooperative group study or something
like that, and the company wasn\'t doing anything.

In fact, we\'ve sort of promised to do that in some settings when we
were aware of uses that were off-label and that seemed to have good
support. Isn\'t this sort of like that, that if we were aware of a
potential useful switch, would it be unreasonable to ask the company if
they were interested? I mean, you don\'t object to that? You just don\'t
want us to be able to force it.

MR. BANTHAM: No, not at all. Through discussion, companies may make
decisions \--

DR. TEMPLE: Come around.

MR. BANTHAM: \-- based on the merits. I\'m sorry. I didn\'t hear your
comment.

DR. TEMPLE: I said come around. That\'s our informal way.

MR. BANTHAM: That happens, too.

MODERATOR DeLAP: Yes, Dave Fox.

MR. FOX: In your view, what\'s the status of Section 503(b)(3) of the
Act, the provision that authorizes the agency by regulation to remove a
prescription restriction on a new drug if it\'s in the public interest
to do so, if it\'s consistent with public health?

MR. BANTHAM: I think that\'s an interpretation. I don\'t think the words
actually say that.

MR. FOX: The provision I\'m referring to is \--

MR. BANTHAM: You mean the switch provision?

MR. FOX: The switch regulation, yes.

MR. BANTHAM: Yes. It\'s not used. I mean, it\'s there.

MR. FOX: But I was just going back to your remarks. I\'m trying to
figure out whether you think it\'s legally a dead letter somehow as a
result of the initiation of the OTC review and somehow as a result of
Hatch-Waxman, or do you think it\'s just unused but legally viable?

MR. BANTHAM: It exists in the law, but there\'s no procedure. There\'s
no \-- There\'s just nothing there that I understand. I mean,
theoretically, something could be, I suppose, fit within those words to
make that an operative section, but there isn\'t one now.

As someone said, it\'s an antique.

MR. FOX: Museum piece.

MR. BANTHAM: It\'s just not used.

MR. FOX: I\'m just trying to understand.

MR. BANTHAM: It\'s clearly there and provided for. It\'s just a mystery
what \--

MR. FOX: And there are regulations that implement it that still exist as
well. So I mean, there\'s a disconnect, I think, between that \-- We
have this extra provision. We have the regulations as to what more
process or regulation we would need to carry out what\'s contemplated
under 503(b)(3).

MR. BANTHAM: I don\'t have an answer, because I would be just
speculating.

MODERATOR DeLAP: Charlie.

DR. GANLEY: Yes. I just want to go back to two of your comments. One is
that the agency has no authority to consider prices or related matters
as part of the approval process. I think, generally, we follow that.

The other concept, that manufacturers are in the best position to decide
when to begin the switch process and thereby avoid premature switches
that could put some members of the public at risk.

I guess the question that, if the FDA is looking at a particular product
and views that it would be in the public interest to have it in the OTC
market, why shouldn\'t we initiate some process to do that?

I mean, we are going through various phases here with accepting foreign
ingredients in the future that have absolutely no marketing experience.
They have OTC marketing experience in other countries. Yet we have
products in this country that are marketed Rx that are in OTC markets in
other parts of the world.

So why is it the company that is the only one who is to make the cut
here?

MR. BANTHAM: Well, I think, if FDA wants to initiate that and the
manufacturer or sponsor is agreeable, I don\'t see any problem. I think
we\'re worried about the situation where there isn\'t agreement, for
reasons that I\'m not sure, whether they are based on safety, whether
they are based on a concern over whether OTC use is appropriate.
There\'s been enough time or enough experience with the prescription use
to satisfy the safety requirements, and the sponsor did not agree with
the suggestion. Then there is a concern.

My comments really went to that.

MODERATOR DeLAP: I think the people that write the laws made a lot of
effort to try and have the incentives match up with the public health
goals of regulations of drugs in this country. One can always envision
that at times, despite those efforts, that the incentives may not
exactly align with the public health interests.

I think what we are grappling with is how we still can get those public
health interests met.

Dr. Jenkins?

DR. JENKINS: I have a question. I wanted to go back to your statement.
You say in here that FDA\'s relevant statutory authority relates
exclusively to drug safety, effectiveness and labeling. The agency has
no authority to consider prices or related matters as part of the
approval process.

I\'m wondering, by that do you mean that when we get an OTC switch
presentation from the sponsor that we are limited solely to considering
the drug\'s safety, effectiveness in the intended patient population who
would use the drug, that the drug would be safe and effective in that
population, and that we have to exclude all consideration of population
or societal benefits of the switch?

For example, societal benefits may be that there\'s an overall reduction
in mortality if this drug were made available over-the-counter. Are you
saying we can\'t consider that, and we have to limit our consideration
to the safety and effectiveness in the actual patients who might use the
drug, and not a broader societal context?

MR. BANTHAM: I think that\'s what the statute provides, and I think Dr.
Wolfe\'s comment about who is responsible for reforming the health care
system \-- that lies someplace else in our system.

DR. JENKINS: Thank you.

MODERATOR DeLAP: Okay. If there are no further questions, thank you very
much.

Our next speaker is Peter Barton Hutt, who has played many roles over
the years, but today is representing himself.

MR. HUTT: Thank you, and good afternoon. As Bob mentioned, I am
appearing today not on behalf of any client or group. I am here to
represent my own personal views.

It occurred to me when I read the [Federal]{.underline}
[Register]{.underline} notice that you were grappling today and tomorrow
with identical issues that those of us who were in the agency 30 years
ago grappled setting up the over-the-counter drug review and, therefore,
that our experience and the lessons learned from that grand effort might
be useful in some of your deliberations.

I will again emphasize, these are my own personal views, and no one
else\'s.

Now I\'d like to make four points. The first one is that we discovered
in the early 1970s that the absolute essential element of any successful
OTC drug program was a very visible, strong OTC presence in the Food and
Drug Administration.

When the OTC drug review was initially started by FDA, it resided in the
then-Bureau of Drugs, now, of course, the Center. It was almost
immediately taken out of there and put in the Commissioner\'s Office,
because it became clear that it would be drowned out by the entire rest
of the Bureau responsibilities and would not have an opportunity to do
the job that was needed.

That was an extraordinarily productive first five years of the OTC drug
review. It was then put back down in the Bureau at a relatively low
position and, I will have to say, that was the beginning of the slide
downward in terms of its productivity.

It was returned to Office status within the Center, then the Center, in
the early 1990s. I believe it again began to develop a vibrant and very
cohesive OTC drug philosophy and program. Once again, however, in the
mid-1990s it was put back down lower in the organizational structure,
and I believe that that is why today we have need for a hearing like
this in order to try to develop a more coherent and sound program for
the future.

It is quite clear to me, based on watching this for 30 years, that if
there is any hope for a truly sound, well thought through, and very
public OTC drug program in the Food and Drug Administration, it is going
to have to rely on a visible office, not a division, staffed with people
who are dedicated to this area of product, who have the responsibility
and the resources to go with it. Certainly, that is what we found in
1972.

My second point is the need to complete what was begun in 1972 and not
just \-- not just the tentative final monographs that are still
languishing in the Center, but rather a much broader program. Completing
those tentative final monographs is indeed an important objective, and
once again, it won\'t be done without an office.

We also need to go back and look for the products, and we know they are
there, that fell through the cracks in the early days of the OTC drug
review. I\'d like to commend the agency, for example, for doing just
that with plaque and gingivitis, a category of products that clearly did
not get addressed and was then readdressed most recently in the early
Nineties with a separate panel. That was a superb way to do it, and that
model should be used.

Third, as the third sort of leg of this stool, we need to take a look at
are we serious about bringing foreign OTC drugs into the United States
market. If so, you ought to tear up the December 1999 proposed
regulation which was designed more to preclude that from happening and
to replace it with the kind of open procedure that worked so well in the
OTC drug review.

Now again, all of these require people who have the authority,
resources, and responsibility and commitment and mandate to do this,
something I don\'t think any of those exist today.

