FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

MEETING OF THE

PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS

ADVISORY COMMITTEE

8:03 a.m.

Thursday, September 25, 2003

Holiday Inn

Versailles Ballroom

8120 Wisconsin Avenue

Bethesda, Maryland

ATTENDEES

COMMITTEE MEMBERS:

CLAUDIA H. KAWAS, M.D., Chair

Professor of Neurology

University of California, Irvine

1121 Gillespie N.R.F.

Irvine, California 92697-4550

ANUJA M. PATEL, M.P.H., Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration

5630 Fishers Lane, HFD-21

Rockville, Maryland 20857

JERRY S. WOLINSKY, M.D.

Professor of Neurology

The University of Texas-Houston

Health Science Center

Department of Neurology, MSB7.044

6431 Fannin Street

Houston, Texas 77030

SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS: (voting)

STEVEN EBERT, PHARM.D., Consumer Representative

Department of Pharmacy

Meriter Hospital

202 South Park Street

Madison, Wisconsin 53715

JORGE C. KATTAH, M.D.

Professor, Department of Neurology

University of Illinois College of Medicine at Peoria

530 NE Glen Oak Avenue

Peoria, Illinois 61637

LOIS E. KRAHN, M.D.

Chair, Department of Psychiatry and Psychology

Mayo Clinic

13400 East Shea Boulevard

Scottsdale, Arizona 85259

ATTENDEES (Continued)

SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS: (voting) (Continued)

EMANUEL J. MIGNOT, M.D., PH.D.

Director, Center for Narcolepsy

Stanford University

701-B Welch Road, Room 146

Palo Alto, California 94304-5742

DAVID NEUBAUER, M.D.

Associate Director, Johns Hopkins Sleep Disorders Center

Johns Hopkins Bayview Medical Center

4940 Eastern Avenue, Suite A-456

Baltimore, Maryland 21224

GERALD van BELLE, PH.D.

Professor, Departments of Biostatistics and

Environmental Health

University of Washington

4225 Roosevelt Way NE, Room 301

Seattle, Washington 98195

ACTING INDUSTRY REPRESENTATIVE: (non-voting)

DANIEL AZARNOFF, M.D.

349 Oyster Point Boulevard

South San Francisco, California 94080-1913

FOOD AND DRUG ADMINISTRATION STAFF:

JOHN FEENEY, III, M.D.

NORMAN HERSHKOWITZ, M.D., PH.D.

RUSSELL KATZ, M.D.

ROBERT TEMPLE, M.D.

ATTENDEES (Continued)

CEPHALON, INC. REPRESENTATIVES:

CHARLES CZEISLER, M.D., PH.D.

DAVID DINGES, PH.D.

ROD HUGHES, PH.D.

GEORGE McCORMICK, PH.D.

GWENDOLYN NIEBLER, D.O.

THOMAS ROTH, PH.D.

LESLEY RUSSELL, MBChB, MRCP

JAMES WALSH, PH.D.

DAVID WHITE, M.D.

ALSO PRESENT:

RICHARD L. GELULA, M.S.W.

CHRISTIN L. ENGELHARDT

C O N T E N T S

sNDA 20-717/s-008 Provigil (modafinil) Tablets,

Cephalon, Inc.,

Indicated for Use to Improve Wakefulness in

Patients with Excessive Sleepiness

Associated with Disorders of Sleep and Wakefulness

\- - -

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Ms. Anuja Patel 7

OVERVIEW OF ISSUES

by Dr. Russell Katz 9

CEPHALON PRESENTATION:

Introduction

by Dr. Lesley Russell 21

Review of Excessive Sleepiness

by Dr. Thomas Roth 25

Overview of Efficacy

by Dr. Rod Hughes 48

Overview of Safety

by Dr. Gwendolyn Niebler 77

Conclusion

by Dr. Lesley Russell 92

COMMITTEE DISCUSSION 93

OPEN PUBLIC HEARING

by Mr. Richard Gelula 165

by Ms. Christin Engelhardt 174

CONTINUATION OF COMMITTEE DISCUSSION

AND RESPONSE TO FDA QUESTIONS 181

P R O C E E D I N G S

(8:03 a.m.)

DR. KAWAS: Good morning and welcome to the September 25th, 2003 meeting
of the Peripheral and Central Nervous System Advisory Committee of the
FDA. Welcome, everybody. I think we are going to have a very interesting
day.

Since some members of the committee are new today, I\'d like to remind
everybody that the entire session will be transcribed, and so we need
everybody who speaks, whether they\'re from the audience, the sponsor,
or the committee, to please speak into a microphone and identify
yourself.

We will begin this morning with a conflict of interest. Actually, let\'s
begin with introducing the committee, and I think we can start at that
end with Dr. Katz.

DR. KATZ: Hi, Russ Katz from the Division of Neuropharmacological Drug
Products, FDA.

DR. FEENEY: John Feeney, neurology team leader, FDA.

DR. HERSHKOWITZ: Norman Hershkowitz, medical officer, FDA.

DR. NEUBAUER: I\'m David Neubauer from the Johns Hopkins University
School of Medicine.

DR. KATTAH: Jorge Kattah, University of Illinois, Peoria.

MS. PATEL: Anuja Patel, Advisors and Consultants Staff, executive
secretary for the meeting, FDA.

DR. KAWAS: Claudia Kawas. I\'m a neurologist from the University of
California, Irvine.

DR. WOLINSKY: Jerry Wolinsky. I\'m a neurologist from the University of
Texas, Houston.

DR. van BELLE: Gerald van Belle, a biostatistician from the University
of Washington.

DR. KRAHN: Lois Krahn, psychiatrist, Mayo Clinic.

DR. MIGNOT: Emanuel Mignot, Stanford University.

DR. EBERT: Steve Ebert, a pharmacist at Meriter Hospital and University
of Wisconsin, Madison.

DR. AZARNOFF: Dan Azarnoff, clinical pharmacologist, D.L. Azarnoff
Associates.

DR. KAWAS: Thank you very much, and we will have a conflict of interest
statement, which will be read by Anuja Patel.

MS. PATEL: The following announcement addresses the issue of conflict of
interest with regard to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by the committee participants, it has been determined
that all interests in firms regulated by the Center for Drug Evaluation
and Research, which have been reported by the participants, present no
potential for an appearance of a conflict of interest at this meeting.

We would like to disclose that Dr. Daniel Azarnoff is participating in
this meeting as an acting industry representative, acting on behalf of
regulated industry.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement and their exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose products they may wish to comment upon.

Thank you.

DR. KAWAS: Thank you.

Today we\'ll be discussing supplementary new drug application sNDA
20-717/S-008, Provigil, modafinil, Tablets from Cephalon indicated for
the use to improve wakefulness in patients with excessive sleepiness
associated with disorders of sleep and wakefulness. And Dr. Rusty Katz
of the FDA will give us opening remarks.

DR. KATZ: Thanks, Claudia. I want to welcome the committee back, those
members who were here yesterday, for today\'s discussion. I particularly
want to acknowledge and thank three experts who have agreed to help us
out with this thorny problem that we have in front of us today, and
that\'s Drs. Neubauer and Krahn and Mignot. So thank you very much for
coming and we appreciate the help.

As you just heard and as you know, today we\'re going to be discussing a
supplement to NDA 20-717, which was submitted by Cephalon, Incorporated
in December of last year, for the use of Provigil in the treatment of
excessive sleepiness associated with disorders or sleep and wakefulness.
As you probably know, Provigil has been marketed since 1998 in this
country to improve wakefulness associated with excessive daytime
sleepiness in patients with narcolepsy. Now they\'re going for a wider
claim, a new claim, with which we have no previous regulatory
experience, and so that\'s why we\'re coming to the committee.

Again, let me apologize briefly to the committee. We had not had a
chance, by the time we sent you the documents, to complete our own
independent review of the data, so we haven\'t sent you our reviews. I
suppose, on the other hand, it\'s less to read, so I won\'t apologize
too vociferously.

We are, again, in general agreement with the results of the analyses
that the sponsor has performed, but we, of course, have questions that
we want you to discuss. The sponsor, again, will present the data in
detail.

So my purpose here this morning, again, is to just really run through
the issues that we would like you to discuss on the way towards voting
on the formal questions that you have in your package.

Again, the sponsor in their document has briefly recounted the
regulatory history. It\'s been long. It\'s been characterized by many
interactions between the sponsor and us. I won\'t go into the details
here.

But basically ‑‑ and this is the fundamental question we think needs to
be dealt with first before anything else ‑‑ the sponsor is going for a
claim for a particular symptom that occurs in multiple clinical
settings. In this case, the symptom is excessive sleepiness and the
multiple clinical settings are primary sleep disorders associated with
excessive sleepiness. This is a somewhat unusual approach. Ordinarily we
are considering approving drugs for a specific indication, a specific
disease, but this is a little different.

But there is precedent for this sort of an approach. Typically in such a
case, the way it works is that the symptom is studied in several
different clinical models or clinical settings in which it occurs. Not
all clinical settings can be studied. That would be impractical, but
nonetheless, the idea is you study the symptom in several different
clinical models and then you hope that you can infer from that that the
drug works against the symptom regardless of what clinical setting it
might occur in, even in those that haven\'t been studied.

So an example might be a simple analgesic where a drug is getting
approved to treat pain. Pain occurs, obviously, in many, many different
settings. They may study post-surgical pain, dental pain, a couple of
models of pain, show it works wherever you study it, and then that
presumably permits the inference that the drug works against pain
regardless of the setting. That\'s not entirely true, but that\'s the
general approach that\'s been taken in the past.

Critically, though, before one can reach the conclusion that the drug is
effective against a symptom regardless of the clinical setting, one has
to be fairly certain that one can extrapolate in that way to settings
that have not been studied. So in a case like this, we\'d like to be
able to conclude that we understand very well the pathophysiology and
the etiology of the particular symptom so that we can be relatively
certain that the clinical models that have been studied are actually
representative of all the models, including models that have not been
studied.

So in the case we\'re discussing today, the sponsor has proposed to
support their claim for excessive sleepiness on the basis of results in
three clinical settings or three clinical models. What the sponsor has
done is it has grouped the primary sleep disorders that are associated
with excessive sleepiness into what I\'ll call an overarching category
which they call disorders of sleep and wakefulness. This category has
been further subdivided into three subcategories, each of which
presumably has been defined on the basis of the sponsor\'s understanding
of the pathophysiology of those three categories. And those three
categories are sleep-wake dysregulation, sleep disruption, and circadian
misalignment.

In each of these categories, the sponsor has studied the effect of the
drug on excessive sleepiness in a so-called representative disorder. So
for the sleep-wake dysregulation subcategory, they\'ve studied
narcolepsy. In fact, they have not done any new studies in narcolepsy.
They are relying on the studies that supported the previous approval of
narcolepsy. In the sleep disruption category, they\'ve studied
obstructive sleep apnea hypopnea syndrome, and in the circadian
misalignment category, they\'ve studied shift work sleep disorder. I\'m
not going to go into the details of what these diagnoses are. The
sponsor will talk about that in detail.

But critically again, based on the results of the studies in these three
individual disorders, the sponsor wishes to obtain a claim for an effect
of Provigil on excessive sleepiness in all the so-called disorders of
sleep and wakefulness. And the critical point I think that needs to be
made here is that the sponsor has created both the overarching category
of disorders of sleep and wakefulness and they have created, again based
on their understanding of the pathophysiology, these three
subcategories.

As I said before, it\'s critical if we\'re going to extrapolate from
studies in a few settings to an effect on the symptom in all the
categories, that we are able to understand the pathophysiology or the
etiology of the symptom across these different categories so that we can
conclude that the drug actually works wherever you would see excessive
daytime sleepiness, even in disorders that have not been studied. So
it\'s critical for us to ask the question whether or not we understand
the etiology of these disorders sufficiently to be able to make that
extrapolation, and I think that\'s the critical question before us. So
that is the first issue that we would like the committee to discuss. So
we need to know whether or not you think it was appropriate to create
these categories and whether or not it\'s appropriate to extrapolate
from the findings in these three disorders to the larger universe of
disorders that are subsumed under the categories that the sponsor has
created.

So ultimately we\'ll want to know whether or not you think that they
have submitted evidence to be able to draw a conclusion about it for a
general claim for excessive sleepiness. And if the committee concludes
that the data don\'t support such a general claim, we\'re very
interested to know whether or not you think it supports any other
perhaps disease-specific claim.

There\'s one other general issue that I think the committee should
discuss as well. The sponsor has assessed the effects of the treatment
on excessive sleepiness by the use of several objective measures, the
Multiple Sleep Latency and the Maintenance of Wakefulness Test, which
assess under different conditions how long it takes a patient to fall
asleep or whether he can stay awake under certain circumstances. These
tests are objective. They\'re timed. They are used widely in this field
to assess drug effect, but they are, of course, in a sense artificial.
They don\'t really look at the real-life situations in which these
patients find themselves. So we\'re interested to know whether or not
the committee thinks that these tests are appropriate for these
settings.

One could, for example, imagine that in these settings there could be
more, I\'ll say, face-valid measures of effectiveness, number of work
accidents, for example, in patients who are shift workers, or automobile
accidents during the day in patients with sleep apnea who are falling
asleep, or number of naps during the day, that sort of thing which are
sort of naturally occurring events. So we\'re interested to know whether
or not you think the primary outcome measures were appropriate here.

Those I think are the primary, larger, fundamental, generic questions
we\'d like the committee to grapple with, but there are a few
disease-specific questions that we have. As I said, one of the models
that the sponsor studied, narcolepsy, has been the subject of a previous
approval, so I\'m not going to ask too many questions about that.

But let me start with questions about the sleep apnea studies. The
changes in the sleep latencies, as judged by these objective sleep
measures, were small, just numerically small, although statistically
significant. And although analyses of other secondary measures were also
statistically significant, we\'re interested to know whether or not the
committee thinks that these treatment effects are meaningful clinically.

In addition, the vast number of patients in the sleep apnea studies were
CPAP-compliant. The sponsor was intending to enroll patients who were
noncompliant or minimally compliant or compliant, but most of the
patients were compliant, at least by the sponsor\'s definition. I\'ll
get to that in a second. So we\'re interested to know whether or not, if
you think the drug has shown itself to be effective in these patients,
it would be appropriate to include under any indication or in labeling
any effects of the drug on patients who were noncompliant.

We\'re also interested in your views on the sponsor\'s definition of
CPAP-compliant, which was I think during a run-in period use of CPAP for
4 nights or greater during that period, 4 nights per week I think or
greater. I\'m sorry. It\'s 4 hours per night for greater than 70 percent
of the nights. That was the definition of compliant. We\'re interested
in your view on this definition because it\'s the view of some, we\'re
under the impression, that if patients were truly CPAP-compliant, that
they wouldn\'t have an excessive sleepiness. So one can ask the question
whether or not the use of Provigil, if it has an effect on excessive
sleepiness, could motivate patients to either become CPAP-noncompliant
or to remain CPAP-noncompliant, if they\'re starting out that way, and
what the long-term consequences, if any, are of that. Again CPAP, in
effect, treats the underlying at least anatomical problem, and one needs
to ask whether or not, if patients become less compliant with CPAP,
there are long-term sequelae of that for the patient. So that\'s an
important question that we think you need to address.

Turning to the shift work studies, again here, the numerical treatment
effects are small, and we\'re interested to know whether or not the
committee has any particular concern about that point, even though
they\'re statistically significant. Here also, the sponsor had intended
to enroll patients who worked intermittent night shifts, as well as
patients who worked more chronically or more frequently on the night
shift, but actually here again almost all the patients enrolled were, I
will call them, more chronic, more steady night shift workers and not
very many intermittent night shift workers. So again here, we\'re
interested to know whether or not the committee thinks that any effects,
if you determine that there are effects, seen in the more chronic night
shift workers are extrapolatable to the people who work much more
intermittently on night shifts. This is sort of a subcategory of the
whole relevance of the models studied question that we wanted to ask you
before.

In addition, the final issue we\'d like you to think about ‑‑ and this
also leads into a more generic issue ‑‑ patients with shift work sleep
disorder have difficulty sleeping during the day, which is when they
need to be sleeping. So the question is if Provigil decreases their
excessive sleepiness at night when they need to be awake, what effects,
if any, are there on their hopefully restorative sleep that they are
trying to get during the day.

And the larger question is has the sponsor addressed the more global
question of the effects of Provigil on normal sleep in a number of these
categories that they\'ve studied. So we\'re interested to know whether
or not you think the sponsor needs to address that question, has
adequately addressed that question, and what you think about those
concerns.

Those are the main issues we\'d like you to discuss. Obviously, we\'re
interested to hear your discussions on any other issues or topics of
interest to you, as usual.

We\'ve handed out a list to the committee of some of these issues just
so you have something in front of you, as the discussion proceeds, to
refer to, but it doesn\'t list all the questions. It\'s just sort of a
little aid.

So what I\'d like to do now is just as I did yesterday in a more formal
way read into the record what the questions are that we actually want
you to vote formally on. It\'s a relatively long list, so I\'ll just
sort of run through it so everyone can hear them.

The first question is, using the International Classification of Sleep
Disorders, the sponsor has defined disorders of sleep and wakefulness
associated with excessive sleepiness. Does the committee agree with this
designation?

The second question is, the sponsor believes that the above group can be
divided into three categories we discussed, based on the presumed cause
of the excessive sleepiness. The categories are sleep-wake
dysregulation, sleep disruption, and circadian misalignment. Again, does
the committee agree with this classification?

The third question. Does the committee agree that the disorders studied
by the sponsor, narcolepsy, obstructive sleep apnea, and shift work
sleep disorder, are representative of the three categories described
above? As I said, these are the critical questions we need to get
answers to first.

The fourth question. Does the committee agree that the sponsor has
submitted substantial evidence of effectiveness for their proposed
indication, the treatment of excessive sleepiness associated with
disorders of sleep and wakefulness?

The fifth question is, has the sponsor demonstrated that Provigil can be
used safely for this broad indication?

And then, if the committee does not vote yes on the first set of
questions, if you find that this approach is not viable, then we have
two additional other questions, and this relates to disease-specific
claims.

The first one is, has the sponsor provided substantial evidence of
effectiveness to support the use of Provigil in the treatment of
excessive sleepiness in patients diagnosed with sleep apnea?

And the second is, has the sponsor provided substantial evidence of
effectiveness to support the use of Provigil in the treatment of shift
work sleep disorder?

With that, I\'ll stop and I\'ll hand the microphone back to Dr. Kawas.

DR. KAWAS: Thank you, Dr. Katz.

The sponsor presentations will occur now from Cephalon, Incorporated,
and the introduction will be done by Lesley Russell, Vice President of
Clinical Research of Cephalon.

DR. RUSSELL: Good morning. Madam Chairperson, members of the advisory
committee, FDA, we are pleased to be here today to present to you data
that we believe supports the use of Provigil as treatment to improve
wakefulness in patients with excessive sleepiness associated with
disorders of sleep and wakefulness.

I\'m Dr. Lesley Russell, Vice President of Clinical Research at
Cephalon. I will start off the presentation by making a brief
introduction.

Dr. Tom Roth, Professor and Division Head of Sleep Medicine at Henry
Ford Health System, Detroit, will give an overview of the symptom of
excessive sleepiness and its underlying pathophysiology, the disorders
of sleep and wakefulness and how they can be categorized, how the
symptom of excessive sleepiness manifests itself and how it can be
measured.

This will be followed by a review of efficacy data generated from five
principal studies by Dr. Rod Hughes, Director of Sleep Medicine at
Cephalon.

Dr. Niebler, Director of Clinical Research at Cephalon, will then give a
comprehensive overview of the safety data, following which I will
conclude and take questions.

As outlined by Dr. Katz, in December 1998, Provigil received orphan drug
approval for the following indication: to improve wakefulness in
patients with excessive daytime sleepiness associated with narcolepsy.
The efficacy and safety for this indication was established in two U.S.
multi-center, randomized, placebo-controlled studies.

The recommended dose was 200 milligrams administered once daily, but in
addition it is noted in the current label that 400 milligrams was well
tolerated but with no consistent evidence for additional benefit beyond
200 milligrams.

Provigil is listed in Schedule IV of the Controlled Substances Act.

I would now like to outline for you some key discussions that have taken
place over the past four years between Cephalon and FDA which led us to
undertake the clinical program that we are presenting to you today.

In June of 1999, Cephalon first met with FDA to discuss the clinical
program that would be required to expand the indication for Provigil
beyond narcolepsy to the treatment of excessive sleepiness associated
with other clinical conditions. The initial proposed indication for
Provigil was for excessive sleepiness secondary to sleep deprivation
associated with obstructive sleep apnea hypopnea syndrome. However, FDA
noted at that time that since excessive sleepiness occurs in multiple
clinical settings, a general claim for the treatment of excessive
sleepiness could be pursued if it could be shown that Provigil had an
effect on the symptom regardless of the clinical setting in which it
occurred.

Several meetings then took place to discuss a clinical program that
could potentially support an indication such as to improve wakefulness
in patients with excessive sleepiness associated with sleep disorders.
In order to support such an indication, FDA requested data from three
representative disorders.

In April 2001, agreement was reached that obstructive sleep apnea and
shift work sleep disorder, in addition to the narcolepsy which had
already been submitted, were appropriate disorders that could, if
positive outcomes occurred, be submitted to support potential approval
of such a claim. In addition, further discussions took place and
agreement was reached on the design and endpoints implemented in the
study undertaken in shift work sleep disorder.

Therefore, in addition to the narcolepsy studies, clinical trials have
now been undertaken and completed in obstructive sleep apnea and shift
work sleep disorder, and as we will show you today, Provigil was
consistently efficacious in improving wakefulness in all three
disorders. In addition and as important, the safety profile of Provigil
was similar in all three disorders. Therefore, we believe that the
results seen in these three disorders are predictive of Provigil\'s
treatment effect on excessive sleepiness in disorders of sleep and
wakefulness.

In December 2002, a supplemental NDA was submitted for the following
indication: to improve wakefulness in patients with excessive sleepiness
associated with disorders of sleep and wakefulness.

I would now like to highlight some key points which underlie the
rationale for the clinical program that was undertaken with Provigil and
which will be presented to you in greater detail by Dr. Roth and Dr.
Hughes.

Firstly, the symptom of excessive sleepiness is associated with
significant morbidity, causing impairment in occupational and social
function, and occurs in qualitatively similar ways in many clinical
settings. Regardless of the underlying etiology, excessive sleepiness is
a consequence of sleep disruption and/or an increased drive for sleep.

Primary sleep disorders that have excessive sleepiness as a primary
complaint have been categorized in the International Classification of
Sleep Disorders as disorders of sleep or wakefulness, and using this
classification, the disorders of sleep and wakefulness can be grouped
into three categories which are operationally definable; namely,
disorders of sleep-wake dysregulation, disorders of sleep disruption,
and disorders of circadian misalignment. Within these three categories,
narcolepsy, obstructive sleep apnea, and shift work sleep disorder are
representative clinical disorders that all have excessive sleepiness as
a primary complaint.

Importantly, regardless of the underlying cause, excessive sleepiness
manifests itself in similar ways and can be measured objectively and
subjectively using standardized, validated, and clinically relevant
instruments.

And finally, as we embarked on the clinical program, we believed that
Provigil would be an effective treatment for excessive sleepiness
associated with disorders of sleep and wakefulness regardless of the
underlying etiology.

I would now like to hand over to Dr. Tom Roth who will give a review of
excessive sleepiness.

DR. ROTH: Thank you, Dr. Russell.

What I would like to do in my presentation is to give you information
about three topics.

One is excessive sleepiness has significant morbidity and that manifests
itself very similarly regardless of the etiology of that.

Two, excessive sleepiness can and is reliably measured in clinical
practice, in clinical trials, and in clinical research on an ongoing
basis.

And finally, excessive sleepiness related to sleep-wake disorders is a
finite number of diseases which can be defined both in terms of what is
included in that category and what is not included in that category.

Those are the three things I would like to cover.

Now, the presentation I\'m about to give was offered not only by myself,
but by three other people, Dr. Charles Czeisler from Harvard Medical
School and Brigham and Women\'s Hospital, Dr. David Dinges from the
University of Pennsylvania School of Medicine, and Dr. Jim Walsh from
St. John\'s/St. Luke\'s Hospital and St. Louis University. The four of
us spent the time developing this presentation. I was chosen to be the
one to give it. I\'m afraid to ask why, but I was the one chosen.

Now, the presentation I\'m about to give will touch on these five
points. One, I will try to define sleepiness and, within that context,
to define what differentiates sleepiness from excessive sleepiness. Two,
I\'m going to talk about etiology of sleepiness, what makes individuals
sleepy both at a normal level and at a pathological level. Then I will
discuss the disorders of sleep and wakefulness, but not all disorders of
sleep and wakefulness, but specifically disorders of sleep and
wakefulness which sometimes give rise to a clinical symptom of excessive
sleepiness. Then finally, I\'ll talk about how this excessive sleepiness
exhibits itself, why it\'s clinically important, and how clinicians and
researchers quantify it on an ongoing basis.

Now, what is normal sleepiness? Normal sleepiness, like hunger, like
thirst, is a drive state, and it is defined very simply by decreased
ability to maintain levels of wakefulness or, conversely, an increased
propensity to sleep. So it is often referred to as a homeostat, drive
state, but we\'re going to talk about that in the context of sleepiness.

Now, very importantly, like other symptoms Dr. Katz mentioned,
sleepiness has adaptive value. It is telling the organism that it is not
functioning at maximal capacity and it ought to either expend effort to
be more careful or to stop that activity because they are not doing it
well. So it has very clear and important adaptive value, and that\'s why
it\'s become the single most important symptom in the practice of sleep
medicine.

Now, what drives normal sleepiness? Two factors normally control
sleepiness.

One is sleep drive, and as I mentioned, it\'s often referred to as sleep
load or the homeostat. It is driven by two things: how long you\'ve been
awake, time since sleep, the longer you\'re awake, the higher the sleep
drive; and the duration and continuity of sleep. Once you go to sleep,
that sleep drive dissipates and you then start over the next day. So
this is a buildup of sleep drive. This is an attention or a diminution
of sleep drive.

The second major output is the circadian phase, and by circadian phase,
we are talking about your biological time of day. Very importantly, it
is a biological time of day. It is not the time of day on your clock.
And what\'s very important is your biological time of day and the time
on your clock are often discrepant, and that becomes an issue, which we
will talk about, in some individuals.

It\'s important to understand two things about that circadian clock.
One, its primary output is an alerting pulse to the cerebral cortex.
That is its primary output. And two, it is primarily governed by light
and dark schedules.

Now, in my presentation I\'m going to use this slide on several
occasions. I\'m going to spend about 30 seconds describing it for you.
This is a 24-hour day. This is 9:00 a.m., 9:00 p.m. This is when people
routinely work. This is when people routinely sleep.

Now, what causes sleepiness? As I mentioned, the first thing is the
homeostat or the sleep drive. As you can see, across the day, it
increases. Across the night, it dissipates. That sleepiness is modulated
by that circadian drive for wakefulness or that cortical activation. You
can see this peaks about 8-9 o\'clock in the evening. What\'s very
important is at 7-8 o\'clock at night, people should be falling asleep
while they\'re eating dinner. They don\'t, and it is because of this
important alerting pulse. These two biological signals result in this
wake propensity.

So each of us, across a 24-hour day, have a wake propensity. Right now,
we have a reasonably high wake propensity. When we go to sleep, we are
able to sleep because you have a decreased wake propensity. So this is
the net. When it moves up, we have a greater wake propensity; when it
moves down, we have a greater sleep propensity.

Now, this green line is very similar to slides you see in the literature
or graphs you see in the literature of measures of sleep tendency. So
how do you operationalize wake propensity? You operationalize it or the
sleep community or the medical community operationalizes it with the
Multiple Sleep Latency Test. So they measure the tendency to fall
asleep. So wake propensity is operationalized and clinically used by
measures of sleep tendency.

Now, the difference between excessive sleepiness is that it is a symptom
of difficulty in maintaining wakefulness and increased propensity to
fall asleep. The difference between normal sleepiness is that it is in
inappropriate circumstances and it importantly interferes with
activities of daily living. So excessive sleepiness, regardless of what
causes it ‑‑ regardless of what causes it ‑‑ is the level of sleepiness
which interferes with activities of daily living. So by definition, it
has morbidity almost.

Now, the prevalence of excessive sleepiness, depending on how you define
it and the population you study ‑‑ and people sort of can define this
clinically in the literature, patient-rated scales, clinical scales.
Basically if you look at the literature, somewhere between 5 and 15
percent of the population will experience excessive sleepiness. So that
is the piece of pie we\'re going to talk about. We\'re going to dismiss
normal sleepiness.

Now, within that pie, we can trichotomize. We can sort of say there are
three causes of sleepiness.

One, the most common, by far the most common, are behavioral,
environmental, and other extrinsic causes. It is not spending enough
time in bed. It\'s not having regular sleep times. There\'s a series of
behavioral causes which give rise to that. That is normal variations
which reach an extreme level. That is not what we\'re going to be
discussing today.

The second is excessive sleepiness due to a variety of medical diseases.
This is very much a neurological panel. Parkinson\'s disease gives rise
to the symptom of excessive sleepiness. Medications used to treat
medical disorders, for example, dopamine agonists, can also lead to
that. Seasonal affective disorders lead to symptoms of excessive
sleepiness. But again, that is not, as Dr. Katz pointed out, what we\'re
going to discuss today.

What we are going to discuss today is very simply the disorders of sleep
and wakefulness. Within the disorders of sleep and wakefulness,
currently the sine qua non of that category and the current indication
for modafinil is in fact narcolepsy. So that is the sine qua non of that
category, and the category is what we\'re going to talk about today.

Now, when you take that group of disorders which give rise to the
symptom, one of the questions becomes how do you dissect that. What we
have sort of come up with is, if you look at all those disorders and you
look at the mechanisms, more importantly, there are three types or three
groups of disorders which lead to sleep and wakefulness associated with
excessive sleepiness. One are disorders of the sleep-wake dysregulation.
Two, there are disorders of sleep disruption. And I\'ll talk about these
individually. And three, there are disorders of circadian misalignment.
So these three groupings represent that universe.

Now, the next question becomes how do these things lead to excessive
sleepiness. So, for example, we\'ll talk about pathologies in sleep-wake
dysregulation in the hypothalamus. But how do they lead to that symptom,
that common symptom in all of these disorders? How do they lead to that
common symptom?

Basically these three groups of disorders have two pathways to excessive
sleepiness. The reason we picked these three groups is they
differentially take these two roads to excessive sleepiness in different
ways.