My third point is the need to convert longstanding over-the-counter drug
New Drug Applications into OTC drug monographs. The whole concept of
switching changed in the early 1990s \-- I\'m sorry, 1980s \-- I
misspoke \-- with probably Ibuprofen where the change was from the OTC
drug review monograph system to the use of supplemental or full NDAs for
this process.

A lot of those are now 20 years old. There is simply no need to continue
to submit abbreviated New Drug Applications, Supplemental New Drug
Applications for every minor change in labeling or in the manufacturing
methods. This is an enormous burden on industry. It\'s an even worse
burden on the Food and Drug Administration.

It\'s the classic example of a short term investment that is needed by
the agency to get these out of the NDA system for a tremendous long term
benefit of being able to spend your resources on more important things
like switch.

Now let me get to the fourth point. The fourth point deals with the need
to focus on appropriate switch candidates, and I\'m going to divide my
remarks into two categories. The first is what we learned in the 1970s
and how we did it. It doesn\'t mean it\'s right, but it, I think, was
quite successful. The second is events that have occurred more recently.

Let\'s go back to the 1970s. No category, no type of drug, no type of
indication was ever taken off limits in terms of consideration of
whether it was a potential candidate for OTC status.

I briefed every single one of the 17 OTC drug panels, and I told them
open up your mind; think of what is possible. We may or may not be able
to accept it, but don\'t take anything off the table until you\'ve
thought it through on an individual drug by drug basis.

There is absolutely no reason under the statute to set arbitrary, rigid
rules and limits on this process. No drug should be simply not
considered.

Now you hear all the time, OTC drugs are palliative, not curative.
That\'s nonsense. You hear about acute versus chronic use. We have
chronic use OTC drugs now, and I heard Sid Wolfe, my good friend Sid
Wolfe who I debate often, make the same mistake that people make all the
time, that the hallmark of an OTC drug is self-diagnosis. It is not, and
never has been self-diagnosis.

It is self-treatment. The concept of physician or professional diagnosis
followed by self-treatment with OTC drugs is a long held concept, and I
would back to the first major discussion of that that I recall was by
Carl Peck when he was Center Director in the mid-1980s.

So let\'s open up the concept, the possibility. Now that doesn\'t mean
all these drugs will, in fact, be switched, but they should be eligible
for consideration.

Now on what basis do you proceed with a switch? There are two
possibilities. I firmly believe, and this was the way it was done in the
early 1970s, that you proceed on the premise that patients, consumers,
are intelligent, educable, interested in their own health, and want a
share of their health care decisions.

One could proceed on the basis that they are unintelligent, uneducable,
and that we ought to ignore their interests and subject them to a
doctor\'s decision. Now that is a difference in philosophy. Needless to
say, you know which way FDA went in the 1970s.

The hallmark of the OTC Drug Review was a collaborative, open process
with pharmacists, doctors, consumers, the regulated industry, all of the
people who had an interest, all of whom participated in the ultimate
decision. That decision was never once in the ultimate, final endpoint
disagreed with among those parties.

Agreement because of the process, because everybody was there working
together in a collaborative joint venture, we all ultimately reached
agreement. Let me say that again. In 30 years there has never been a
successful switch in which it was a confrontation. It has always been a
collaborative collaboration.

Now my time is up, and I, therefore, will not talk about the more recent
events except to say that I applaud the agency for its attempts to make
better use of labeling, to require, for example, that there be label
comprehension and actual use studies to reform the OTC drug label in
totality, to begin to use electronic means of communication that
weren\'t available to us 30 years ago when we were considering this. But
this just means that there are greater opportunity to educate consumes
and to bring them into the process, to bring them into the individual
decision making on individual drugs on their own merits.

So there is no limit, in my judgment, to what could be OTC. There are
clear limits to how to go about it. Bob Temple, you said is it all right
for FDA to initiate discussion? Of course, it\'s always all right for
FDA to initiate discussion. But if you get into confrontation, if you
get into \"we\" versus \"them\" rather than how to work this out
together, then I think the process will not work. Thank you.

MODERATOR DeLAP: Thank you very much. You certainly have a unique
perspective from your unique involvement with this process over the
years, and it\'s very interesting.

Do we have questions from the panel?

MR. HUTT: Thank you very much.

MODERATOR DeLAP: Thank you. We are going to have a break now. It\'s
about a quarter of four. We are going to start up again promptly at four
o\'clock. Thank you.

(Whereupon, the foregoing matter went off the record at 3:44 p.m. and
went back on the record at 4:05 p.m.)

MODERATOR DeLAP: Our first speaker for the remainder of the afternoon
session is Dr. John Dent for SmithKline Beecham. Dr. Dent.

DR. DENT: Thank you. Good afternoon, ladies and gentlemen.

In calling this hearing, the FDA have asked a series of probing
questions about the Rx to OTC switch process, questions which to the
casual observer might indicate that serious issues exist with the
current process of switching products from prescription to
over-the-counter status.

SmithKline Beecham is a leading consumer health care company which has
been involved in Rx to OTC switching since the 1960s. We are also in a
unique position to give a global perspective, as we switch and market
medicines throughout the world.

It\'s the view of SmithKline Beecham Consumer Healthcare that the
existing statutes and regulations, when employed in an open and
collaborative manner between the FDA and the sponsor company, allow FDA
to make determinations as to the safety and effectiveness of products in
the OTC setting and to determine whether or not these products can be
properly labeled for use without the supervision of a medical
professional.

In employing the existing statutes and regulations, we believe FDA
should consider each application on a case by case basis using the
weight of scientific evidence to make an informed benefit/risk decision.

There are common issues which need to be addressed in all switches.
These are covered, for example, in the UK Medicines Act, in the WHO
Guidelines, and in recently issued suggestions from the EMEA, and they
are comparable in principle to the U.S. FDA-sponsor switch
considerations. However, there are specific questions which need to be
addressed with each individual switch.

On balance, we believe it\'s unnecessary for the FDA to issue a broad
switch guidance, especially on an entire class of drugs or an entire
therapeutic area. We support the need for a collaborative approach where
FDA works with the sponsor company to identify the issues and to work
out acceptable ways to address them.

Working together, FDA and industry can answer the public\'s desire for
more opportunity for self-care while appropriately managing the
risk-benefit equation for each proposed switch.

One of the best examples of the process in action is the 1996 switch of
Nicorette, nicotine polyacrylics gum, to OTC status. Nicorette was the
first nicotine containing smoking cessation product to obtain OTC
status. The switch of Nicorette represented a significant challenge for
both the sponsor and for the FDA.

I will briefly tell you how we addressed the difficult issues that this
switch had raised, how we developed the data-driven solutions to these
issues, how by providing the agency with a post-approval assurances we
were able to address the issues that could not be prospectively answered
by facts and data, and how the decision by the FDA to approve the switch
of Nicorette, which at the time was a courageous decision, has led to
substantial public health benefit.

I think at the end you will agree that this switch resulted from an
effective collaboration between the regulator, the FDA, and the
regulated, SmithKline Beecham.

There were many issues that concerned both the agency and us as the
sponsoring company. Could nicotine replacement therapy be as effective
in the OTC environment as it was as a prescription medicine? Would the
loss of health care professional involvement in the process of smoking
cessation reduce the number of people trying assisted quitting or even
reduce the effectiveness of the product?

Nicotine is classed as an addictive agent. Dr. DeLap pointed out at the
beginning of this morning that that was one of the specific exclusions
for an OTC product. Setting aside the obvious contradiction that a
highly addicting form of this drug, cigarettes, was already available in
general sale, there were many who at the time questioned whether a
medicine containing nicotine could ever be made OTC because of the
addicting classification.

Many questioned whether diseases like tobacco dependence with such a
significant behavioral component could be self-treated or whether a
physician\'s intervention and counseling was absolutely essential to
achieve effectiveness.

Of great concern was how in an OTC environment could access to the
product be controlled so that the product was not used inappropriately,
especially by minors.

The answers to these issues resulted from a series of data driven
solutions and from a set of agreements between SmithKline Beecham and
the FDA. The OTC efficacy study demonstrated that Nicorette was safe and
effective in helping consumers quit smoking, and that users were able to
correctly understand the label and to self-medicate.

The \"real world\" quit study demonstrated that quit rates for smokes
receiving Nicorette from a physician not participating in a clinical
trial were not different from the quit rates achieved in the OTC trial.

In the Rx to OTC switch process, consumer research can be as important
as clinical research. In the Nicorette switch it allowed us to identify
the target population who were most likely to benefit from the use of
nicotine replacement therapy, a group we termed committed quitters.

By targeting advertising preferentially to this group, we were able to
maximize efficacy and minimize the potential for misuse and abuse.
Research in teenagers clearly pointed to the fact that Nicorette did not
appeal to them as a substitute for smoking nor as a product for the
initiation of nicotine dependence.

In addition to the extensive pre-approval work that we did, SmithKline
Beecham proposed 14 specific post-approval actions. These included: A
free behavioral program, training of doctors and pharmacists who are the
major players in the war against smoking; surveillance designed to
identify and report on the sales and use of nicotine by people less than
18 years of age, and we reported this information quarterly to the FDA;
age verification at point of sale; targeting advertising to adult
smokers; voluntarily agreeing to no trial sizes and no sample packs;
targeting distribution to settings where OTC drugs were sold, all
measures designed to reduce the risks associated with the availability
of nicotine replacement therapy over-the-counter and demonstrating the
ability to go beyond what is normally required for an OTC drug.

The fact that we proposed and the agency accepted these 14 specific
post-approval actions demonstrates the ability of a sponsor company to
work with the agency. To tailor the marketing and availability of an OTC
product this way makes moot the question of a third class of drugs.

Based on the data on the efficacy of nicotine gum and the impact of
increased access to this therapy, the bold and difficult decision that
the FDA made in 1996 has had a huge public health benefit.

Based on the work by Shiffman, [et]{.underline} [al.]{.underline}, it is
estimated that since the approval of Nicorette, approximately 1 million
people have quit smoking who would not otherwise have done so. The
benefits of the switch of Nicorette gum were achieved, and the risks
were not realized.

So the current Rx to OTC switch process works. It requires an open and
honest dialogue between the agency and the sponsor company. There is no
magic formula that works for all drugs. Each drug must be considered on
a case by case basis. Each will have its own difficult issues, which can
be answered with data driven solutions.

Those questions which cannot be answered prospectively can be addressed
with post-approval agreements or commitments from the sponsor, and in
the final analysis the public health benefit must occur.

I hope I\'ve made a compelling case that the system can work. Using an
example that falls out of the usual expectations for an over-the-counter
medicine, I hope you will agree that the system does not need radical
overhaul.

Case by case, data driven solutions which derive from a meaningful
collaboration between the agency and the sponsor are the key to ensuring
effective public health benefits resulting from Rx to OTC switching.
Thank you for your time and attention.

MODERATOR DeLAP: Thank you. Dr. Houn.

DR. HOUN: The post-approval assurances program \-- I guess a new term
for them would be risk management program, dealing with safety issues of
the drug. Did these come about as you were working toward the switch or
was it close to switchover time that these things were discussed?

I just want to know if there are some lessons learned on how to
incorporate developing these programs earlier on or \-- your advice?

DR. DENT: I think the key is to think about what the risks are, identify
them, talk with the agency about how to minimize them, put forward
proposals about how you are going to do that once you\'ve marketed the
product, get the agency to agree that that\'s appropriate, and then,
most importantly, make sure you follow up on it.

MODERATOR DeLAP: Well, if there are no other questions, thank you very
much.

Our next speaker is Dr. Dunaway from AMMSYS Research.

DR. DUNAWAY: Good afternoon. My name is Gerry Dunaway. I am President of
AMMSYS Research. We are a contract research organization headquartered
in Annapolis, Maryland. Prior to my founding this company, I spent 30
years with Proctor & Gamble.

As far as the hearing today, I represent myself, and I\'m not being
compensated for this presentation.

At the outset, I\'d like to thank the agency for scheduling these
hearings, and especially giving me an opportunity to speak. As way of
background of our company, we specialize in large Rx to OTC switch
studies. In the past 30 months, we have completed seven larger OTC
studies with a total enrollment of 16,936 patients, marginally over 2200
enrolled in each study.

My comments today are directed toward the agenda, that part of the
agenda which is headed consumer understanding, specifically the question
of how can the FDA be assured of consumer understanding.

Now the reason I\'m here is actually to convey the importance of
consumer \-- or we believe consumer research as a part of the current
and future switch decisions, especially when that research is captured
through a well designed use study.

In case Ms. Titus gets me with the time hook here, let me switch to the
conclusions and tell you what our conclusions are, and then if I get in
trouble on timewise, at least you will go home knowing what we thought.

There is no need for radical change in the Rx to OTC process. We suggest
that the Rx to OTC switch process should be considered on a case by case
basis. Categories of products should not be excluded from OTC
consideration. Research should clearly drive those decisions.

Rx to OTC should be viewed as a consumer driven process. The FDA should
consider \-- seriously consider accepting the principles of behavioral
science as valid research tools. FDA should frame questions that the
agency has concerns about and then charge industry with the
responsibility of finding answers because, clearly, research techniques
are available.

Finally, use studies with appropriate design features can answer
virtually all questions or any question related to what the consumer
will do, specifically self-recognition questions, self-selection and
whether or not the consumer complies with the label.

Now let me make four points on consumer understanding or consumer
behavior. First of all, perhaps the definition should be given, and
we\'re talking attitudes, comprehension, and observational research.

A more functional definition related to clinical research might be the
study of the consumer in the decision process of selecting drugs in a
retail setting and, of course, the environment in which they are
acquired. Again, to restate, we think Rx to OTC should be a consumer
driven process.

Understanding consumer behavior is essential to current and future
switch decisions, especially related to self-recognizable and
self-selection issues. Another way, what does the consumer know? What
can the consumer do, and what will the consumer do faced with that
product in a retail setting?

We think, of course, as I\'ve already stated, that the best way to
capture that information is through an actual use study.

There\'s a very strong case for consumer behavior by examining the
history of switch decisions. We looked at the switch decisions over the
last 20 years, and we divided them into three groups, and these are just
our headings, early, intermediate and current.

We wanted to see what impact consumer behavior had on each one of those
periods. The early phase studies, as you know, involved drug products
that provided primarily symptomatic relief and limited public health
impact. Consumer behavior was not a defining issue.

The intermediate phase: Easily self-recognizable conditions, heartburn,
diarrhea, baldness, again had a greater public health impact, but did
not require major self-selection decisions on the part of the consumer.

Then the current phased switches, not as easily self-recognizable,
osteoporosis, high cholesterol. It may require simple tests, have a
major, major public impact if they are approved, and consumer behavior
is just absolutely \-- we think, absolutely essential to these
decisions.

Now in summarizing why we think consumer behavior is important and why
we urge the agency to adopt research techniques that will look at that
is that these complex questions associated with current and future
switch products must be \-- the answers must be driven by research.

Those questions must be framed properly in open discussion between the
FDA and the sponsor, and research designs developed that will supply the
answers on which decisions can be made.

Let me talk for just a minute about actual use studies. Dr. Bradford
covered that very well, and I compliment you on that. Let me talk \--
Let me summarize what I was going to say about actual use studies by
saying that essentially we agree with his analysis of the use study.

We tend to talk about the static traditional model, which is somewhat
restrictive from a recruiting standpoint, may not measure the real
universe, does not provide the consumer with an opportunity to be the
consumer and probably make the decisions they would make in a store; and
we see that as very static and highly restrictive and not appropriate,
as it\'s designed now, to research consumer behavior in the future.

We see an evolving model. There may be a better name for it, but that
evolving model would continue to do what a use study is designed to do,
and that\'s to answer specific safety and efficacy questions. But it
would also do a number of other things.

It would be designed to answer consumer behavior questions that we\'ve
talked about today and that we all need to know. Be somewhat more
progressive in recruiting. It may be all comers. It may be naturalistic,
all of the buzzwords that we now use for at least making or attempting
to make sure that the study sample represents the universe.

It has a real life retail environment. It\'s somewhat less restrictive
in measurements than the current model, lets the consumer be the
consumer, and lets the consumer do what the consumer would do if they
entered a retail establishment to buy this product.