The disorders of sleep-wake dysregulation primarily impact sleepiness by
increasing sleep drive for impacting the homeostat. So disorders of
sleep disruption, obviously, primarily have as their pathway leading
sleep disruption in losing the recuperative value of sleep. The third
are disorders of circadian misalignment and they impact both of those
equally. So you have three groups of disorders and two pathways, all
leading up to the symptom of excessive sleepiness associated with
sleep-wake disorders.

Now, the International Classification of Sleep Disorders is developed by
the American Academy of Sleep Medicine, and it has developed a
nosological system which codifies and provides codes for all the various
sleep disorders. They put them into four categories. They\'re proposed
sleep disorders and that\'s because all researchers always say more
research is needed, so that\'s what that means.

Then there are disorders associated with mental, neurological, and other
medical disorders. We dismiss those in that part because we\'re
interested in sleep-wake disorders. We\'re not interested in those
associated with medical disorders.

There are parasomnias, and there are arousal disorders. Now, the reason
we\'re not particularly interested in that is because they don\'t
present with excessive sleepiness. If you look in the nosological
system, they don\'t present with excessive sleepiness.

So we are left with dyssomnias which are defined in the ICSD as
disorders of sleep or wakefulness.

Now, within the disorders of sleep and wakefulness, we\'re primarily
interested in intrinsic sleep disorders and circadian rhythm sleep
disorders. We\'re not particularly interested in extrinsic sleep
disorders because those are disorders where, if you treat the source of
that extrinsic factor, such as noise in environment and allergy, it goes
away. So these are the ones we\'re primarily interested in.

Now, besides giving this myriad of diagnostic entities, the ICSD
provides us with a differential diagnosis, and this has much more
clinical utility. So the differential diagnosis of sleepiness falls into
two groups that I\'m going to call \"other,\" and these are the ones we
dismissed now twice. And these are the four which are disorders of sleep
and wakefulness, which I sort of had on the previous slide. They are
sleep-induced respiratory impairments, sleep-related movement disorders
‑‑ sleep-related movement disorders, not other movement disorders ‑‑
disorders of timing of the sleep-wake pattern, and neurological, not all
neurological disorders, but specifically neurological sleep disorders.
So those are the four groups in the nosological system we\'re interested
in.

Now, this slide melds the two nosological systems I just gave you. This
is the categorization of sleep disorders we created: sleep-wake
dysregulation, sleep disruption, and circadian rhythm misalignment.
These are the ICSD classifications in their system which correspond to
these, and they\'re very tight. So this is a melding of those two
systems. In here we have all those things that the nosological
categorization associated with neurological sleep disorders. In here we
have disorders associated with the timing of sleep and wakefulness. In
here in sleep disruption, we have those associated with respiratory
impairments and those associated with sleep-related movement disorders.
So that is a melding of the ICSD system and the way we broke these up.
They\'re almost identical and almost one-to-one categories, and I\'ll
get back to discussing those. So those are very important.

Now, if you go one step lower or further into the nosological system,
within each of these categories, this is the ICSD category which
corresponds to it. It\'s exactly one-to-one, and these are the specific
disorders within that category. These are the disorders within that
category, excessive sleepiness due to restless leg syndrome, periodic
limb movements, or in that category. And these are excessive sleepiness
in shift work sleep disorder and other disorders.

So the question really becomes this is the universe of symptoms. This
represents the individuals in each category, and this is how we picked
the representative nature of all disorders of sleep and wakefulness. So
in this slide, you have all of the disorders of sleep and wakefulness
associated with excessive sleepiness. If they\'re not on this slide, we
do not consider them or the ICSD, more importantly, does not consider
them a disorder of excessive sleepiness due to sleep-wake disorders.

I\'m going to now deal with them individually.

Now, narcolepsy is a disorder which we picked in terms of sleep-wake
dysregulation. Now, why do we pick that? Well, we picked it because,
one, at this point in time it is the most common one seen in the
practice of medicine. By far, of all of these disorders, that is the one
most commonly seen in the area of medicine.

Now, what is the pathology in these things? Well, for example, one of
the things we know, based on the work of Professor Mignot, is that
narcolepsy represents a degeneration of a group of hypothalamic neurons
which lead to a down-regulation or diminution of the arousal system.
That is the pathology there. Idiopathic hypersomnia, recurrent
hypersomnia, post-traumatic hypersomnias have different lesions, albeit
it ill-defined at this point in time, but they all have the same exact
common pathway. They decrease arousal level.

How do we draw that out? The way we draw it out is by going back to the
original slide. This is the normal I showed you before. This would be
one of the disorders of sleep-wake dysregulation. Sleep drive, sleep
load ‑‑ use those interchangeably ‑‑ is significantly increased. That
results in an increased sleep propensity or, most importantly, a
decreased wake propensity. So this wake propensity is significantly
lower than it is in the normal individual.

Now, one of the things that was pointed out by both speakers who
preceded me is modafinil is indicated for excessive sleepiness in
narcolepsy. And how does it do that? Basically the efficaciousness of
the compound is defined by its ability to move wake propensity from here
to here. That is the definition of efficacy.

Let\'s go to the next group of disorders, what we call disorders of
sleep disruption. In that, what we have is a group of disorders, all of
which have a common pathophysiology, and the common pathophysiology is
that they fragment your sleep. So it doesn\'t make a difference if you
have leg movements causing sleep fragmentation. It doesn\'t make a
difference if you have respiratory events causing sleep fragmentation.
The commonality is all of these fragment your sleep. That fragmentation
of sleep specifically leads to an attenuation of the recuperative value
of sleep and leads to the symptom of excessive sleepiness. So they are
very common in their pathology. They differ in the source of the
stimulus, very much like before. They all lead to a decreased arousal.
The site of the lesion is different. The same thing here. They all lead
to sleep fragmentation. The site of the lesion is different.

Why do we pick obstructive sleep apnea syndrome? Because of all of the
disorders, it\'s the one most commonly seen in clinical practice today.

How does that work? Well, the major pathology in these disorders is
right here. In other words, this we showed you before, the recuperative
value of sleep. Here the recuperative value of sleep is profoundly
attenuated. So when you get out of bed the next morning, you still have
a very high sleep drive.

Now, the questions in front of you and which the speakers which follow
me have to address is the question of this decreased wake propensity
associated with disorders of sleep and wakefulness. Does modafinil
increase that wake propensity just as it did in narcolepsy? So I drew
you a schematic which shows that the effect is exactly the same as in
the approved indication. Does that effect in sleep apnea show the same
thing?

The other requirement that is important for you to consider is, does it
do this without impacting the primary treatment? So the primary
treatment for sleep apnea is CPAP. Does this change CPAP compliance?
Does it, as Dr. Katz pointed out, disturb nocturnal sleep by making it
more disturbed? Or does it change issues related to sleep apnea such as
cardiovascular disease? So two things. It has to increase that level of
alertness, and two, it has to do it without changing the primary disease
or its therapy.

The third group of disorders are the disorders of excessive sleepiness,
for example, shift work sleep disorder. But again, it is no different
from time zone change. It\'s no different than jet lag in the sense that
the pathology is these individuals are waking at a time when the
circadian pacemaker does not have its maximum output again to the
cortical arousal. We keep going to cortical arousal. So we decrease
cortical arousal because of fragmented sleep. We decrease cortical
arousal because of a lesion in the hypothalamus. We decrease cortical
arousal because it is the time of day when the SCN isn\'t putting out
its maximal pulse for cortical arousal. So these are all the same in
terms of the fact that that is what\'s causing the sleepiness.

Why did we pick shift work disorder? Because in clinical practice today,
this is the most common one seen on a daily basis.

Now, again, this is the schematic. The only difference here is that when
you had sleep here before, you now have sleep here. You had work here
before, you have sleep here. So what one of the things that\'s happening
is in fact when people are waking at this point in time or working, you
have a maximum sleep drive because it\'s the wrong time. We simply
flipped that slide.

So what is the challenge, again, for modafinil data? Well, we want to
show that like narcolepsy, like sleep apnea, this wake propensity is
enhanced, and again, enhanced without the primary therapy. The primary
therapy of these disorders is to make sure that nocturnal sleep is
adequately managed. So we want to make sure that this enhancement of
alertness occurs without disturbing nocturnal sleep as measured by sleep
studies, polysomnography as mentioned by Dr. Katz, or without impacting
patients\' compliance. Specifically, are they reporting an equal amount
of time in bed or are they sort of decreasing their time in bed?

Now, one of the things that becomes important to understand is we have
these various disorders. We said they have a common pathology, and that
common pathology is a decrease in cortical activation. We don\'t really
know what modafinil does at a cellular level, and certainly there are
people on the panel who know that better than I do.

But what are we talking about here? Well, basically what we have here
are the various mechanisms involved in the normal arousal system because
we have activated the cortex. These are mediated by hypothalamic neurons
which then give signals up to the cortex. And there is a variety of
transmitter systems, mostly in the hypothalamus, hypercretin, histamine.
All have outputs which increase that.

In disorders of sleep and wakefulness, there is a decreased activation
of these hypothalamic centers. For example, in narcolepsy, as I
mentioned, Dr. Mignot showed that there\'s an impairment in the
hypercretin system, and you wind up with a decreased activation of that
system.

How does modafinil work? Well, as I mentioned, we don\'t know how it
works at a molecular level, but work from Professor Jouvet in Lyon has
shown that modafinil leads to an activation of hypothalamic centers in
the brain, and he demonstrated that by early genes, such as specifically
Cfos. So what that activation does is it restores a normal level of
cortical activation. So these disorders decreased our level of cortical
activation. Modafinil, working through the hypothalamus ‑‑ again, I
can\'t specify exactly where or what transmitter systems ‑‑ leads to a
restoration of that normal cortical activation.

So let us move on to the whole issue of understanding the data. As I
mentioned, disorders of sleep and wakefulness which produce excessive
sleepiness have significant morbidity. There\'s very little question
that they have effects on productivity, accidents. They manifest
themselves in very homogeneous ways, and that\'s what makes this a
single category. They have comparable morbidity. Decreased productivity
is the same in apnea as it is in shift work sleep disorder as it is in
narcolepsy. They manifest themselves the same way and they are measured
in clinical practice and clinical research in the same ways.

Now, there\'s a lot of morbidity associated with excessive sleepiness,
and in fact today there\'s a tremendous amount of research on the
physiological consequences of excessive sleepiness. People look at
things like insulin resistance and a variety of other measures. But
without any question, the most clear, most imminent morbidity associated
with excessive sleepiness, regardless of the cause that we\'re talking
about, is an impact on behaviors and mood. Behaviors which are impacted
are you wind up with undesired sleep episodes, either working, driving,
lapses of attention, decreased work productivity, and at its worst,
accidents. The impacts on mood are irritability, fatigue, depressed
mood, not depression, loss of energy, and very importantly, lack of
motivation. So these are the morbidities of excessive sleepiness due to
all of the causes I spoke about.

Now, how do they manifest themselves? Well, sleepiness/alertness
manifests itself from its highest point, sustained wakefulness. You\'re
able to sit behind the wheel of your car and drive for 10 hours. At the
other end is continuous sleep and you go from concentration all the way
down to undesired sleep episodes. Disorders of excessive sleepiness are
in this part of the continuum. We are going to deal with drowsy
wakefulness, sleep-wake instability. What sleep-wake instability means
is you\'re sort awake except for about 100 milliseconds you have a
lapse. To sort of put that in context for you, if you\'re driving your
car at 70 miles an hour and you have a 500 millisecond lapse, you stop
your car 50 feet later, better known as off the highway. So very clearly
lapses are an important measure. And there\'s undesirable sleep
episodes, which are longer than those micro-sleeps, those lapses.

Now, excessive sleepiness is measured regardless of etiology. Again, it
doesn\'t make a difference if you\'re Dr. Walsh doing studies in shift
workers or if you\'re Dr. White doing studies in sleep apnea, they\'re
measured in exactly the same way. The gold standard of measuring
sleepiness regardless of which of the causes is measures of sleep
propensity, and there are two measures of sleep propensity originally
described by Drs. Mary Carskadon and William DeMint. The first one is
the Multiple Sleep Latency Test and the other one is the Maintenance of
Wakefulness Test. In a meta-analysis recently done by the academy, they
give very similar results, albeit slightly different numbers, but they
functionally measure the same thing and get very comparable results.

It is very important to understand that these are very, very sensitive
assays and are very valuable to measuring pathology, very valuable in
terms of measuring treatment outcome. There is not a single treatment
for any sleep-wake disorder, whether that\'s apnea, shift work sleep
disorder ‑‑ and I\'m not talking about modafinil ‑‑ CPAP ‑‑ there\'s not
a single treatment in sleep medicine which does not have a study with a
measure of sleep tendency as its primary endpoint. So the big advantage
is it\'s profoundly sensitive.

The problem is how do you translate a 1-minute change in MSLT. If you
take an analysis of all the CPAP studies done to date for the treatment
of sleep apnea syndrome ‑‑ I think Dr. White did this ‑‑ the mean change
in MSLT is .93 minutes. What does that mean? And since we can\'t mean
that, one of the things that\'s very incumbent on the clinician is to
translate that into real-world clinical outputs, and that is done in a
couple of different ways: one, by making clinical judgments. So things
like the CGI are very important. In the sleep and neurology community,
the Epworth Sleepiness Scale is becoming a total mainstay for the
evaluation of sleepiness. You have physician-rated, you have
patient-rated evaluations of sleepiness, Epworth Sleepiness Scale,
Karolinska Sleepiness Scale, specifically used in occupational medicine
rather than general medicine.

Beyond that, we have measures of neurobehavioral performance. I\'m
sorry. Since I sort of mentioned that is the most commonly used scale in
medicine, I\'m going to spend about 30 seconds on the Epworth Sleepiness
Scale.

What is it? Well, it is nothing more than having listened to patients
with excessive sleepiness for many years. You sort of ask them, what\'s
your problem? My problem is why do they present. I fall asleep driving a
car. I fall asleep in meetings. Basically what Dr. Johns has done is he
took those symptoms ‑‑ I fall asleep sitting and reading; I fall asleep
watching television; I fall asleep in a public place, in a theater ‑‑
and he sort of quantified those, gave it psychometric properties, and
identified a pathological level of 10. That has been shown in a variety
of conditions. So it is a self-rating scale which has been validated in
a variety of ways, and it is by face value a clinical measure. It talks
about do you fall asleep driving, do you fall asleep while talking to
your friends. So very clearly it has clinical face validity.

Beyond that, there are neurobehavioral measures. Originally what was
commonly used, especially in the apnea literature, was the Steer Clear,
but more recently the PVT, the Psychomotor Vigilance Task, worked on
mostly by Dr. Dinges, has become the standard measure of excessive
sleepiness in occupational medicine, in sleep medicine, and in normal
variations in sleepiness we talked about. That is now the gold standard
of neurobehavioral measures.

Finally, there\'s a series of outcome measures such as the SF-36 and one
specifically for sleep, which will be discussed.

So one of the things I want to emphasize to you is in evaluating the
efficacy of these compounds, the sine qua non is multiple measurements.
It is multiple measurements. This is the continuum that I talked about
in terms of the manifestations. These are the measuring instruments.
These complement each other. You can\'t use one without the other. In
one case, you wind up with no clinical relevance; in the other case, you
lose precision. So these are complementary parallel measures of the
impact of the disease state and the treatment of the disease state.

So in conclusion, I want to make two things: one, about the symptom
which we\'re talking about today, and then two, about the disorders
we\'re talking about today. So, in conclusion, excessive sleepiness is
associated with significant morbidity, well-defined, well-documented.
Excessive sleepiness manifests itself in very similar ways regardless of
which disorders are causing it. It manifests itself in similar ways;
hence, we can measure it in similar ways. So excessive sleepiness can be
measured objectively, subjectively using standard, reliable, validated
tools which are used in clinical practice and in clinical research.