It creates a self-selection environment, and it provides maximum
consumer flexibility. Our experience \-- and we have done a number of
this type study \-- is consumers love it. They are more comfortable.
They are more relaxed, and we believe their decisions are more in tune
in this virtual retail environment than it would be in any other
environment you could put them in.

Now in conclusion and for purposes of credibility, it\'s very easy to
talk about these issues, but I would like to review very quickly in the
remaining time I have a large switch study that we did for the McNeil
Consumer Healthcare, and you want to guess what that\'s on.

You\'re going to swear there\'s a competition gong on here, but it was
on the Nicotrol transdermal patch system. We really didn\'t \-- No one
knew who was going to talk about what here.

We worked with Dr. Barbara Corberly in running the study, and she said
several things to us. Number one is here\'s the way I want the study
design based on the protocol, but she also said we want to learn as much
as we can from the study about the consumer. That\'s exactly what we
did. She also said we want to do that as quickly as possible.

Let me just run through the objectives: To achieve a comparable efficacy
in OTC and Rx arms. This was a two-arm parallel OTC arm and conventional
Rx sites. Create virtual OTC retail environment. Permit the patients to
self-select, and there were a series, which I don\'t have time to cover
here, but it\'s in the material that I handed out to the agency \-- a
series of consumer behavior questions that we successfully measured.

This is a flow chart of the study. We used primarily radio advertising.
We thought that was the best way to reach the large audience. They
called the 800 telephonic screening number, which is ours. We screened
them, randomized them, randomized to the ten retail OTC sites.

These were actual stores in active shopping centers, stores that we
leased. We then equipped them as an office, and we staffed them with
nurses or pharmacists or whatever is called for. On the Rx side there
were 13 physician offices.

This is a picture of some of them. I think we have maybe three, and
we\'ll flip through those very quickly. You can see, they really are
real life permanent kind of retail establishments, and those people who
are randomized to the OTC site feel that they are going into a real live
retail environment.

This gives you an idea of the summary of enrollment. We generated, total
calls in response to the advertising, 14,809 calls, and that\'s quite a
burden \-- not a burden, but it\'s quite a struggle to answer the phone
that many times.

Out of that we enrolled 3385 subjects. Out of the 3385, 150 failed to
initiate treatment, and in the study we had 3235.

Now just a word about the geographic area we used \-- I\'m not sure,
John. Do we have that slide? We did something different on this, and
again aiming toward redesigning the use study to where it meets the
needs today, and it delivers the kind of answers today.

We did that in one population area instead of across the country with 30
or 40 sites, which you would normally have for this kind of study. We
did it in a populated area of 5.9 million people, of which 1.2 million
were smokers, and of that 1.2 million we estimated fairly accurately
that 120,000 were motivated. That was really the study population we
were aiming for, for a sample size of 2500.

We ended up with 3385 enrolled and 3285 treated. The message today, and
I see the red light is really beginning to pick up tempo here \--
Consumer research is very, very important. It\'s very important to your
decisions today and your decisions tomorrow, and I know you know that.

We see the use study modified, and there\'s many ways to modify that, as
the ideal tool for actually delivering the kind of information you want.
Now it does not \-- Final statement: It does not replace \-- What we are
saying does not replace the comprehensive label study. That actually
validates what we find, the consumer research we find.

The label study tells us what the consumer understands. The kind of
consumer research we\'re talking about tells us what the consumer will
do when they go into that store, if the product were sold
over-the-counter, the kind of compliance decisions they would make, in
tune with the label.

Thank you very much for this time.

MODERATOR DeLAP: Well, thank you, Dr. Dunaway. Do we have questions?

DR. MURPHY: Could you tell us what is the longest time in which you have
involved the consumer in follow-up in any of these studies?

DR. DUNAWAY: Can you be a little more specific on follow-up?

DR. MURPHY: In other words, you\'re talking about what they do, but then
after they take an action and they use a product or use it
inappropriately, is it days, weeks?

DR. DUNAWAY: It\'s a year. We follow up for a year.

DR. MURPHY: So your follow-up is the longest has been a year.

DR. DUNAWAY: Yes.

DR. MURPHY: And the usual is \-- Of the seven studies, what was the
usual time? All of them for a year?

DR. DUNAWAY: The last seven studies? No. Five of them \-- Four of them
were for a year. The others were for six months, but they \-- different
compounds. So like a smoking study, it\'s more important. In fact, I
think you require it when the protocol is written that we follow six
months and a year. But we have not done a study where we do not do
follow-up.

Now, obviously, we carry out the protocol. We don\'t write the protocol,
but that\'s \-- We collaborate with our sponsors on that.

DR. MURPHY: And this is very interesting. So I probably shouldn\'t take
this much time. But in that six-month follow-up, what percentage of
dropout to follow did you have?

DR. DUNAWAY: I\'m sorry, I don\'t have that. We could get that. I would
have to, I think, get the sponsor\'s okay to release that, but are you
saying, for example, in the smoking study what percentage of them would
be abstinent at six months?

DR. MURPHY: How many of them were you actually able to measure? Let\'s
say you had 1,000 who you randomized to your OTC site, and how many of
that 1,000 actually were there at six months?

DR. DUNAWAY: In a different study, not this study, we had very good
follow-up. Approximately 60 percent of them we could reach. So 40
percent of them were lost. They moved away or you couldn\'t get back to
them or they didn\'t answer the phone with endless number of telephone
calls to try to get them back.

DR. MURPHY: Thank you very much.

DR. DUNAWAY: You bet. Yes?

DR. JENKINS: A couple of quick questions. In these studies could you
address how you\'ve handled the issue that a raised earlier about the
self-selection. If someone incorrectly self-selects to enroll in the
study and they have an obvious contraindication, how have you handled
that in those studies?

DR. DUNAWAY: In all of these studies with the exception of one, we said
they self-selected, but there were guidelines that defined consumers
with certain medical conditions that would not be accepted, pregnancy
being one and other conditions.

So we have never done a study where \-- Now we talk about all comers,
and I think we have to talk about all comers, but there are shades of
that. There are certain medical conditions that, I think, our position
would be that you simply could not accept everyone who comes to enroll
in the study. Ethically and medically, you could not do that.

DR. JENKINS: The second question I wanted to ask is: Do you see any
limitations to the ability of this type of study to answer questions?
Let me just give you the scenario I\'m envisioning.

For a lot of these chronic asymptomatic therapies that people are
proposing for over-the-counter marketing, if the question the agency
were to formulate to the sponsor was, okay, show us clinical benefit
that your anti-hypertensive drug when used in an OTC setting reduces
cardiovascular risk, mortality, morbidity, could you do a 100,000
patient OTC use study for five or ten years?

DR. DUNAWAY: Well, we\'d sure like to try. You would expect me to say
yes, and I want to be very careful in using good judgment here. It
depends \-- Sure, you can. Yes, you can. There\'s no reason why you
can\'t. It costs a lot of money, but you can certainly do that.

In this retail sites that we have, there are a number of benefits, and I
don\'t want to give you a sales presentation here, but you can either
\-- In some cases, we\'ve had doctors involved in the actual \-- at the
site, pharmacists, research nurses. You could keep them open 24 hours a
day, if you want to, because we own them. We own the lease.

If you want to bring people in the morning before work or after work, it
has a tremendous impact on being able to \-- we think \-- our experience
says, on being able to get a balanced enrollment.

I\'m coming to your point that you can apply \-- You can do whatever you
want to do there. We\'ve even done studies where we \-- involving blood,
and we have to get an okay for that, regulatory okay. So the answer
would be yes.

It would require a lot of coordination, but yet if you contrast that to
the logistics of a 100,000 patient study through a traditional Rx site,
it\'s probably more simplified and, my guess is, a little more cost
effective.

Again, if you know someone who is interested, we\'d sure like to talk to
them. And I say that with respect.

DR. JENKINS: We just formulate the questions.

MODERATOR DeLAP: Thank you very much. Our next speaker is Dr. Frederick
Sparling, Chairman of the Infectious Diseases Society of America.

DR. SPARLING: Good afternoon. I do come before you representing the
Infectious Diseases Society of America in my capacity as the Chair of
their Public Policy Committee and as former President of the Society. We
appreciate very much the opportunity to address you here late in a busy
day.

The IDSA represents more than 5500 physicians, scientists and other
health care professionals who specialize in infectious diseases, and the
mission of the Society is to promote and recognize excellence in patient
care, education, research, public health and prevention of infection.

My statement concerns the IDSA\'s initial comments to your notice
concerning the approach to regulating over-the-counter antimicrobials.
We ordinarily would have addressed this topic tomorrow, but we
appreciate the chance to speak to it out of order today when we are
available.

The IDSA strongly opposes changing the regulations to allow antibiotics
to be dispensed OTC without prescription from a physician, primarily
because it would increase the risks, in our opinion, for additional
development of antibiotic resistance.

There also could be other adverse effects, including patient
misdiagnoses of causes of apparent infection, as well as drug
interactions and toxicities.

Antibiotic resistance is a clinically significant problem at present and
has been getting worse throughout the world for many years. Indeed, the
problem has become sufficiently serious that the public media have given
much coverage to the emergence of antibiotic resistance superbugs. It\'s
hard to avoid movies, television, radio, magazines that discuss these
problems.

These problems are particularly severe within hospitals, but also
increasingly involve common outpatient infectious, in part due to
shifting of care to the outpatient arena. Patients have been infected
with bacteria that were resistant to every existing antimicrobial agent
and literally could not be treated.

Fortunately, our good colleagues in the pharmaceutical industry continue
to be successful in developing new drugs to treat resistant infections,
but we cannot assume that this will always be the case. We must do
whatever we can to preserve the effectiveness of currently marketed
drugs.

Resistant bacteria are contagious, and a single adverse event, rare as
it might be, has the potential to spread in an exponential way to other
contacts of the index case. The health of the public depends on these
decisions that you make.

Allow me to list just a few specific instances for illustrative
purposes. The pneumococcus, the most common cause of community acquired
pneumonia and a common cause of middle ear infections in children,
meningitis and other serious diseases, has gradually become resistant to
penicillins and other antimicrobials, including the macrolides and
trimethoprim and sulfas, and their continued effectiveness in treating
these classic infections is severely threatened.

The gonococcus, a common cause of general infections and a cause of
fetal death and female sterility, has become resistant to penicillins
and tetracyclines throughout the world, and is becoming seriously
resistant to fluoroquinolones.

The emergence of resistant gonococci and pneumococci was noted first in
areas of the world where antibiotics are freely available without
prescription. Many have concluded from these and many other examples
that development of resistance is fostered by free availability of OTC
antibiotics, because this leads to use of inadequate doses and/or
abbreviated courses of therapy, both of which favor emergence of
resistance.

Any move to allow similar OTC distribution of antibiotics and
antimicrobials in this country would undermine the public health
safeguards that we currently have in place to protect our citizens, and
place us on a par with lesser developed nations in this respect. This
would be a very serious step backward.

There are many, many other examples of similar problems. For instance,
resistance of the bacteria that commonly cause middle ear infections in
small children has increased dramatically in recent years, and many
believe this is the result of inappropriate use of antibiotics to treat
nonbacterial upper respiratory infections. Over-prescription of
antibiotics by physicians, both in their office and the hospital, is
well recognized to be a problem.

IDSA is working with policy makers within government and other societies
to develop better guidelines and educational strategies to limit
antibiotic use to those situations where they are really necessary.

If we accept that over-prescription of antibiotics leads to emergence of
resistance bacteria, then anything that liberalizes the uninformed use
of antibiotics for nonindicated conditions would aggravate the problem.

It could be argued that antibiotics might be approved for OTC use for
syndromes for which good algorithms for treatment exist and in which
diagnosis is relatively simple, such as urinary tract infections or
diarrhea. However, inappropriate use because of misdiagnosis still is to
be expected.

OTC antibiotics might be restricted to only certain common classes of
drugs such as the currently approved neomycin bacitracin for topical
use, reasoning that this should be unlikely to cause problems of
resistance to more commonly used antimicrobials. However, this would not
necessarily prevent emergence of resistance to common used drugs, for
the reason that genes for resistance to different kinds of drugs are
commonly carried on single mobile genetic elements or may result from a
single mutation in an efflux pump. Treatment, in other words, with a
single drug may result in emergence of resistance to multiple drugs.

The only safe policy is to restrict as much as possible use of all
antibiotics to situations where informed evidence suggests they are
needed. We urge you not to approve further OTC distribution of any
antibiotic or antimicrobial agent for topical or oral use in humans
without clear and convincing evidence that such a policy would not
result in selection for resistance to these or other antimicrobial
agents or an increased incidence of important misdiagnoses or other
adverse effects.

The IDSA looks forward to having the opportunity to continue to work
with you on developing good public health policy. Thank you.

MODERATOR DeLAP: Thank you, Dr. Sparling. Comments, questions? Dr.
Murphy?

DR. MURPHY: When you state clear and convincing evidence, some of the
evidence that has been presented to FDA is modeling. There is also
evidence from actual experience in other countries. Would you give us
your opinion of what you mean of clear and convincing evidence?

DR. SPARLING: Well, there\'s all kinds of evidence and all kinds of
questions. So I don\'t know that I can give a generic, all inclusive
answer that\'s satisfying to me or to you.

In general, I\'d like to see experiential evidence as opposed to
modeling evidence. I would not personally want to exclude evidence from
other countries, were it well gathered under conditions that we
understand and with similar criteria for evaluation, but evidence that
informed observers, unbiased, could look at and draw reasonable
conclusions from.

DR. MURPHY: This question has been asked of a lot of people today. So
I\'m not going to let you escape.

Would the use of a third process for certain of these syndromes \--
let\'s say, recurrent UTI where one had an initial physician diagnosis
and then a third process, the learned intermediary pharmacist \-- would
that be a system that the infectious disease community would consider or
feels we don\'t have enough information to go that route, or you just
think the problem is so large we shouldn\'t do anything in that
direction?

DR. SPARLING: I couldn\'t stand before you and say you should never
consider something. I think you\'re probably best advised to have an
open mind, as others have told you.

On the other hand, I would urge you, because of the unusual public
health implications of potential exponential spread of problems to other
people in the public as a whole with infectious diseases, to have a
negative bias and demand evidence when proposals are brought forward.

With regard to the specific question of UTI, I would argue that an
initial diagnosis and prescription with recurrent episodes in the
patient subsequently is a clear case where the patient does need to go
back to the physician and not to be treated over-the-counter, because it
is very likely, if there is either an anatomical problem or a resistant
infection, something is wrong.

So that\'s an easy answer. That would be an inappropriate use of such an
under-the-counter strategy.

MODERATOR DeLAP: Now Dr. Cantilena?

DR. CANTILENA: Yes. Dr. Sparling, just a couple of quick questions. So
you\'re not saying that there is absolutely no indication or infection
that should never be over-the-counter? It\'s just \--

DR. SPARLING: No, I would not say that. Indeed, we have neomycin
polymix, and it works. There are no problems. And as far as I know,
topical therapy for vulvovaginal candidiasis is not causing lots of
problems, and it may very well be that there will be topical
microbicides for general tract infections that will be very important.

So I don\'t think we can say categorically that it doesn\'t work now,
and it won\'t work in the future. But there are very great risks of
allowing wider use of drugs, as has been done in so much of the world,
with very, very bad consequences for the public as a whole.

DR. CANTILENA: And just another question. Your premise is that \-- I\'m
just trying to understand. Are you saying that, in terms of
self-therapeutic concentrations and abbreviated courses of therapy, that
that does not occur with prescription antibiotics?

DR. SPARLING: Oh, no, I didn\'t say that, because it does occur, and
compliance is imperfect, as we all know. But I would also argue that it
is more common if antibiotics are self-prescribed and traded on the
street.

DR. CANTILENA: But how do we know that?

DR. SPARLING: Well, there\'s not controlled prospective trials. It is an
educated opinion on the basis of a very large population of physicians
who work in this area that it is so, and it is drawn primarily from the
experience that resistant bacteria \-- This is certainly true \-- have
emerged first and are more prevalent in areas of the world where, among
other factors, oral antibiotics are readily available over-the-counter
and are commonly traded among people after very short courses of
therapy.