Now, in terms of the disorders, excessive sleepiness is caused by
increased sleep drive and/or disturbed sleep. Those are the two routes.

Two, disorders of sleep and sleepiness can be defined based upon the
underlying pathophysiology. There\'s a basic impairment of the sleep
drive system which we are called sleep-wake dysregulation. It could be
due to sleep disruption. It could be due to circadian misalignment.
Those are the three routes. Narcolepsy, obstructive sleep apnea
syndrome, refractory, and shift work sleep disorder are the most common
and most representative disorders in each of those categories.

I want to thank you for your attention. And I would like to take this
opportunity to introduce Dr. Hughes who will be our next presenter.

DR. HUGHES: Thank you very much, Dr. Roth. Good morning, everyone.

As Dr. Roth said, I will be presenting our efficacy data today. In doing
that, I will show you that Provigil significantly improves wakefulness
in patients with excessive sleepiness associated with narcolepsy, as Dr.
Katz correctly pointed out as in our original submission and our current
indication, and in addition, in patients with residual excessive
sleepiness associated with obstructive sleep apnea syndrome and in
patients with excessive sleepiness associated with shift work sleep
disorder.

I will show you that these clinical effects are indeed clinically
significant, as evidenced not only by the fact that the clinicians can
recognize the improvement and judge these patients to having been at
least minimally and, in most circumstances, much or very much improved
in the severity of their overall clinical condition.

Secondly, the data clearly show that the patients themselves can
recognize the improvement and report by subjective scales that an
increased ability to maintain wakefulness while they are doing daily
activities in their social and occupational settings.

Finally, I\'ll highlight for you that despite differences in the
underlying pathophysiology, as Dr. Roth has described, Provigil
consistently improves wakefulness across these disorders of sleep and
wakefulness.

I\'ll start with a few slides that point out the similarities in study
design and assessment of excessive sleepiness across the disorders that
we have studied. Our inclusion and exclusion criteria led to a patient
population, all of whom presented with a subjective symptom of excessive
sleepiness, met formal ICSD criteria for one disorder of sleep and
wakefulness, either narcolepsy, obstructive sleep apnea, or shift work
sleep disorder. All patients had no other sleep disorders, no
uncontrolled medical, neurologic, or psychiatric conditions, and were
taking no sedating or activating medications.

Of the studies that I\'ll show you today, all studies employed a
double-blind, placebo-controlled, randomized, parallel groups design. In
our first two studies, part of our original submission, we studied the
effects of a morning dose of 200 or 400 milligrams of Provigil across 9
weeks in patients with excessive sleepiness associated with narcolepsy.

We studied two additional studies in patients with residual excessive
sleepiness in OSA. In one study, we assessed the effects of a 200 and
400 milligram dose, again administered in the morning, across 12 weeks,
and in an additional study, we assessed the effects of a 400 milligram
dose across 4 weeks.

In our study of shift work sleep disorder patients, we assessed the
effects of a 200 milligram dose importantly administered 30 to 60
minutes prior to their shift work, in contrast the two previous groups,
in a 12-week design.

Throughout the presentation, I\'ll spend most of my time talking,
however, about the four studies that are highlighted for you here. These
studies have in common the employment of co-primary endpoints. Now, as
Dr. Roth just described, using multiple measures to assess the clinical
effects is important in this condition, as it is in many others. In
these studies we, indeed, employed two co-primary endpoints, the first
of which was using the gold standard assessments of physiological
sleepiness that Dr. Roth has described, the assessment of an objective
measure of physiologic sleepiness either by the MWT, the Maintenance of
Wakefulness Test, or the MSLT, the Multiple Sleep Latency Test.

For both of these tests, the outcome measure is the latency to sleep in
minutes as recorded by polysomnography and as scored according to
standardized criteria. And the primary analysis was the change from
baseline in these measurements at the final visit. Analysis was done by
analysis of covariance using the baseline as a covariate.

Our second co-primary endpoint was the change in overall clinical
condition as assessed by the clinician raters themselves. In discussions
with the patients, these raters independently obtained a rating of the
severity of their overall clinical condition at baseline and the outcome
measure that we will be measuring is the CGI-C, and that is the change
in the severity of their overall clinical condition on a seven-category
scale, ranging from very much worse to very much improved.

In this analysis, the primary analysis was again done at the final visit
and was done upon the distribution for each treatment group in the
patients who fell into each of these seven categories. The analyses
statistically were done with the non-parametric chi-square test.

Now, it\'s very important to highlight the use of these co-primary
endpoints because, as Dr. Roth said, while the objective gold standard
measurements of excessive sleepiness or physiologic sleepiness are
necessary for determining the extent to which or the degree to which
Provigil significantly led to improvements in underlying physiologic
sleepiness, the change in overall clinical condition is used and has
been used primarily as a judgment to the extent to which Provigil
treatment is clinically significant.

But as Dr. Roth described, there are a variety of tools that can and
have been used to assess sleepiness and the effect of sleepiness in the
sleep community. We employed many of these tests in our studies. In
three of our studies, we employed a second objective measure of
physiologic sleepiness, the MSLT. And in all studies, we employed at
least one subjective measure of sleepiness.

In our narcolepsy NOSA studies, we employed the Epworth Sleepiness
Scale, which simply, as Dr. Roth described, assesses the extent to which
these patients are able to maintain wakefulness in their daily lives
while they\'re in their social and occupational settings. And in the
shift work disorder study, we utilized the Karolinska Sleepiness Scale.

We also employed objective measures of performance in these studies, the
Steer Clear Performance Test, or in our newer studies, the Psychomotor
Vigilance Test. And in addition, we employed the assessment of quality
of life, functional status, and diary data to assess the extent to which
Provigil improved excessive sleepiness or affected aspects of their
daily lives that might be impacted by excessive sleepiness.

Now, throughout the presentation, I will show you data from not all but
a variety of these tests. On these slides in which I have data points, I
have p values only on those tests, where appropriate, that were either
primary efficacy analyses or prespecified secondary analyses.

I\'ll start with a review of some of the data from our original
narcolepsy program. This is important to do for two reasons, the first
of which is that we utilized the results of this program as the
foundation upon which we built the rest of the program. So the results
of these studies were used to predict the results of our subsequent
studies in OSA and shift work sleep disorder.

Secondly, as Dr. Roth described and as Dr. Russell described, this
disorder, narcolepsy, excessive sleepiness associated with narcolepsy,
is included here in our current proposal as our representative disorder
of those patients who present with excessive sleepiness associated with
sleep-wake dysregulation.

Again, I\'ll just highlight for you here that in the narcolepsy studies,
studies 301 and 302, the primary outcome measures were the MWT and the
CGI-C, and that all patients met objective criteria for physiologic
sleepiness as indicated by an MSLT score of no greater than 8 minutes.

You can see here that the severity of their excessive sleepiness and the
degree of excessive sleepiness at baseline were balanced across the
treatment condition. These individuals demonstrated at baseline, as we
would predict because of their disorder, severe excessive sleepiness as
indicated by mean MWT sleep latencies of approximately 6 minutes and
mean MSLT scores of approximately 3 minutes at baseline.

Similarly, these individuals were judged by their independent clinical
raters to be, for the most part, at least moderately ill with respect to
their overall clinical condition, and in fact, between 75 and 85 percent
approximately were rated as at least moderately ill on this category.

The sleepiness markedly interfered or severely interfered with their
activities of daily living and their social and occupational settings
can be seen here by a mean Epworth Sleepiness Scale that is of the
highest that have been reported. 24 is the highest on this scale. So
clearly, these individuals had at baseline a difficulty, a substantial
difficulty in maintaining wakefulness.

Again, these individuals also demonstrated at baseline significant sleep
disruption as evidenced by a greater than 30 minutes of wakefulness in
their sleep episode.

You can see here the results of our first co-primary endpoint at final
visit for the MWT. Provigil significantly increased the ability of these
patients to maintain wakefulness on this task. I\'ll remind you that
statistical significance here is based upon the change from baseline for
each of the active groups compared to the change from baseline in
placebo. The nearly 3-minute increase or the 3-minute difference between
active and placebo demonstrated in study 301 was nearly identical in
study 302.

The independent raters of overall clinical condition also judged and
were able to recognize the improvement in sleepiness. Here statistical
significance is based upon the distribution, as I said, of the treatment
groups across these seven categories, and that Provigil significantly
improved these patients\' overall clinical condition can be highlighted
by the percent of patients who were rated as much or very much improved
at the final visit in the active groups compared to the majority of
patients who were rated in the placebo group as having not changed.
Again, these results were remarkably consistent in study 302,
highlighting the fact that the independent raters judged these
individuals to be predominantly at least minimally improved and more so
in the active groups to be much or very much improved.

That these individuals were able to recognize that sleepiness and
demonstrate by their subjective assessment of their sleepiness that
Provigil was improving their wakefulness in their daily lives can be
seen here by a significant reduction at the final visit in the mean
Epworth Sleepiness Scale score, strongly suggesting that Provigil
treatment significantly improved their ability to maintain wakefulness
in their daily lives.

Provigil treatment was also associated with an improvement in
performance in this case on the Steer Clear Performance Task as denoted
by a reduction in the percent of objects hit while they were performing
this task. This effect, similar in study 302, did in fact achieve
statistical significance in our second study in narcolepsy.

Here I\'m going to show you just some of the diary data that we had
collected in this study and, in fact, the most important data with
respect to the degree to which sleepiness affected these individuals\'
daily lives. Now, in narcolepsy patients, unlike in other patients, and
in fact, thankfully, unlike in most patients, on a daily basis they, as
most of you know, can and often do experience unintended sleep episodes
if not unintentional naps. If you look at those patients who experienced
unintended or undesired sleep episodes at baseline and look by diary
data at the percent reduction, you can see that between 33 and 38
percent in study 301 experienced a reduction in the percentage of
unintended sleep episodes and a nearly 50 percent, approximately 50
percent decrease in these unintended sleep episodes in study 302.

So to summarize our effects in narcolepsy, Provigil significantly
improved wakefulness as evidenced by the objective measure of
physiologic sleepiness, the MWT; significantly improved overall clinical
condition as assessed by the CGI-C and as specifically highlighted by
the higher percent of patients who reported to be very much or much
improved. Provigil improvements were supported by the results of the
secondary outcome measures that demonstrated improvements in MSLT in
their ability to sustain wakefulness in their daily lives, reductions in
the number of errors on the objective performance test, and a reduction
in the unintended sleep episodes by sleep diary. And again, similar
results were seen in this study between the 200 and 400 milligram
treatment groups.

As you recall, residual excessive sleepiness associated with OSA is the
disorder that we chose to be representative for those individuals who
report with excessive sleepiness associated primarily with sleep
disruption.

Just to take a few moments to talk about excessive sleepiness in OSA, of
course, the primary treatment for obstructive sleep apnea is nasal CPAP
or some similar mechanical device designed to treat the underlying
sleep-disordered breathing. In fact, as Dr. Roth described, it is well
accepted in the sleep and pulmonary communities and, indeed, the medical
communities that treatment of this underlying disruption can lead to
important and clinically significant improvements in alertness or
wakefulness as evidenced by a reduction in the amount of sleepiness in
their daily lives, as measured by the ESS, or just as we\'ve done in
narcolepsy, an increase in the MSLT.

As Dr. Roth described, a recent meta-analysis of every study that\'s
been reported on the effects of CPAP on excessive sleepiness shows that
a combined MSLT and MWT difference on treatment from placebo in most
cases or in many cases is about a 0.93 minute change in objective sleep
latency and that these improvements, not all in the same studies ‑‑ CPAP
improvement is indeed associated with a slightly less, about a 2.9
decrease in the mean Epworth Sleepiness Scale score.

Despite the clear clinical benefit in reducing excessive sleepiness
associated with nasal CPAP, some patients, despite regular use of this
therapy, still experience excessive sleepiness. The CPAP therapy fails
to fully resolve these symptoms. And this residual excessive sleepiness
has been associated and can be associated with moderate impairment in
social and occupational function.

In study 303, I\'ll remind you that we assessed a 200 and 400 milligram
dose of Provigil and utilized again, like narcolepsy, the MWT and the
CGI-C as our co-primary endpoints. All patients met formal criteria for
a diagnosis of obstructive sleep apnea syndrome and demonstrated
residual excessive sleepiness as indicated by an Epworth Sleepiness
Scale score of greater than or equal to 10.

Importantly, these individuals had to demonstrate in nocturnal
polysomnography that their CPAPs were indeed effective as
operationalized by an apnea-hypopnea index while on treatment. An
apnea-hypopnea, for those of you who may need reminding, is simply just
the number of apneas or hypopneas, the number of sleep disordered
respiratory events, per hour. So while on treatment, their
apnea-hypopnea index had to be less 10 and had to have demonstrated at
least a 50 percent reduction or improvement in their sleep-related
breathing disorder compared to historic AHIs.

We also stratified in this study according to CPAP use at baseline as
assessed nightly on a minute-by-minute basis for approximately 2 weeks
prior to the study. That stratification was based upon in the literature
the prespecified definition of regular use, which as Dr. Katz rightly
pointed out, is greater than or equal to 4 hours per night on
approximately 5 nights or more. Partial users were simply those
individuals who were using their CPAP but not for the amount of time
that would quite meet the formal criteria for regular use.

Originally 18 patients were enrolled into the trial who demonstrated no
use on their CPAP at all. But importantly, upon discussion with our
advisors and upon further reflection, we made the decision to amend the
protocol to exclude those individuals who were not using their CPAP. We
did this because of the importance of CPAP in treating the underlying
pathology and in the ongoing clinical difficulty in the sleep community
about CPAP compliance. Those 18 individuals are not presented in the
efficacy data that I\'ll show you in a minute, but are presented in the
safety data that Dr. Niebler will be describing for you soon.

At baseline you can see approximately an equal number of patients were
randomized to each of the treatment groups. There was a low withdrawal
rate due to adverse events. However, I\'ll highlight indeed a higher
withdrawal rate due to adverse events in the Provigil treatment groups.

The treatment groups were balanced with respect to age and race. More
males than females were enrolled into the 200 milligram group. However,
I\'ll point out for you that we looked at this in our statistical
analyses and found it to have no effect on our efficacy analyses.

Like in narcolepsy, the severity of excessive sleepiness and the degree
of sleep disruption was balanced across the treatment condition. Unlike
in narcolepsy, however, these individuals did not, as we would expect
based upon the fact that they were being partially treated, they were
having residual sleepiness and not sleepiness ‑‑ we found that these
individuals had moderate excessive sleepiness at baseline as indicated
by a mean MWT of approximately 13 minutes.

About 65 percent or so of these individuals were judged to be at least
moderately ill in overall clinical condition by their clinicians, and
the patients themselves rated approximately a 16 on the Epworth
Sleepiness Scale, suggesting that there was a moderate, at least a
moderate, impairment in their ability to maintain wakefulness at
baseline while performing daily activities.

As in the other study, these individuals did still demonstrate
significant sleep disruption as indicated by a greater than 30 minutes
of wakefulness within their sleep episode.

Finally, I\'ll highlight for you that these individuals, although the
criteria for inclusion in the study maximally could have been the
greater than 4 hours per night on 5 nights, the mean average use was
very high and well above the national average. So these individuals were
using their CPAPs on average about 6 hours per night, which is quite
high if you look at the literature.