That doesn\'t prove it, but it\'s the best we have, and we have to make
informed judgments. My judgment is that it\'s likely to be a cause for
why we\'ve seen these problems emerging in those countries. I believe
that\'s exactly how one does it in the laboratory.

MODERATOR DeLAP: Dr. Kweder.

DR. KWEDER: Earlier today \-- I\'m not sure if you were here to hear
those comments \-- we heard from several speakers that decisions about
OTC \-- in the case of OTC switches on the part of the agency, for the
agency to try and make public health assessments and take those into
account in granting switches is beyond the purview of the FDA, that we
shouldn\'t be making public health assessments.

I would gather from your comments that you see that differently.

DR. SPARLING: Yes. I don\'t see how one can deal with a situation,
especially, let\'s say, of communicable disease without considering the
innocent partners or contacts of the index patient who become infected
and then are not treated. We could cite so many examples, multiple drug
resistant tuberculosis and on and on and on.

So it is important and should inform policy.

MODERATOR DeLAP: One other thought that we don\'t have so much control
over, but seems to overhang this discussion, that we can be very
virtuous and fastidious in our approach to these issues, and yet when
there are large parts of the world and other ways in which these
products are being used, clearly the infectious agents do develop
resistance, and they are transmitted around the world then.

Are there any other things that we could think about or ways that we
could advocate or anything, leverage, anything to try and keep these
drugs useful longer, so that our pharmaceutical industry doesn\'t have
to keep coming up with a new one every couple of years?

DR. SPARLING: Is that a question to me?

MODERATOR DeLAP: Yes.

DR. SPARLING: There are many things that might work, but I think the
thing we know the best is that judicious use when indicated only, for
the right length of time with the right dose, is the best thing we can
do. Indeed, when resistance has become an overwhelming problem, the ways
it\'s been managed is very assiduous attention to giving the right drugs
in the right way by directly observed therapy in the case of
tuberculosis or, let\'s say, in in-patient units to restrict the use of
antibiotics or to close the unit and stop the antibiotics, at which
point the bacteria revert back to sensitivity again.

So taking the pressure off of them or treating them broadly to really
get them all are the only ways to really manage the problem, that I\'m
know, and a little bit of antibiotics here and there is what leads to
the emergence of resistance.

MODERATOR DeLAP: It sounds like we should do our part and hope that
others will do enough of their part that it will work out well enough.

Okay. Well, are there other questions? If not, thank you very much.

We\'ll continue to Warren Pinchert of Cholestech Corporation.

MR. PINCHERT: I\'m going to be running my own slide show here. So I\'ll
try and speak up.

Well, the bad news is that I\'m your 3:30 speaker, but the good news is
there\'s only one left after me.

I\'m here today representing Cholestech. We are a publicly owned company
on the West Coast. That\'s why I\'m the only person here and running the
only slide \-- my slide show by myself.

Our goal is to provide convenient, accurate risk assessment for certain
chronic diseases, and also to provide tools to help people reduce that
risk, and then also provide convenient monitoring of the progress of
that treatment.

I\'m sure you are all aware that there is a lot of technology that is
rapidly developing that allows for more effective personal health
management. I think we have to look at three different things as far as
technology.

One is, obviously, the diagnostic piece of the equation, and then the
method of testing and how wide and how easy that access is to the
general public, and then what kind of tools are you going to allow the
individual consumer to have to monitor their progress.

The diagnostic part will stratify your risk so that you know whether you
should be just improving your lifestyle or whether you should possibly
be on an OTC medication or whether you should go see your doctor and be
on a prescription drug. There is technology today that allows that
stratification.

The national testing will allow access of venues that are convenient to
the ordinary, everyday person, so that they don\'t have to get up at
seven in the morning and go down to the hospital lab to get a venous
draw of blood.

They can go to Wal-Mart, Walgreen\'s and get an accurate and precise
reading and risk assessment at a place that is convenient to them, and
then the ability to get tools offered to them so that they can improve
their lot in life.

Now, obviously, you\'ve already guessed from the name of the company
that Cholestech deals in cholesterol. There are a lot of other
diagnostic pieces of equipment out there that address chronic diseases,
but I know, obviously, that Cholestech L.D.X. is the best. So that\'s
what \-- At the risk of being commercial, I\'m going to talk about that
today, because I think, if you just forget about the L.D.X. and think
about what I\'m going to talk about as the delivery system, I think
that\'s really what is important.

Now the Cholestech L.D.X. provides a full lipid profile on a single drop
of blood in less than five minutes. That means you get total
cholesterol, HDL cholesterol, triglycerides, a calculated LDL, and we
can also do glucose on that same drop of blood.

So you can have within five minutes an accurate assessment of the
person\'s cholesterol reading, and then as long as you are addressing
the other risk factors for coronary heart disease, you can evaluate
somebody\'s risk and point them toward their doctor. That is what I mean
by technology on the diagnostic side becoming more accessible to people.

We shipped over 3.5 million tests last year. So it\'s not like this is
just starting. It\'s already out there in the marketplace.

One of the things that is driving quality in this area, and as coming
from a diagnostic company it\'s hard for me to speak up for CLIA, but
I\'ve got to be honest and say that having to go through the pains of
getting a product waived under CLIA certainly has improved our product;
because if you focus on the last bullet there, we had to do additional
clinical studies beyond what is required in a 510(k), and we had to
prove that our product was accurate and precise at medical decision
points.

Now, obviously, for cholesterol, you know, that\'s 200, 240, but there
are other technologies that address osteoporosis and asthma. So those
are already on the market.

This is very important when you talk about extending the reach to
consumers and in the discussion today, because if somebody is going to
make a decision on an OTC product, they need to have an accurate risk
assessment at the point where they are going to purchase that product,
not away from the decision but right there.

The national testing: Cholestech on its own is being used at General
Motors, Sears. It\'s been used at Walgreen\'s, all kinds of different
locations. But Cholestech has recently started a national testing
service called WellCheck.

The goal there is to have an approach to testing that is the same
quality across the United States at whatever site you go to, and this is
all chronic disease related. So that when somebody goes in in California
and has their cardiovascular risk assessed, that is the same assessment
as they will receive in Maine. That is the goal of WellCheck.

We will have consistent high quality service, and the results will be
treated the same across the United States. The goal is to have this free
to the individual.

What that means is Cholestech is not going to make any money on the
testing service, but we want the other cholesterol interested parties to
be able to offset the cost of testing the people out there. That way,
more people become aware of their cardiovascular risk and can be
directed to their doctor and evaluated appropriately.

You can tell I haven\'t done this a lot. You have to bear with me.

The last part of our chronic disease system is actually a Website, and I
invite you all to log on, wellcheck.com. It is clearly cardiovascular
oriented at the moment, but we plan to add other disease states, chronic
disease states, as we go forward.

The content from this site was developed by Stanford, their Center for
Disease Prevention, and we also use the NCEP diet planner and other
things from that agency on the Website.

Somebody will be tested \-- Let\'s say we did a screening here. Each one
of you would get a PIN number. You go home, and you could either log on
or you get direct mail if you\'re not on the Web. You would get direct
mail from us.

You would be able to access as a result of that your own private area in
this Website, and Stanford has developed with us interactive tools that
first take a risk assessment based on NCP guideline and NIH guidelines,
evaluate your risk, and then set goals for you.

It has a goal tracker. It allows you to plot how you\'re doing against
those goals, and then eventually reset them. So this is a way that \-- I
know Dr. Wolfe was concerned about people not being aware of their risk
in a retail setting. I can tell you that the technology is there as we
go forward for people to be able to assess their risk, and this is
linked to the physician.

The physician is sent his actual \-- the person\'s results, and can be
sent the medical record that is off of the Website. So the technology is
there.

I know I\'ve probably been too commercial, but I would just say to the
panel that when you are considering an OTC switch and somebody is
saying, well, you know, all this has got to be done in the doctor\'s
office, I would submit that a lot of the risk assessment can be done
outside of the physician office with appropriate follow-up. Thank you.