Provigil treatment was associated with significant improvement in
wakefulness on the objective measure of physiologic sleepiness. Again,
I\'ll remind you that statistical significance was based upon the change
from baseline in the active groups compared to the change in baseline in
the placebo group.

As in narcolepsy, clinicians not only noticed the change, but
significantly rated these individuals as having statistical and clinical
significance in overall clinical condition, as denoted by the shift in
the two active treatment arms towards the at least minimally improved
category and highlighted by the greater number of patients who were
rated as at least much or very much improved in the active groups
compared to the majority of patients again who were rated as having no
change in the placebo group.

As in narcolepsy, still, these individuals were able to recognize that
Provigil was improving their wakefulness and indeed demonstrated on the
Epworth Sleepiness Scale that Provigil improved their ability to
maintain wakefulness in their daily lives as denoted by statistically
significant reduction in the mean Epworth Sleepiness Scale score at
final visit.

Now, in this test, we used the Psychomotor Vigilance Test not only in
this study but in the subsequent studies. As you may know, the
narcolepsy studies were done in the early to mid-\'90s, and at this
time, the Psychomotor Vigilance Test had clearly replaced the Steer
Clear Performance Test as the gold standard assessment in the sleep
community of performance.

The PVT is a very boring task I\'ll highlight for you. One just simply
watches a computer monitor for 10 minutes and waits for a stimulus to
occur. Once it occurs, they just press a button as quickly as they can.
Now, you and I should be able to press this button in approximately 250
milliseconds, probably on average maybe 300 milliseconds as a high, and
we should be able to perform this 10-minute task with about 1 lapse. A
lapse is defined as responding or failing to respond to the stimulus
within 500 milliseconds and typically either in the best case represents
a lapse of attention, or in the worst case represents a micro-sleep
episode or an unintended sleep episode.

You can see that the two active groups were unequal at baseline.
However, statistical significance was achieved in both groups, and more
importantly both groups represent approximately a 50 percent decrease in
the number of lapses.

So to summarize our results in study 303, Provigil significantly
improved wakefulness as assessed by the objective measure, improved
overall clinical condition, significantly improved wakefulness as
assessed by secondary outcome measures, and again as in narcolepsy,
similar results were seen for the 200 and the 400 milligram dose.

In our additional 4-week study in these patients, we used the Epworth
Sleepiness Scale score as the primary outcome measure, but notably
included an objective measure of physiologic sleepiness, the MSLT, and
of course, the CGI-C.

The patient population was very similar in that they all had a diagnosis
of OSA. All demonstrated residual excessive sleepiness. All had to
demonstrate that their CPAPs, when they were being used, were effective
in treating their underlying sleep-disordered breathing, but this study
only included those individuals who were regularly using their CPAP.

As in the three previous studies I showed you, Provigil was associated
with significant improvement in these patients\' ability to maintain
wakefulness in their daily lives as denoted by statistically significant
reductions in the mean Epworth Sleepiness Scale score at the final
visit.

And Provigil was associated with significant increases at the final
visit in the latency to fall asleep on the Mean Sleep Latency Test.

And the clinicians rated statistically significant improvements in
overall clinical condition, although I\'ll point out for you that in
this study alone, of all the studies I\'ll show you, statistical
significance was driven primarily by the increase in the percentage of
patients who were rated as at least minimally improved compared to those
patients, the vast majority of whom, were rated as having at least no
change in the placebo condition.

So here again, in our second study of OSA, we found very similar results
to study 303, suggesting that Provigil significantly improves
wakefulness on objective measures of physiologic sleepiness. This
improvement in wakefulness is recognized both by the clinicians and by
the patients.

In the last study I\'ll show you today, I\'ll highlight for you the
results of what you may recall is our representative disorder of those
patients who present with excessive sleepiness associated with primarily
circadian misalignment. But I\'ll spend just a few moments talking about
the differences between shift work and shift work sleep disorder.

Approximately 20 million Americans work nonstandard schedules. It could
be arbitrarily defined between the hours of 7:00 a.m. and 7:00 p.m. Many
of these individuals would change their work schedule if they could, as
denoted by a recent study that was done by Dr. Ohayon.

Working nonstandard hours has, for many, many decades, been associated
with increased morbidity, most notably excessive sleepiness and
insomnia. In fact, approximately 2 to 5 percent report a sleep-related
difficulty associated with working nonstandard hours, and these
individuals have, in many instances, been shown to have significantly
increased risk for errors, lapses of attention, near misses, and
accidents, particularly during the commute home. This risk has been
recently reported to be significantly greater in those patients with a
formal diagnosis of a circadian rhythm sleep disorder or shift work
sleep disorder. But it\'s important to recognize that while all patients
with shift work sleep disorder are shift workers, not all shift workers
have shift work sleep disorder.

The highest assessment of the prevalence of shift work sleep disorder
has recently been published in a very rigorous way assessing the minimal
diagnostic criteria, and in this study, Dr. Ohayon found that
approximately 19 percent of individuals working the night shift report
moderate to severe excessive sleepiness, and approximately 23 percent of
these individuals would meet minimal criteria for shift work sleep
disorder.

But what is shift work sleep disorder? Shift work sleep disorder is
simply a circadian rhythm-related sleep disorder in which the primary
complaint is either insomnia or excessive sleepiness. I\'ve highlighted
excessive sleepiness because this is what we\'re here to talk about. The
primary symptom is temporally associated with working the night shift
and that simply means that on their days off, they\'re not excessively
sleepy.

PSG and MSLT demonstrate loss of normal sleep-wake pattern. That\'s just
a very roundabout way of saying that when you assess their sleep during
the daytime by daytime polysomnography, you see significant sleep
disruption, and when you assess their sleepiness at night by the MSLT,
you see significant sleepiness. These individuals, of course, have no
other mental, neurologic, or psychiatric condition nor have another
sleep disorder.

In our study, I\'ll highlight for you that we assessed the effects of a
200 milligram dose administered 30 to 60 minutes prior to their work
shift on those nights that they worked the night shift. The primary
outcome measure for the physiologic sleepiness was the MSLT, and we also
included, of course, as our co-primary the CGI-C. The MSLT was included
in this study primarily because of the predominance of evidence in the
literature validating the MSLT assessment of sleepiness at night at the
time that we designed the trial, and because this was the very first
clinical trial of this nature done in patients with shift work sleep
disorder, we wanted to choose the most conservative of the two objective
measures of physiologic sleepiness, both with respect to the
predominance of evidence in the literature, but also with respect to
modafinil\'s effects.

We also included the Karolinska Sleepiness Scale for very similar
reasons as our subjective measure of sleepiness. The Karolinska
Sleepiness Scale is the predominant scale of excessive sleepiness used
in occupational medicine and in occupational settings and has been
widely validated in assessing sleepiness subjectively across the day and
particularly at night.

With the important help of the FDA ‑‑ thank you ‑‑ and with our advisors
here, we took great pains to design a trial that would allow individuals
an opportunity to adapt to their night shift but still include patients
who, despite that opportunity, met very rigorous definition and formal
criteria for shift work sleep disorder. In doing that, these individuals
were either fixed-night workers or rotating night workers who had to
work at least 5 nights a month, not individuals who just simply worked 1
night every 3 months and were sleepy. They had to work at least 5 nights
per month. We originally stratified by the number of nights that they
worked, between 5 and 10 nights or greater than 10 nights. At least 3 of
these nights had to be consecutive, and the work shifts themselves had
to be no greater than 12 hours with at least 6 of those hours falling in
between the nighttime hours, as we defined, 10:00 p.m. to 8:00 a.m.

All individuals met formal criteria for a diagnosis of shift work sleep
disorder, but also reported excessive sleepiness for at least 3 months,
so they clearly had the opportunity to adjust, if they would have, to
working this schedule.

In addition to these, we had the independent clinician raters judge them
to be at least moderately ill with respect to excessive sleepiness on
their work nights and including the commute home.

And finally, all patients met objective criteria for excessive
sleepiness as indicated by a mean sleep latency of no greater than 6
minutes and objective measure of disrupted sleep during the daytime, as
indicated by no greater than 87.5 percent of sleep efficiency.

I\'ll take a moment to describe the clinic visits because they were
somewhat more complex given the nature of how we assessed sleepiness.
The clinic visits occurred on the first night immediately following
their final night of working the work shift. So if they had a work week
that was 3 nights long, then this clinic visit would occur on night 4.
If it was 5 nights long, the clinic visit would be on night 6.

The clinic visits began with a dose of Provigil administered at 10:00
p.m., with objective measurements beginning and continuing throughout
the night, beginning about 3 hours after. The MSLT was done between 2:00
a.m. and 8:00 a.m. every 2 hours, as is standardized. PVT was done
between 1:00 and 7:00 a.m., with the Karolinska Sleepiness Scale being
done hourly just before each of those.

Importantly, the CGI-C assessments were done after the last MSLT but
prior to the daytime sleep episode in which we assessed at the final
visit polysomnographically their daytime sleep which occurred between
10:00 a.m. and 6:00 p.m.

A roughly equal number of patients were enrolled into each of the
treatment groups, and again, there was a low discontinuation rate due to
adverse events, approximately equal between the two treatments. Again,
the two treatment groups were balanced with respect to age, gender, and
race.

As in our previous trials, the severity of excessive sleepiness and
degree of sleep disruption was balanced across the two treatments and
unlike in those patients with residual excessive sleepiness in OSA and
in fact more so, at least at the time that we looked, than the patients
with narcolepsy. These individuals were, as you can see by the
highlighting here, significantly and severely sleepy as evidenced by a
mean MSLT of approximately 2 minutes.

The clinicians rated them also to be moderately to severely ill, as
indicated by the approximately 50 percent of the patients who were rated
as at least markedly ill in overall clinical condition. And again, these
patients could recognize this sleepiness and rated it themselves as
moderately to severely ill on the Karolinska Sleepiness Scale score.

Now, because of the nature of the disorder, these individuals did,
indeed, have a greater degree of sleep disruption, which has been
characterized many, many times and as Dr. Roth described, as a
consequence of the misalignment that they are living under.

Provigil significantly improved wakefulness on the MSLT test at final
visit, as indicated by significant increases in the mean sleep latency
of this test, and these effects and the Provigil treatment was judged by
the clinicians as having significantly improved their overall clinical
condition, as indicated by a greater number of patients shifted to the
improved category in the active group and as highlighted by the greater
percentage of patients who were rated as much or very much improved in
overall clinical condition.

As in our other trials, these data provide strong support for the
clinical significance of this treatment, as do the data from our
secondary outcome measures. Shown here is the improvement in subjective
sleepiness at the final visit on the Karolinska Sleepiness Scale and the
improvement in lapses from the Psychomotor Vigilance Test again at the
final visit. Here you can see that we employed a 20-minute test, not a
10-minute test, which is one of the reasons why these individuals, along
with their greater impairment compared to the OSA patients, were having
at baseline greater than 1 lapse per minute. That Provigil significantly
improved performance in this task can seen by ‑‑ again I\'ll highlight
statistical significance was based upon the improvement in the active
group compared to what was a worsening in the placebo group, and that
the difference between these two groups at final visit represents about
10 lapses. So in fact Provigil treatment on this task was associated
with approximately 1 less lapse every 2 minutes.

We also measured subjective sleepiness by use of electronic diaries
assessed every 2 hours during the night shift and during the commute
home, not during the home, rather, but for the commute home. You can see
that Provigil was associated with a reduction in subjective sleepiness
while they were at work on the night shift, as well as a reduction,
using the same scale we used in the clinic, of their sleepiness during
the commute home.

If one looks at the percent of patients who reported at least one
mistake, near miss, or accident during the night shift throughout the
treatment period, you can see that there was a reduction in the percent
of patients who reported at least one of these events throughout the
entire treatment period for the night shift and about a 15 percent
reduction in the percent of patients who reported an unintended sleep
episode during the night shift.

Similarly, there was a reduction in the percent of patients who reported
a mistake, near miss, or accident during the commute home, as well as
approximately a 9 percent reduction in the percent of patients who
reported at least one unintended sleep episode during the commute home.

So to summarize our shift work sleep disorder data, again, as in our
other models, we demonstrated consistent and significant improvements in
objective measures of physiologic sleepiness using, in this case, the
MSLT gold standard measure of objective sleepiness. Provigil treatment
was recognized by the clinicians and judged to have been associated with
improvements in overall clinical condition. Provigil treatment also in
our secondary outcome measures was associated with improvements in
subjective sleepiness, improvements in performance, and importantly,
improvements in subjective sleepiness in their social and occupational
settings.

So I\'ve talked about within each disorder the effects of Provigil on
wakefulness on most of the measures that we\'ve used. Now I want to
spend just a few moments summarizing the effects of Provigil across
these disorders.

What\'s shown for you here are the MWT data in those studies in which we
assessed the MWT, and notably in each of these studies, it was a primary
endpoint. I\'ve included a lot of the data, but what I want to highlight
for you is that in all instances statistical significance was reached in
each of these studies for both doses and in the far right-hand column,
if you compare the difference on active, the net difference from
placebo, what you see is in the narcolepsy studies, between a 2.7- and
3.0-minute change, and in the additional study in which this assessment
was done in OSA, between a 2.6- and a 2.7-net minute change.

If you look at the data in which we utilized the Multiple Sleep Latency
Test, you see very similar effects. Again, statistical significance was
reached in nearly all cases except for the 200 milligram group in which
there was a trend but didn\'t reach statistical significance in our
original narcolepsy program. And if you look at the net difference in
the far right-hand column, the variability in treatment effect outside
and across these disorders were in fact less than the variability within
narcolepsy. So in narcolepsy, the net difference was between .7 minutes
and 1.4 minutes, while in OSA and shift work sleep disorder, we
demonstrated a 1.2‑net minute change and a 1.4-net minute change,
respectively.

If one looks at the overall clinical condition, you can see up here the
percent of patients who were rated as at least minimally improved in
overall clinical condition, which clearly shows a consistent improvement
in the percent of individuals who the clinicians could recognize the
treatment and judged this treatment to be clinically important.

You can also notice the remarkable similarity in the percent of patients
who were judged to be at least minimally improved in placebo.

Again, I\'ll highlight for you that in all studies except one, there was
a striking effect for those individuals who were rated as at least much
or very much improved in their overall clinical condition.

If you look at the Epworth Sleepiness Scale score, finally, the
subjective measure that at least in OSA and in narcolepsy represents a
quite face-valid assessment of the extent to which these individuals are
able to maintain wakefulness in their daily lives, you can see again
remarkable consistency in the effects where Provigil treatment is
associated here with significant reductions in the Epworth Sleepiness
Scale score and quite consistent across those two disorders in which we
employed this measure.

Plotting on the same scale ‑‑ and again, this is a different scale I\'ll
highlight ‑‑ you can see that the effect size was quite similar for the
subjective scale that we employed in our other measure of excessive
sleepiness associated with disorders of sleep and wakefulness, shift
work sleep disorder.

So, in summary, Provigil significantly improved wakefulness in patients
with narcolepsy, obstructive sleep apnea, and shift work sleep disorder.

Provigil improvements were judged by the clinicians to be recognized and
clinically significant as indicated by significant improvements in
overall clinical condition.

Too, the patients were able to recognize this improvement and judged
that Provigil was associated with a significant improvement in their
ability to maintain wakefulness in their daily lives.

And finally, despite the differences in the pathophysiology associated
with these three disorders, Provigil consistently improved wakefulness
across these disorders of excessive sleepiness associated with sleep and
wakefulness.

I\'d like to thank you for your time and your attention, and I\'d like
to turn the podium over to Dr. Wendy Niebler who will be describing our
safety data.

DR. NIEBLER: Good morning.

Dr. Roth and Dr. Hughes have highlighted for you the commonality of the
symptom of excessive sleepiness across the disorders of sleep and
wakefulness, as well as the consistency of the wake-promoting effects of
Provigil in three representative disorders of sleep and wakefulness,
specifically narcolepsy, OSA, and shift work sleep disorder. I will now
show you the safety data for Provigil.

As you have heard, Provigil has been approved to treat the symptom of
excessive sleepiness associated with narcolepsy since 1998 in the United
States and is actually approved in 27 countries worldwide. Extensive
worldwide experience and clinical trial data have shown us that Provigil
is well tolerated.

The key message that I want to leave you with today is that the safety
profile of Provigil treatment for the symptom of excessive sleepiness
associated with OSA and shift work sleep disorder is the same and in
some cases better than the safety profile already outlined in the
current Provigil package insert, with no new safety concerns identified.
Therefore, because the safety profile is so consistent across the three
representative disorders studied, it is reasonable to conclude that the
safety profile can be generalized to the other disorders of sleep and
wakefulness.

During the clinical development program, a significant number of
patients and subjects have received Provigil. As highlighted for you
here, over 1,000 patients have received Provigil for at least 6 months,
over 700 for at least 1 year, and over 300 for at least 2 years in
clinical studies. I want to point out that there has been long-term
exposure to Provigil in all three of the representative disorders. This
safety presentation includes information on over 480 narcoleptics, over
160 patients with OSA, and 90 patients with shift work sleep disorder
who have been treated with Provigil for at least 12 months in clinical
studies. Of note, the open-label treatment extension of the shift work
sleep disorder study 305 is still ongoing, and as of the end of August,
actually over 120 patients with shift work sleep disorder have been
treated with Provigil for at least 1 year. Altogether, there have been
over 2,000 patient treatment-years in clinical studies.

For the purpose of the safety review for this supplemental NDA, studies
were grouped into populations and data integrated. I will now walk you
through these study groupings.

The briefing document provided details on the six principal studies
across the three representative disorders of sleep and wakefulness. The
number of patients who received Provigil or placebo within each disorder
is presented for you here. As you have heard earlier, these studies
ranged between 4 and 12 weeks in length.

The integrated population of the six principal studies includes almost
1,000 patients who have been treated with Provigil and almost 600 who
have been treated with placebo. This population was referred to as the
principal studies in the briefing document.

When the long-term, open-label extensions of the six principal studies,
as well as a few additional supportive studies in narcolepsy and OSA,
are added to the data from the principal studies, an expanded population
that includes information on over 2,100 patients is created. This
population was referred to in the briefing document as all narcolepsy,
OSA, and shift work sleep disorder studies.

With the addition of data from studies done in other therapeutic areas,
as well as pharmacology studies to the previous group, we create a
population that contains information on nearly 3,800 adult patients and
subjects treated with Provigil. This population was referred to as \"all
studies\" in the briefing document.

The last two populations include patients treated with Provigil in
clinical trials for well over 2 years. The studies by disorders and the
integrated principal studies population form the basis of this
presentation because of the availability of comparator arms.

Over the next three slides, I will review the adverse event profile, the
serious adverse events, and the adverse events leading to study
withdrawal from the principal studies and highlight the similarities
between the disorders.

Presented here is the adverse event profile for the treatment of
excessive sleepiness associated with narcolepsy from the current
Provigil label. The adverse events can be conceptualized as occurring in
two clinical areas, those related to the central nervous system, such as
headache, nervousness, and dizziness, and those related to the
gastrointestinal system, such as nausea, diarrhea, and anorexia.
Headache and nausea are the most common adverse events, and other
adverse events occur at a low frequency.

The important point here is that with the addition of the adverse event
profiles from the OSA and shift work sleep disorder studies, the overall
type and incidence of adverse events seen in OSA and shift work sleep
disorder patients treated with Provigil are similar to those seen in
narcolepsy patients treated with Provigil. Headache and nausea are the
most common adverse events in both of these disorders with Provigil
treatment as was seen in narcolepsy.

The incidence of headache actually declined in the OSA and shift work
sleep disorder population, and this is not surprising because an
association between headaches and narcolepsy is well established in the
literature.

Over 90 percent of the adverse events were judged by the investigators
to be mild to moderate in severity and most of the adverse events
occurred within the first month of treatment for all three of the
disorders.

Presented here is the serious adverse event profile by body system seen
with Provigil treatment for the currently approved indication of
excessive sleepiness associated with narcolepsy. Serious adverse events
occurred at a low rate, and there were no trends as to the types of
serious adverse events.

With the addition of the data from the OSA and shift work sleep disorder
studies, you can see that serious adverse events occurred at a low
frequency of 2 percent or less in these disorders as well. As with
narcolepsy, there were no trends or patterns as to the types of serious
adverse events seen within each disorder or between the disorders. The
only serious adverse event that occurred in all three disorders with
Provigil treatment was chest pain which is included as part of body as a
whole on this slide and was reported in 1 patient each with narcolepsy,
OSA, and shift work sleep disorder out of 934 Provigil-treated patients.
Of note, there were no deaths in the principal studies in any of the
disorders.

Adverse events leading to withdrawal can be examined in a similar
manner. Specific adverse events leading to withdrawal occurred at a low
rate in narcolepsy. The most frequent reason for withdrawal that was at
a higher incidence in the Provigil group than in the placebo group was
headache, which is included as part of body as a whole on this slide.

Similarly, in patients with OSA and shift work sleep disorder, there was
no predominance of any one adverse event leading to withdrawal from the
study. As with narcolepsy, headache was one of the most common reasons
for study withdrawal both in patients with OSA and shift work sleep
disorder. However, again like narcolepsy, it was the cause for
withdrawal infrequently, specifically in only 3 percent of OSA patients
and 2 percent of patients with shift work sleep disorder.

The other most common adverse event leading to withdrawal in patients
with OSA was dizziness and in patients with shift work sleep disorder
was insomnia, each reported in 2 percent of patients. These are included
as part of the nervous body system on this slide.

I have now demonstrated for you that Provigil was well tolerated when
compared to placebo treatment across the principal studies which, as you
will recall, were up to 12 weeks in length.

Since many of these disorders are chronic in nature, I want to now show
you the adverse event profile of Provigil when it was administered over
a 1-year period.

Longer-term treatment with Provigil for excessive sleepiness associated
with narcolepsy did not reveal patterns of adverse events different from
that in the principal studies, and the incidence did not significantly
change compared to the principal studies. Over the first year of
treatment with Provigil, headache remained the most common adverse
event. In general, the adverse events occurred early in treatment except
for infection which occurred at a steady rate throughout the year.

When the adverse event profiles seen in the first year of treatment from
the OSA and shift work sleep disorder studies are added, you can see
that the type and incidence of adverse events are similar to narcolepsy
over the same time period, as well as similar to what was seen in the
principal studies.

In addition, as I mentioned earlier, studies in this supplemental NDA
were integrated into expanded populations that included patients treated
for well over 2 years with Provigil. The adverse event profile seen in
these populations is similar to that already outlined for you and
Provigil continued to be well tolerated with longer treatment.

Across all the studies with Provigil, again with some of them involving
years of treatment, a total of 13 deaths have been reported. All of
these deaths were considered unrelated to Provigil treatment. No trends
were seen in the cause of death, and no deaths occurred in patients with
OSA or shift work sleep disorder.

On the next slide now I will summarize the lack of clinically relevant
changes on vital signs, ECGs, and laboratory measures seen with Provigil
treatment.

In the clinical studies, there were no changes in vital signs or ECGs
including intervals with Provigil treatment. No changes in laboratory
values were seen with Provigil treatment except for alkaline phosphatase
and GGT variables. Mean values for alkaline phosphatase and GGT showed
small increases with increasing duration of exposure to Provigil.
However, few patients had elevations outside of the normal range, and
there were no effects seen on other liver function tests. An important
point here is that all of these results are similar to those already
described in the current Provigil label.

To end this section of the safety presentation, I want to show you the
adverse event profile from the principal studies integrated across all
three disorders of sleep and wakefulness. As discussed, the type and
incidence of adverse events was similar between the disorders studied
and there was no concerning trend within any disorder or between
disorders with regard to serious adverse events or adverse events
leading to withdrawal. Therefore, it was felt that the adverse events
for Provigil could be integrated as a way of presenting the adverse
event profile across the disorders of sleep and wakefulness.

When the current Provigil label for the treatment of excessive
sleepiness associated with narcolepsy is shown next to the integrated
profile, it is possible to see the similarities between the two. Both
the types and incidence of adverse events are comparable between the two
profiles. Headache and nausea remain the two most common adverse events,
but the incidence of headache is actually less in the new integrated
profile. As in the current label, other adverse events occurred at a low
frequency in the profile from the integrated principal studies.

The next several slides will now focus on specific topics of interest
with regard to the use of Provigil in the disorders studied. In this
section, I will review for you Provigil\'s effect on blood pressure in
patients with residual excessive sleepiness associated with OSA, nasal
CPAP use in patients with residual excessive sleepiness associated with
OSA, and sleep when sleep is desired.

I mentioned earlier that there was no effect on vital signs with
Provigil treatment. However, I want to specifically highlight the lack
of effect of Provigil on blood pressure in patients with OSA because OSA
is known to be an independent risk factor for hypertension, and you may
recall from the briefing document that an adverse event of hypertension
was reported in a few patients in the OSA study.

Blood pressure was obtained at each visit during the principal studies,
and the mean systolic and diastolic blood pressure over time is
presented for you here for the two principal studies in OSA. As you can
see, blood pressure did not change during the studies with Provigil
treatment.

Besides evaluating the mean changes, it is useful to look for specific
changes. The percentage of OSA patients with a clinically significant
change in blood pressure at final visit in the clinical studies is
presented here. A clinically significant change was defined as either
systolic blood pressure of at least 140 millimeters of mercury or a
diastolic blood pressure of at least 90 millimeters of mercury and a
greater than 10 percent increase. As you can see, the percent of
patients with a clinically significant change is comparable between the
Provigil and placebo treatment groups.

As you have heard, as part of managing excessive sleepiness, the
treatment of the underlying disorder should be optimized and the
treatment for excessive sleepiness should not interfere with the primary
treatment. In the case of patients with OSA, as you have heard, nasal
CPAP is considered the primary treatment. Because of this, I want to
highlight for you the lack of effect of Provigil on nasal CPAP use in
patients with residual excessive sleepiness associated with OSA.

The results of nasal CPAP use seen during the principal OSA studies are
presented for you here. Study 303, the 12-week study, is on the left and
study 402, the 4-week study, is on the right. Hours of nasal CPAP use
are presented on the y axis. As you can see, nasal CPAP use was high at
baseline, above the national average of 4 to 6 hours per night, and that
level of use was maintained throughout both studies.

It is well established in the literature that nasal CPAP use decreases
over time, and if you are wondering what happened to nasal CPAP use with
long-term Provigil treatment, here are the results from the 1-year
long-term treatment extension of OSA study 303. Presented here are
patients who completed the study with mean nasal CPAP use for the same
group of patients presented for each interval of time. There was a small
decrement in mean nasal CPAP use over the first 9 months and none after
that. Of note, the decline in nasal CPAP use is similar to that reported
in the literature and mean use over the year of treatment remained well
above the average nightly use of 4 to 6 hours established in the
literature.

Next I will show you the lack of effect of Provigil on sleep when sleep
is desired. As you will recall, Dr. Roth mentioned that a wake-promoting
agent should not adversely affect sleep when sleep is desired. You may
also recall from the briefing document and earlier in my presentation
that insomnia was reported as an adverse event in a few patients in the
Provigil clinical studies. In the clinical studies, polysomnograms were
conducted at night in patients with narcolepsy and OSA and during the
daytime in patients with shift work sleep disorder to objectively assess
whether Provigil treatment adversely affected sleep when sleep was
desired.

One measure of disturbed sleep from the PSG is sleep efficiency which is
the percent of time in bed spent asleep and which is presented for you
here with narcolepsy studies across the top and OSA and shift work sleep
disorder studies across the bottom. As you can see, there was no change
in sleep efficiency in any of the three disorders with Provigil
treatment.

Another measure of disturbed sleep from the PSG is the time awake after
sleep onset, which is presented for you here with narcolepsy studies
again across the top and OSA and shift work sleep disorder studies
across the bottom. As you can see, there was no deleterious effect on
the patient\'s ability to stay asleep in any of the disorders with
Provigil treatment.

I want to further highlight the lack of effect on sleep when sleep is
desired, specifically in patients with shift work sleep disorder,
because as many of you know, these patients have difficulty sleeping
during the daytime. Therefore, besides assessing sleep with daytime
PSGs, subjective evaluation of daytime sleep was undertaken in the shift
work sleep disorder studies with the use of diaries.

Of specific interest in these patients is whether nighttime
administration of Provigil led to patients spending less time in bed
during the day, and this data is presented for you here. As you can see,
Provigil treatment did not lead to a decrease in the amount of time
patients spent in bed during the day after working night shifts. These
data all support the conclusion that there appears to be no adverse
effect on sleep when sleep is desired with Provigil treatment for any of
the disorders of sleep and wakefulness.

I want to end the safety presentation by briefly highlighting for you
the data collected through pharmacovigilance surveillance since the
approval of Provigil. As I mentioned earlier, Provigil is approved in 27
countries worldwide. Nearly a quarter million patient treatment-years
have occurred with Provigil since the first approval through February of
this year. Postmarketing adverse drug reactions have been reported with
a low frequency similar to adverse events in the clinical studies. Also
consistent with the clinical studies, the most common postmarketing
adverse drug reactions reported have been headache and nausea. These
results from real-world use validate the safety profile from the
clinical studies that I have presented to you today.

So, in summary, Provigil has been extensively evaluated and Provigil is
well tolerated.

In the clinical studies, Provigil treatment did not result in any
clinically relevant changes in laboratory measures, ECGs, or vital
signs, did not interfere with nasal CPAP use in patients with residual
excessive sleepiness associated with obstructive sleep apnea, and did
not interfere with sleep when sleep was desired in any disorder.

The safety profile of Provigil for the treatment of excessive sleepiness
associated with OSA and shift work sleep disorder is the same as the
safety profile in the currently approved Provigil label for narcolepsy
with no new safety concerns identified.

Lastly and most importantly, because the safety profile of Provigil is
so favorable and consistent across the three disorders studied, we can
conclude that Provigil will be well tolerated for the treatment of
excessive sleepiness associated with other disorders of sleep and
wakefulness.

Thank you for your time, and Dr. Russell will now provide concluding
remarks.

DR. RUSSELL: Thank you, Dr. Niebler.

So, in summary, what you have heard today from Dr. Roth and Dr. Hughes
is that excessive sleepiness is a prominent and disabling symptom of
disorders of sleep and wakefulness and that narcolepsy, obstructive
sleep apnea, and shift work sleep disorder are representative disorders
of sleep and wakefulness which have excessive sleepiness as a primary
complaint. In clinical studies conducted with Provigil, Provigil
treatment significantly and consistently improved wakefulness across the
disorders and across both objective and subjective efficacy measures.

The safety profile of Provigil was comparable across all disorders
studied with no population-specific safety concerns noted. And
importantly, the safety profile of the expanded patient population is
comparable to the safety profile in the current Provigil label with no
new trends emerging.