MODERATOR DeLAP: Thank you. Questions? Dr. Temple?

DR. TEMPLE: I think you said this, but I may have been drifting. You get
your advice about what to do from the National Cholesterol Education
Program and assembled experts or how do you create the guidances as to
exactly what to do and when to go see your doctor or whatever it is?

MR. PINCHERT: We use the NCP guidelines for risk assessment. We also use
the Framingham study as part of that assessment, and then we use a
broader assessment that was developed by the Stanford Center for Disease
Prevention.

DR. TEMPLE: Do you run it by a collection of experts or \--

MR. PINCHERT: We have a medical advisory board that not only talk about
our testing procedures but also have gone and looked at the content on
the site to make sure that it is good stuff.

DR. TEMPLE: Just one narrow question: Some of the tests you describe are
best done fasting. How do you deal with that in the setting in which
these tests are done?

MR. PINCHERT: What we do is \-- Let\'s say that we are going to test at
a Walgreen\'s. People will be alerted prior to the screening that they
should fast. The Website allows them to log on and make an appointment
actually at that site. It has a test locator that you can find a testing
site near you.

So you\'re told prior to showing up that you should be fasting. If
somebody is not fasting, they are told that, you know, the results are
not appropriate; you should come back.

DR. WOODCOCK: Do you have information about comprehension by people who
interact with your site? Have you done some \-- With your test method
and your site and everything, have you done some assessments of how well
people understand what they are engaged in?

MR. PINCHERT: We actually have counselors there who talk to people,
because if you just get your numbers on a piece of paper and it\'s given
to you, the vast majority of people, you know, don\'t really understand
what an HDL lower than 35 means.

So what we\'ve done is through software at the site we have a report
that comes out that is given to the individual that explains all that.
Then there is a face to face consultation also.

DR. WOODCOCK: Right. But have you assessed that process for how well it
actually relays information to people?

MR. PINCHERT: No, we have not.

MODERATOR DeLAP: What kind of advice do people end up with? I mean, is
it more like a risk assessment or are there certain levels which
triggers an alert of some sort, to see your doctor or \-- I\'m just kind
of wondering what kind of \--

MR. PINCHERT: We have set just, I guess, a line in the sand that anybody
over 220, we tell them to go see their physician. Then we also offer to
send the test results to their physician. If they tell us no, we can\'t
do that, but if they do, we send the results to the physician.

DR. GANLEY: Would you envision a time in the future where someone could
go in and get this and then be instructed to buy an OTC cholesterol
lowering agent?

MR. PINCHERT: I think \-- You know, that is something that we would have
to take direction from the panel on. I mean, I could envision it, but I
think there would have to be very clear cut-marks as to when that can
occur and under what circumstances we should be saying that. But I\'m
assuming that the labeling of the product would set all that out. But,
yes, because our system does stratify the risk.

You know, we can measure LDL or total cholesterol, whichever one you
want to measure, and if it\'s below 200, we can tell them they are not
at risk. If it\'s 200 to 220, if that\'s what the labeling says, we
could say, you know, you\'re a candidate for over-the-counter drugs.

We are not in the business of selling over-the-counter drugs or
prescription drugs. We just give the information and try and direct
people to their physician.

MR. FOX: I just want a clarification of that. You mentioned before that
your business model revolves around other cholesterol interested
parties, other than the consumer. But that group of other cholesterol
interested parties, at least as you envision it in the reasonable
future, does not include specific drug sponsors. Is that what you\'re
saying?

MR. PINCHERT: It could. It could, but our policy is to not sell a
product. What we\'re looking for is, you know, to develop the market for
those companies like Quaker Oats or Nabisco or Benecol or whatever it
might be, and to have, you know, maybe their logo at the testing site so
that people are aware of it. But we do not want to be in the business of
selling any product ourselves.

We want to assess the risk and point people in the right direction.

MODERATOR DeLAP: I can envision that you can do an increasingly better
job of assessing risk. I mean, obviously, cholesterol, be it below 200
or over 240, is not a complete answer. There are a lot of other factors
that weigh individually into what the risk is, which is, I think, why
traditionally doctors have worried about that.

It\'s very interesting technology, and it\'s fascinating to see how much
you can do these days in this setting.

If there are no other questions, we\'ll go on, and we have Dr.
Kahlenborn who has been patiently waiting this afternoon. We\'ll be
happy to hear your comments. Thank you.

DR. KAHLENBORN: Can you all hear me in the back? Is that a yes? Can you
hear me? If you can hear me, put your hand up. Okay, thank you.

I am an internist from Pennsylvania, and am not receiving an honorarium.
There has been some discussion of over-the-counter use of the birth
control pill and the morning-after pill. I\'m going to address one
specific aspect of the birth control pill today, and that is its link to
breast cancer.

I have studied this during my own time over the last six years, and I\'m
going to present some of the findings to you today and, hopefully, spark
some questions.

Just a minute on breast cancer. There are 175,000 women every year who
get breast cancer in this country alone. It is the number one cancer in
the world, as far as prevalence. Forty-three thousand women die each
year of breast cancer, and roughly one in eight women will die of breast
cancer during her lifetime.

There is an increased risk in breast cancer in both young, white women
and young, black women, from the sera data from 1973 to 1992, about ten
percent increased risk; and the mortality of breast cancer in young
black women is going up much more quickly than young white women. It\'s
gone up 12 percent in those years, and in young white women it\'s gone
down nine percent.

Now what is the evidence that the pill causes breast cancer? As far as
starting from block 1, in 1972 a gentleman named Kirschstein noted that
one out of six rhesus monkeys developed breast cancer after that monkey
received oral contraceptives. That\'s significant, because until that
time, rhesus monkeys \-- there were only two cases in the world
literature of rhesus monkeys developing breast cancer.

Further studies, which are in the handout given to the FDA members, show
that both rats and dogs develop breast cancer when given some of the
hormones that are commonly used in today\'s birth control pills. Now if
you do believe after today that the pill causes breast cancer, how could
it cause breast cancer? A researcher named Anderson noted that, if women
take the birth control pill prior to having children, which is when the
breast cancer cells are most vulnerable to carcinogens, the mitotic rate
of breast cancer cells increases roughly 40 to 50 percent, and cells
that are dividing more rapidly are more prone to go through DNA errors
and less likely to have good mechanisms of DNA repair.

So that\'s probably the reason that the pill is most dangerous when
taken prior to a first term pregnancy, which is when most women in this
country take the birth control pill.

The second mechanism, which is probably not as strong but should be a
consideration, is that the birth control pill has had a lower dose of
either mestranol or ethinyl estradiol over the last 15 to 20 years. That
has allowed for a lot of break-through ovulation.

In fact, Linda Potter says that the efficacy rate or, quote, \"failure
rate\" is seven percent, despite the PDR\'s statement of three percent.
In any case, the pill will likely work at times by causing an early
abortion.

Now what\'s the significance of that? First of all, that statement is
supported best by a recent article in the [Archives of Family
Medicine]{.underline} of February 2000 which showed all the recent
evidence as to why that statement is true.

Recently, a paper in the \-- Well, not that recent, 1996, the largest
meta-analysis to date by Joel Brind showed that induced abortion, even
early on, causes a 50 percent increased risk in breast cancer when
performed prior to a full term pregnancy. So if the birth control pill
causes very early abortions, it may be working that way also.

What about the history of this? In 1981 a preventive epidemiologist
named Malcolm Pike from California showed that taking the pill resulted
in 125 percent increased risk in breast cancer in women prior to the age
of 32.

A large trial called the CASH trial, Cancer and Steroid Hormone study,
showed that women who took the pill prior to first term pregnancy had a
40 percent increased risk in breast cancer.

In England a woman named Chilvers showed that women under the age of 36
who took the birth control pill for at least four years had a 44 percent
risk, increased risk. Finally, in our country Louise Brinton from the
National Cancer Institute, although she didn\'t print it in her 1995
paper, if you take the subgroups together and analyze them and do an
odds ratio, she showed that if you take the pill prior to first term
pregnancy, there\'s a 42 percent increased risk in breast cancer.

Now if all of this is true, then why do so few people seem to emphasize
it or speak about it? Perhaps the greatest reason is a recent large
meta-analysis that came out in preliminary form in [The
Lancet]{.underline} and in larger form in the journal called
[Contraception]{.underline} which was a 100-page study put out in 1996
which basically stated, quote, \"Women who are currently using combined
oral contraceptives or have used them in the past ten years are at a
slightly increased risk of having breast cancer, although the additional
cancers tend to be localized to the breast. There is no evidence of an
increased risk of having breast cancer diagnosed ten or more years after
cessation of use.\"

Now there\'s a major problem with this meta-analysis. There\'s three
problems. The first is you cannot pool all the studies together and get
a pooled risk. Because the pill came out in the 1960s, you cannot take
information from the Sixties and Seventies. There\'s not a long enough
latent period. It\'s like cigarettes. If you would smoke today, you
would have to wait 30 or 40 years and pool the latter studies.

Secondly, in their paper which was, as I stated, 100 pages long, there
was no table or chart for women who took the pill prior to their first
term pregnancy. Now this is important, because this is when women
usually take the birth control pill. So the one subgroup that\'s most
prevalent was not specifically mentioned in their paper.

Finally, you cannot include women who are 60 and 70 in these studies,
which they did, since a woman who is 70 would have little access to the
birth control pill prior to her first term pregnancy. In fact, she would
have probably not known what it was when she was young. It wasn\'t
around at that time.

Now what is the evidence? Since 1980 there have been 17 out of 20
retrospective studies that have shown taking the pill prior to a first
term pregnancy increases the risk of breast cancer at least by 40
percent.

I didn\'t have time to go into a detailed analysis in this small
handout, but I do print the largest ones. For those who have the handout
or those who wish to see it later, it\'s up on the Web. Anybody can look
at it.

All four studies show at least a 40 percent increased risk in breast
cancer, including the CASH study, the Rosenberg study, the study by
White, and by Louise Brinton. So four of the 20 studies show at least a
40 percent increased risk, and the other 13 out of those 17 also show
about 40 percent or more.

Additionally, women who are at risk are those who take the pill for
longer periods of time or after the age of 25 or those who have never
had children.

Two sort of counter-arguments: Some people would say, well, the pill
decreases uterine cancer, and it decreases ovarian cancer. That is true,
but breast cancer and cervical cancer are the number one and number two
most prevalent cancers in the world in women, and they increase breast
cancer. They also \-- I won\'t go into it in detail, but the risk of
invasive cervical cancer goes up by 45 percent if a woman takes the
birth control pill prior to age twenty-five.

I think I\'m just about out of time. It seems to be going up in time,
for some reason. I guess that\'s time I\'m over.

One more comment: There\'s a question that hasn\'t even been asked. As
many of you know, diethylstilbestrol (DES) for a long period of time was
claimed to be safe and used in diabetic women to prevent miscarriages.

It was only 25 years later that the mothers who took DES, not the
daughters \-- the mothers were noted to have an increased risk in breast
cancer. But as you know or as some of you know, the daughters also had
an increased risk of vaginal and cervical cancer.

In my research, I haven\'t seen a single study to date that\'s looked at
the sons or daughters of women who have conceived while taking the birth
control pill. This is sort of scary when one considers that the rate of
testicular cancer has gone up by 50 percent in the last 20 years, and no
one really knows the etiology of that.

Could their mothers have taken the pill at that time and infected those
sons 20 or 30 years later? That may or may not be true, but it\'s at
least a question that should be asked.

So now I\'m open to any questions on that material.

MODERATOR DeLAP: Thank you very much. Do we have questions from the
panel? Do you have other thoughts as to where this information leads or
what other things are important questions to look at?

DR. KAHLENBORN: Well, this information will be going further into the
journals and into a manuscript, and it will be available on the Internet
at some period.

I really believe that, if this is true, then tens of thousands of women
after a period of time, probably after the year 2000 which is where we
are in, will be developing breast cancer. So the question no longer is
should or at sometime could this be over-the-counter, but why isn\'t it
taken off the market, which if it truly is causing breast cancer, has to
be a serious question.

That may not be asked much, but if the evidence is there, it needs to
be.

MODERATOR DeLAP: I\'m not aware of a pattern of epidemiology of breast
cancer that would indicate something like that developing. You\'re
saying, though, that it might come later?

DR. KAHLENBORN: No. I\'m saying it\'s already there. It just \-- It
hasn\'t been organized until now, and I think it will be soon. In fact,
I\'m going to submit some information. I think the written date is
August, and in fact, it\'s right in my briefcase. So if anybody wants to
look at that, I\'ll be happy to show them the 20 studies and the 17 that
are positive.

It\'s all there. The reason that people may have not perhaps have heard
it, of course, there\'s a tremendous financial interest from the drug
companies, but in addition, you have to take the studies in a certain
way.

If you take the studies after 1980, almost every study, retrospective
study, shows that taking the pill prior to first term pregnancy
dramatically increases breast cancer risk, where the studies before
1980, very few of them are positive because they don\'t allow a long
enough latent period.

I should add that, although this is a topic for tomorrow that apparently
you are discussing the \"morning after\" pill, which is a combination of
two different birth control pills, a lot of similar concerns apply to
that. But I have to work tomorrow. So I can\'t speak on that.

MODERATOR DeLAP: Well, thank you for your comments. Certainly, if there
is additional information that you think is useful to us, we would
appreciate seeing it in the docket.

DR. HOUN: Bob, I think that the SEER data was showing that the incidence
of breast cancer was particularly dramatically going up in the late
Eighties, peaking around the early Nineties, and has decreased, just as,
I think, the mortality actually has also decreased.

In some of the rising incidents, there was a concern that maybe that was
due to detection, more people going for mammography, and that maybe the
decline in the mortality might be that effect of early detection as
well.

MODERATOR DeLAP: Yes. We certainly have seen that pattern. That\'s, I
think, similar to the prostate cancer diagnosis pattern with the advent
of PSA testing. But, certainly, these things bear watching.

I think \-- Are there other comments or questions from the panel?

DR. MURPHY: I just wanted to say that, when submitting comments, one of
the issues that we have for pediatrics is long term follow-ups. So any
of your thoughts on the studies, trials that you thought were
particularly useful or effective in long term follow-up, because that is
an issue as we develop therapies in the pediatric population.

DR. KAHLENBORN: I couldn\'t really hear the question. It\'s pediatrics
long term follow-up?

DR. MURPHY: Yes. In other words, you said you\'re submitting your
information, and I was saying, when you are submitting your documents to
the docket that, if you have any comments on long term studies or long
term follow-up, that would be also helpful.

DR. KAHLENBORN: Okay. I can tell you now that there are specific tables
in the material that I\'ll submit that show that the risk of breast
cancer in women who take the pill does not seem to decrease with time,
although the contraception study said it does. That\'s because they
weren\'t looking at the subgroup of women who took it before their first
term pregnancy which is where it\'s especially vulnerable.

Studies by Rosenberg and Miller and others show that even 20 years after
taking the pill, there\'s usually \-- It can go as high as 90 to 100
percent. I\'ll be submitting that so you can look at it.

MODERATOR DeLAP: Okay. Well, I think that this is perhaps a good time
then to finish, and I would like to reemphasize \-- I\'d like to thank
you for your comments, and I would like to reemphasize that we do have a
docket for comments, and we are interested in information.

We will mention this again tomorrow, just to reemphasize, but there is a
yellow sheet out there with information about the public docket for the
information that we receive and how you can access it and how you can
file comments to it. So I would encourage people to avail themselves of
this as well and understand that the public docket will remain open
until August to collect comments after the meeting.

We will reconvene at 8:30 in the morning tomorrow, and I would \-- The
last comment I have to say is that, again, we had a sign-up process for
people that wanted to speak in the afternoon after all the scheduled
sessions.

If that is something that people have in mind, they really need to sign
up, because we will be trying to plan that session.

Thank you very much for coming, and we\'ll see you in the morning.
Thanks.

(Whereupon, the foregoing matter went off the record at 5:26 p.m.)