So, in conclusion, Provigil is consistently effective and well
tolerated, and therefore the treatment effect of Provigil can, we
believe, be generalized to disorders of sleep and wakefulness. And
therefore, Provigil should be indicated to improve wakefulness in
patients with excessive sleepiness associated with disorders of sleep
wakefulness.

Thank you for your attention and we\'re now happy to take questions, but
before doing that, I just would like to highlight that we have several
advisors sitting with us who would be happy to answer questions too.

DR. KAWAS: Thank you very much, Dr. Russell and the company.

The floor is now open for questions to the sponsor.

DR. AZARNOFF: In view of one of the questions, I wonder if either in the
protocol or in discussions with the FDA a clinically significant
difference in the endpoints was determined.

DR. RUSSELL: Sorry. I didn\'t quite catch that question.

DR. AZARNOFF: Was there a definitive decision in the protocol stating
that so much change was clinically significant or was a discussion with
the FDA done in which a clinically significant endpoint was determined?

DR. RUSSELL: The discussion with the FDA revolved largely around the use
of two primary outcome measures for all of the populations studied. They
wanted us to include an objective measure of sleep latency, so either
the MWT or the MSLT, and a clinical measure, which was the CGI-C. Those
were largely the discussions that took place around endpoints.

DR. KAWAS: Dr. Katz?

DR. KATZ: Yes. I just want to ask a question related to the fundamental
issue that we are particularly concerned about which has to do with how
we know that the disorders studied actually are representative of the
various categories that have been created and in which they presumably
are the most common. And of course, the next critical question is how do
you know that the drug is going to work the same in those. So I don\'t
know whether or not you want to have that discussion now, but I thought
maybe we could ask the sponsor.

The categories you\'ve created are constructs, and for that matter, the
pathophysiology, the description, the sleep drive, the circadian drive,
the wake propensity, these are concepts that have been developed or
constructed or created. They don\'t necessarily, I don\'t believe,
represent actual truth, and there are ways that people have tried to
understand these conditions. The pathophysiology of these categories or
even of the specific conditions you studied, let alone the ones that
weren\'t studied, isn\'t known with certainty, is it? I think that\'s
probably a fair statement.

So what allows us to conclude, other than the fact that there is an
assertion that the pathophysiology is the same within a particular
category, reliably that in fact these diseases are interchangeable
within a given category? And how do I know that if the drug works in
shift work that it must, perforce, work in jet lag? Again, the
pathophysiology, the etiology of these things are all not known
completely, and so I\'m wondering how we make that leap. We could either
talk about that now or ‑‑

DR. RUSSELL: Dr. Czeisler?

DR. CZEISLER: Thank you very much, Dr. Katz.

The question about these constructs that you\'ve raised and the question
about the pathophysiology, you\'ve said that they don\'t necessarily
represent actual truth. While that may be literally correct, there has
been extensive work on looking at the pathophysiology and the concepts
that Dr. Roth talked about in terms of length of prior waking, in terms
of the duration of the nightly sleep episode and the buildup of the
sleep drive and the sleep load versus the impact of circadian phase that
have been formalized into mathematical models. And these mathematical
models have been reviewed at a series of international workshops that
began first in Switzerland, continued with the workshop that we
sponsored at Harvard, and most recently with a workshop that was
sponsored by NASA and organized by Dr. Dinges.

At those workshops, these models that Dr. Roth described of this
physiologic and pathophysiologic system have been subjected to rigorous
comparisons with data from laboratory investigations. The model that Dr.
Roth showed of these different factors and specifically the way that
they interact to drive changes in sleepiness and sleep tendency have
been validated by those kinds of studies in direct comparison with the
predicted results from the model. I don\'t exactly know what actual
truth is, but in comparison with the results of carefully conducted
trials, those constructs that Dr. Roth presented have been
systematically validated.

The way they interact to produce disease has also been studied in
laboratory investigations in which, for example, the interruptions of
sleep that are associated with sleep apnea have been simulated even in
individuals who don\'t have sleep apnea but whose sleep is similarly
interrupted, producing similar levels of increased sleep tendency.

With respect to the way circadian misalignment interacts with both acute
and chronic sleep deprivation, those have also been systematically
investigated by recreating what occurs in the clinical situation in the
laboratory and demonstrating the same kinds of deficits.

So in every way that we know how to investigate these conditions, what
we understand about them is that they go through this final common
pathway to produce excessive sleepiness in the manner that Dr. Roth
described.

DR. KATZ: And those studies have been done ‑‑ I\'m not exactly sure I
understand what those studies are ‑‑ in all of the disorders that are
subsumed under these various categories, let\'s say, circadian
misalignment ‑‑ I forget the other two. So there have been studies done?
Let\'s say in circadian misalignment, there\'s a number of ‑‑ I forget
how many entities are subsumed under that. Six or seven or eight,
whatever it was. There have been the studies of the sort you\'re
describing that have demonstrated, in quotes, a similar final common
pathway for all of those?

DR. CZEISLER: Yes, that\'s true, Dr. Katz. If we look, for example, at
the category of circadian misalignment and we look at each of the
specific disorders that are associated with circadian misalignment,
these have each been systematically investigated in not just one or two,
but hundreds of laboratory studies in which delayed sleep phase syndrome
has been simulated by shifting, even in individuals who don\'t have
delayed sleep phase syndrome, their sleep to the same phase relationship
that a patient would have with delayed sleep phase syndrome with respect
to the output of their circadian pacemaker. And the same kinds of
symptoms can be created in normal healthy individuals without this
complaint simply be recreating the misalignment of circadian phase that
was illustrated in the slides that Dr. Roth gave. Importantly, in
patients with delayed sleep phase or advanced sleep phase or non-24-hour
sleep-wake syndrome by changing the timing of their sleep-wake schedule,
with respect to known markers of the output of the circadian pacemaker,
all of their symptoms can be completely resolved.

So, for example, if you take a patient ‑‑ and this has been done in
laboratory studies ‑‑ with non-24-hour sleep-wake schedule and put them
in an environment where the period of the timing of their sleep-wake
schedule, instead of being 24 hours, is put on a schedule so that it is
consistent with the period of the circadian pacemaker that they are
exhibiting on the outside world, their clinical condition goes away. So
we can take patients and have taken patients with delayed sleep phase
syndrome, shifted the timing of their sleep in the laboratory, had them
sleep at a properly aligned phase relationship to their output of their
circadian pacemaker, and again the clinical condition goes away.

So we believe that we do understand the pathophysiology of these
disorders and that shift work sleep disorder is representative of these
conditions and produces, through the same final common pathway, the
symptoms that are observed of excessive sleepiness.

DR. KAWAS: I need to understand this a little bit better, Dr. Czeisler,
because I do agree this is a crucial point today.

While I certainly understand that all those people might be sleepy and
while I also understand that you can put people in the lab and do things
to make them sleepy, what I still don\'t completely understand is how
you know from mathematical modeling or systematic studies, which are the
terms you keep using, how that tells us that all of these people will
respond equivalently to treating their sleepiness in the same way.

DR. CZEISLER: My understanding of the question that Dr. Katz asked
originally was taking these heuristic models that Dr. Roth presented,
how do we know that these models of the system represent the final
pathophysiologic pathways to produce excessive sleepiness. What I said
or tried to say was that the mathematical models that have been
developed have systematically investigated by, for example, to answer
your question, changing the duration chronically of nightly sleep
episodes, shifting the phase of sleep episodes with respect to the time
at which they ordinarily occur, and through investigations of that
nature have tested mathematical models, a series of different ones, that
have been proposed. We have been working on the development of these
models for over two decades in our own group, and the model that Dr.
Roth presented is consistent with the best of the models and consistent
with models in which there is consensus worldwide among investigators at
many different institutions looking into this question that it is an
interaction between increasing sleep drive that is associated with
length of time awake. So just as we all learn when we were children, the
longer that you\'re awake, the greater will be the drive for sleep, this
increasing homeostatic sleep drive. That is one important factor that
has to be considered in determining how sleepy we are.

The second is how long we sleep at night because this restorative value
of sleep reduces homeostatic sleep drive when we are asleep if the sleep
is consolidated and not interrupted, as it is, for example, hundreds of
times per night potentially in sleep apnea, but if you are able to
maintain consolidated sleep without interruption, then the increasing
homeostatic sleep drive should dissipate when you are asleep.

And the third principal interacting factor is this circadian drive for
wakefulness, and it is the circadian drive for wakefulness that helps us
to maintain a consolidated bout of waking throughout the day because
unlike other mammals, we don\'t take little rat naps and cat naps
throughout day and night. We have a consolidated bout of waking and a
consolidated bout of sleep.

The way that is achieved is by the interaction of two opponent
processes, and those two opponent processes are illustrated here. The
circadian system has its maximal drive for waking just before we go to
sleep at night, which is paradoxical, and its maximal drive for sleep
just before we wake up in the morning. That opposes what would otherwise
be an increasing drive for sleep that occurs during the daytime, as we
are awake for an extended number of hours, and it is that interaction
that allows us to maintain a relatively stable level of wake propensity
in the normal consolidated waking day.

But this interacting system is fragile so that if we don\'t get the
restorative sleep that we need at night, this doesn\'t decline, and then
you begin the next day, as Dr. Roth said, with an increased homeostatic
drive for sleep which drives down your wake propensity and leads to
excessive sleepiness. If you have sleep that is too short during the
night, the same thing happens. If you have it shifted, the same thing
happens.

DR. KAWAS: Okay. You got me more than halfway there. I now have a better
appreciation of the mathematics of that model and how the balance is
relevant for the outcome of sleepiness.

So now the part I need to better understand, though, is how do I know?
That\'s a mathematical model as opposed to physiologic disease processes
because we\'re not talking about normal sleepiness now. We\'re talking
about disease. So how do I know that if an individual has excessive
sleepiness because something is wrong with the sleep drive, the blue
lines up there, that they will respond equally and equivalently and just
as well as somebody who has a problem with the yellow lines? That is,
their pathology is in the circadian drive for wakefulness. How do I know
that a drug will work on a disease no matter how it\'s affecting the
left side?

DR. CZEISLER: So the model has been tested by simulating the pathologies
in the laboratory and showing that it produces a similar level of
increased sleep drive. Some models can\'t be tested in the laboratory
that way. For example, narcolepsy, because that is a disorder of
sleep-wake regulation that can\'t be simulated by recreating the
abnormalities of the hypocretin producing neurons in the brain.

In each of those clinical instances, clinical studies, such as the ones
that Cephalon has presented here, have been conducted in which
predictions of the impact of modafinil have been evaluated, and the
outcome in each of those clinical conditions is consistent with a
reduction in either homeostatic sleep drive or the adverse impact of
misalignment of the circadian phase that is consistent with a common
mechanism.

If we could show slide 30, as Dr. Roth pointed out, the drive for
wakefulness that is coming to the cortex from these hypothalamic regions
‑‑ modafinil, by a mechanism that is not completely understood, as Dr.
Roth pointed out, increases that drive for wakefulness and helps to
overcome the excessive sleepiness that is produced in each of these
three different categories of sleep disorders by what we think is a
common mechanism.

DR. KAWAS: We think it\'s a common mechanism, again, because of this
mathematical modeling ‑‑

DR. CZEISLER: No.

DR. KAWAS: ‑‑ or because of some other reason I\'m missing here?

DR. CZEISLER: We think that it\'s a common mechanism because of what is
known about, as Dr. Roth pointed out, modafinil increasing the drive
from these hypothalamic areas that produces cortical arousal.

DR. KAWAS: And you would then predict, if a patient\'s problem has
nothing to do with reduced wakefulness drive, but rather has to do with
excessive sleepiness drive, that the drug still should work equivalently
in the same effect size?

I mean, to bring it down to a different level, to explain my confusion,
obesity, for example, is either because you eat too much or you exercise
too little or you have a thyroid problem or whatever. But a drug to
suppress appetite will only work presumably in the people who have
obesity on the basis of increased appetite, not on somebody who has it
on the basis of thyroid dysfunction or whatever.

DR. CZEISLER: Right.

DR. KAWAS: So I\'m trying to understand to what extent we understand
that the mechanisms really are the same in these disorders.

DR. ROTH: I\'m just going to repeat what was said. Basically, there are
two questions. One, what are the units within each one, and then how do
they go to the same thing? How does modafinil then work?

How the units work, very simply as I tried to show and as Dr. Czeisler
just pointed out, those groups, for example, sleep-related breathing
disorders, periodic leg movements ‑‑ it\'s very clear if you fragment
sleep, whether that\'s due to leg movements, whether that\'s due to
respiratory events ‑‑ and in both of those instances clinically, there
are publications which show that the degree of sleepiness is directly
correlated with the degree of sleepiness. So there is a one-to-one
relationship with that.

Similarly, if I experimentally do that ‑‑ as Dr. Czeisler said, Dr.
Bonnet has published that; our laboratory has published that ‑‑ you then
increase sleepiness in a normal individual. If you decrease arousal in
an apnea patient, in the leg movement patient, or in that experimental
situation, you get rid of that sleepiness. So these systems ‑‑ Dr.
Czeisler said that very elegantly in the area of circadian rhythm
disorders.

You know, again, one of the things that\'s very important is what is the
reality of these categories fitting together. Well, they fit together
because they\'re exactly one-to-one with what the ICSD has. You have
circadian rhythm disorders. We call them misalignment. They\'re called
neurological sleep disorders. We call them sleep-wake dysregulation. The
only thing we collapse are these sleep-related movement disorders and
respiratory disorders. So very clearly, they all fit into that category.

Now, what do those three have in common? I think, again, what we just
pointed out. What they have in common is the major output of the SCN,
the major output of all the hypothalamic areas is to produce cortical
activation. All of these disorders decrease cortical activation.

What modafinil does ‑‑ again, this data comes from Jouvet ‑‑ in terms of
where it does it, it does it at the hypothalamus. But also very good
imaging data that shows that regardless of the cause, if you give
modafinil, you wind up with greater activation of cortical activity. So
they all lead up to cortical activity. That\'s what the final effect of
modafinil is on cortical activity.

So you\'re absolutely right. There are 15 different ways you get up
there, but you wind up in the same place, a decrease in cortical
activation, and that\'s what you\'re treating.

DR. KAWAS: Yes, please. Dr. Krahn and then Dr. Mignot.

DR. KRAHN: I\'d appreciate it if you\'d comment on the choice of sleep
diaries, subjective data, for assessing total sleep time in patients
with shift work sleep disorder. One issue is whether people will
voluntarily restrict their sleep even though they may have the capacity
to sleep when having access to an alerting agent for a condition like
that.

DR. RUSSELL: I think that\'s why we looked specifically at the total
time in bed, and so if they were taking a wake-promoting drug, would
they therefore say, oh, I don\'t need to go to bed anymore during the
day in the shift work sleep disorder population. I think what Dr.
Niebler showed you is that that really wasn\'t the case. Despite taking
modafinil, or Provigil, they actually spent the same amount of time in
bed that they did before, highly suggesting that they weren\'t
neglecting the time in bed because they were taking the drug, and
that\'s depicted for you here again.

DR. KRAHN: My concern is that that\'s subjective data based on the
participant\'s self-report, and that\'s the issue I\'d like to just hear
more about.

DR. RUSSELL: This is from diaries, so yes, it\'s their self-report.

What we also did was daytime polysomnograms at the end of the study
where they had a fixed time in bed, and that was where the sleep
parameters, in terms of sleep efficiency, and wake after sleep onset
were shown from.

DR. MIGNOT: I have two small questions. One of them was regarding the
adverse events leading to stopping the treatment in the sleep apnea
group. It looks like there were more people stopping treatment in the
sleep apnea group than in other groups due to adverse events. I was
wondering, it looked like the profile of the effect of the drug was
slightly different in that group. I was wondering if you can comment on
that in terms of dizziness or ‑‑

DR. RUSSELL: The actual overall adverse event profile was pretty similar
in the obstructive sleep apnea patients, specifically the adverse events
leading to withdrawal, as outlined by body system here. The profile is
kind of the same. Perhaps there\'s a little bit more in the nervous
system. If I could have the breakdown of the actual OSA adverse events,
I\'ll be able to show you that.

DR. MIGNOT: These are body as a whole, for example.

DR. RUSSELL: Body as a whole includes a number of adverse events, and I
just need to get you the actual adverse events leading to withdrawal.

DR. MIGNOT: And the other question ‑‑ maybe during that time you can
answer ‑‑ I had was regarding restless leg syndrome, obviously another
cause of sleep disruption that\'s fairly common. I think in your
presentation, you\'re indeed touching the three main areas of sleep
medicine, but another very common sleep disorder is indeed periodic leg
movements during sleep or restless legs syndrome. Obviously, I\'m sure
you had some data in terms of leg movements in your population because
it\'s fairly common.

I know the data in narcolepsy because I\'ve looked at it when it was
published. With modafinil, there was no effect, I think, on leg
movements during sleep in patients with narcolepsy that have also
periodic leg movements. But I\'m wondering what happened in these other
groups. I\'m sure you looked at that.

DR. RUSSELL: Just like in narcolepsy, we saw really no incidence of
increased leg movements when it was looked at by PSG.

DR. KAWAS: Are you concluded, Dr. Mignot? Do you have the ASEs waiting
for right now, or should we go on to another question while you\'re
looking?

DR. RUSSELL: Can I have the actual adverse events leading to withdrawal
please? I\'m sorry. They\'re just getting it. I\'m sorry for the delay.

These are the actual adverse events that led to withdrawal in the OSA
studies. As you can see, the actual numbers for each particular adverse
event are really pretty small, and similar to those that we\'ve
identified in the other programs as adverse events that may lead to
withdrawal.

DR. MIGNOT: Thank you.

DR. KAWAS: Dr. Temple?

DR. TEMPLE: You\'ve made the case that the normal attempts to sleep in
all of these conditions are not adversely affected, but they\'re also
not improved. If a shift worker has trouble getting a good night\'s
sleep, this doesn\'t change that, right, because the total sleep was
about the same in both cases?

DR. RUSSELL: That\'s correct.

DR. TEMPLE: So if I were to say the only thing you need to postulate is
that this stimulates your drive for wakefulness and there\'s no reason
to presume anything else, would there be something wrong with that
conclusion?

I ask that because that\'s not an unfamiliar property of drugs, as you
probably can see me I\'m trying to make sure of this morning. It seems
to me that\'s probably the best basis for your argument, that whenever
whatever is going on, whether it\'s apnea, shift work, or narcolepsy,
and you might add, sleep deprivation, if you take this stuff at the time
you want to stay awake, it probably helps you stay awake, not unlike
coffee, but maybe better than coffee and without as much tachycardia or
something.

DR. RUSSELL: That\'s certainly our conclusion.

DR. TEMPLE: Okay. Now, why doesn\'t it keep you awake at night? Is that
a pharmacokinetic thing? Is the effect of the drug gone by that time? I
probably should remember this from the original submission, but I
don\'t. There are all these tests of wakefulness and things like that. I
presume that by the time it\'s time to go to bed, the drug isn\'t having
an effect on those things. You don\'t have increased sleep latency, and
is that just simply because the drug is gone?

DR. RUSSELL: Yes, pretty much so. From the pharmacokinetic parameters we
can say that you\'ve fallen well below the plasma level of modafinil
required for wakefulness by the time you go to bed.

DR. TEMPLE: Presumably if you took this at the wrong time and you got
screwed up and took it just before bed, that would probably not be a
good thing.

DR. RUSSELL: That\'s probably not a good thing to do.

DR. TEMPLE: I noticed in the shift work thing, you take it before you go
to work or just before. So that\'s right at the time you want to do it.
Well, with narcolepsy, you take it in the morning I suppose.

DR. RUSSELL: Yes.

DR. KAWAS: Dr. Ebert?

DR. EBERT: Just a follow-up related to the pharmacology of the drug.
Most of the studies, of course, have used long-term therapies in
patients with persistent problems. Is there evidence that the drug works
after just one or two doses in activating the cortex so that if you were
going to use it, for example, on a time zone change syndrome where you
might only need to take this for 1 or 2 days, that its onset would be
rapid enough that it would work in that circumstance?

DR. RUSSELL: I\'d like to ask Dr. Dinges to answer that because he
specifically looked at this.

DR. DINGES: I\'m David Dinges from the University of Pennsylvania.

We have done laboratory studies on how rapidly the drug affects people
who are performing, as well as recording EEG, et cetera, and the effect
is very rapid. It\'s certainly within an hour and actually even shorter
than that. You begin to see benefits from it. By 2 hours, it looks like
it\'s up at whatever you\'re going to get and then it sustains for its
half-life of about 12 hours.

DR. KAWAS: Just for my information, can you tell me what kind of study
you did to show the effect in an hour?

DR. DINGES: These were studies in which healthy adults were kept in a
laboratory for 10 days in double-blind placebo-controlled trials, were
given the medication at different times or given placebo at different
times, and the placebo group always got placebo, and were being tested
on test bouts, and had EEG continuously recorded and a series of other
biological markers, cardiovascular, et cetera, and blood levels for key
hormones, catecholamines, et cetera, in part because we were interested
in how this drug compared to caffeine and some other substances we had
studied.

DR. KAWAS: And the specific outcome that showed a difference between
placebo and ‑‑

DR. DINGES: Some of those that you saw here, as well as others. So the
lapses on the psychomotor vigilance task, cognitive throughput on the
digit symbol substitution task, mental arithmetic performance, all
showed fairly rapid responses. Critically important are the number of
lapses drop off dramatically if the drug is given to someone who\'s
healthy but sleep-deprived.

Obviously, if you give it to people before they\'re sleep-deprived and
they\'re otherwise healthy, you don\'t see anything at all in the
performance. There\'s no additional improvement in performance. It looks
pretty much like they looked in the placebo group. There\'s no
fundamental difference.

DR. KAWAS: So those studies were done in sleep-deprived people, but most
people on jet lag aren\'t necessarily sleep-deprived. They\'re just
trying to sleep at a completely different time and wake at a completely
different time. So can you relate your results to the jet lag issue for
us?

DR. DINGES: Well, as Dr. Czeisler said, this heuristic model ‑‑ it\'s
true that in jet lag you\'re trying to be awake at a time your brain is
trying to go to sleep and vice versa in that sense, but because the
circadian system also influences sleep duration, you can actually build
up a sleep debt in jet lag as well, and it\'s really both of those
things. That\'s really why the slide showed the two together. It\'s the
two processes interacting in the neurobiology that sort of determined
the cortical level of capability, the ability to sustain the
wakefulness, et cetera.

In fact, just to be thorough, we do studies. We\'ve run more than 100
people where we flip their circadian time. We simulate jet lag and shift
work and have them live chronically on that. We, in fact, do that in the
laboratory as well where we\'ll give the sleep during the day and keep
them up at night, and we\'ve looked at this. Again, you get pretty much
an immediate, within an hour response in neurobehavioral functioning if
there is sleep pressure in the system or if they\'re at an adverse
circadian phase.

DR. RUSSELL: I think Dr. Jim Walsh has also got a comment on this aspect
too.

DR. WALSH: This is Jim Walsh from St. Louis.

Let me just add that we did a study of simulated shift work, the first
night or two of which you could call simulated jet lag. We used the PVT,
the MWT, the Karolinska scale and compared in a double-blind,
placebo-controlled fashion at night from approximately 11:00 p.m. at
night to approximately 7:00 a.m. in the morning and showed robust
differences between modafinil 200 milligrams and placebo all night long
and in fact for 5 successive nights.

DR. KAWAS: Dr. Kattah?

DR. KATTAH: I want to explore a little further the presence of headache
in these patients. If you look at the studies 303 and 402, the incidence
on modafinil of headache was about twofold that of the baseline. These
patients, because of the body habitus, obesity and so forth, are
propensed to have pseudotumor cerebri, and I wonder if you can tell us
more about the nature of the headache. You showed a slide saying that
not many withdrew from the trial because of the headache, but it makes
me wonder. In all the other groups, although headache is present, it\'s
not as much as the patients with sleep apnea. You have 25 percent of 292
patients; whereas, the placebo was 12 percent of 188 patients.

DR. RUSSELL: We have looked at headache. The incidence is as you
describe. Very generally, the headaches are mild to moderate in
severity, start early on in the course of treatment, and are of short
duration. So they go away with continued dosing. This is the same across
the treatment groups.

DR. KAWAS: Dr. Katz?

DR. KATZ: Yes. I just want to go back to the fundamental approach that
we\'re dealing with here today. I just want to make explicit, in
particular for the new committee members and our guests who will be
voting, how this situation differs in part in a very fundamental way
from what we ordinarily do.

Typically when we approve a drug, it\'s for a specific disease or a
symptom of a disease in that one setting and we\'re very empirically
driven. If the patients are better on the drug compared to placebo for
that particular condition, Parkinson\'s, epilepsy, whatever it is, we
approve the drug. We don\'t usually have or perhaps we never have a
complete understanding of the pathophysiology of the disease and we
certainly never have a complete understanding of all the possible
mechanisms of action of the drug. We just know that the patients were
better. We rarely are in a position to extrapolate beyond the condition
that was studied. So if you study a drug in patients with Parkinson\'s
disease, for that matter, we make distinctions between early and late
Parkinson\'s disease. If it works, we say it works. It\'s indicated for
that condition.

Here, obviously, there\'s empirical data. They\'ve studied several
different settings and the drug has been shown to be effective I
believe. But we\'re being asked to do something else as well. We\'re
being asked to extrapolate those results beyond the conditions studied.
As I said before and as you\'re hearing, typically when you do that ‑‑
it doesn\'t happen that often, but when we do that, we have to pretty
much believe we understand the pathophysiology of the disease and the
mechanism of action of the drug so that we can predict with a reasonable
high level of certainty that the drug is going to work in those
situations in which it has not yet been studied. Those are predictions
and we usually don\'t make those sorts of predictions and we usually
don\'t have that kind of detailed understanding about the
pathophysiology or the mechanism of action of the drug, as I said.

So this is unusual. It\'s certainly not that it can\'t be done, and
it\'s been done in the past. But we have to acknowledge explicitly the
fundamentally different approach we\'re being asked to take here. You
may find, of course, that the argument has been made, that the case has
been made that we really do understand the pathophysiology at least of
the symptom of excessive sleepiness across this universe of disorders
and we understand enough about how the drug works to be able to say, oh,
yes, it\'s going to work in all these conditions that have not yet been
empirically studied. But I think it\'s important to get on the table the
fundamentally distinct nature of the question we\'re being asked
compared to what we usually ask.

DR. TEMPLE: It\'s worth thinking about some of the cases where we do at
least seem to treat a symptom or a condition that has many origins. As
everybody knows, we ask people to study a few pain models, and then you
get a general pain indication. However, not everybody agrees on what the
right models are, and not all pains are the same. Nobody thinks migraine
is the same as other pains, and it turns out menstrual pain, menstrual
cramps don\'t exactly track perfectly either. So even within probably
the most established place where we treat a symptom, there\'s at least a
little bit to worry about, although maybe not that much.

Another example actually is all the cases where we treat a surrogate
like blood pressure. Well, we just ask that a drug be shown to lower
blood pressure. We don\'t ask what the origin of the blood pressure is,
but there are members of the hypertension community, probably a
minority, who think we\'re all wrong and that drugs should be targeted
toward whether you\'re high renin or low renin and a bunch of other
things like that. So even in a well-established place like that,
there\'s at least some potential debate, although nonetheless, we still
do it.

And then we treat elevated cholesterols and we don\'t actually care what
your enzyme deficiency is whether you over-eat. Well, we do care. We say
you should try lifestyle alterations, and then after they fail, you
treat them.

(Laughter.)

DR. TEMPLE: Yet, within that category, there are a lot of different
reasons for having an elevated LDL cholesterol.

So there are some cases, and I think as Russ says, is this one of those
cases where that\'s reasonable or is it not? That\'s really the issue.
But there\'s some precedent for all of those things.

DR. KAWAS: Dr. Wolinsky.

DR. WOLINSKY: Yes. There are a couple of questions I\'d like to be
educated on. One of them actually has to do with side effects. You\'ve
shown us a lot about the side effects that occur in patients who are
exposed to the drug and, for that matter, for patients who are exposed
to this drug for quite a long period of time.

What I\'d like to know is whether or not there have been any studies or
data that you can share with us about what might happen to sleep-wake
cycles or excessive daytime sleepiness in either patients or individuals
who have been on the drug for X period of days, months, or years and
then stop it.

DR. RUSSELL: That has been specifically looked at in a couple of
studies. One was a study done in Canada, a double-blind,
placebo-controlled study, where they had an open-label extension of 16
weeks and then randomized discontinuation at the end of the study. What
happened during the discontinuation of the drug was that no adverse
effects in terms of side effects, but they went back to their normal
level of sleepiness that they experienced before they went on that
study.

In addition, we had done a double-blind withdrawal phase in one of the
narcolepsy studies, and I have the data here which again shows during
the withdrawal phase ‑‑ this was done in a double-blind fashion ‑‑ that
those patients who withdraw from the drug revert back to their original
level of sleepiness.

DR. WOLINSKY: So I guess I\'m a little bit less concerned about whether
or not patients ‑‑ \"patients\" ‑‑ and I\'m going to be very specific
with at least the way I think I\'m using that term ‑‑ revert back to
their primary target symptoms and I guess you\'re showing me without
rebound.

DR. RUSSELL: That\'s correct.

DR. WOLINSKY: Now I\'d like to know about people and what happens to
their problem complex.

DR. RUSSELL: In terms of ‑‑

DR. WOLINSKY: Let me go for a little bit more background. In this model
that\'s been presented, at least the kind of clinician I am, I think
that your Venn diagrams define two categories which include within them
groups of patients with pathophysiologic disorders which we do or do not
understand fully, but I think most of us would agree they have something
that\'s out of the normal physiology. Then there\'s another part of the
diagram which represents something that can happen to anyone depending
upon what they\'ve done tomorrow going to England or going to work
tomorrow night or whatever it is. Within that, there is a spectrum of
response to that shift of circadian rhythm. So I\'m not sure I consider
this to be a pathophysiologic mechanism, but rather a shift on the
normal physiology.

So I\'m particularly concerned about people who might be using this
medication for their perceived problems and whether or not that would in
any way accentuate the problems either with continued chronic use or
with withdrawal from that chronic use. I think the question perhaps is
resonating with some of the experts. So perhaps you could give us some
insight into that.

DR. RUSSELL: Dr. Roth?

DR. ROTH: I think that\'s a very important distinction that I may have
failed to make. But again, we\'re not talking about shift work. The
numbers from Professor Ohayon\'s study was that 23 percent of those
people who do shift work wind up with that condition, and why do they
wind up with the condition? Because they wind up with the symptom of
insomnia or excessive sleepiness. So again, not everybody. The minority
of people. The majority of people, as you point out, make that circadian
adjustment very, very well, or at least well enough not to be
symptomatic.

So the answer to the first part of your question, which I think is
outstanding, is it\'s not a variant on physiology. It is a variant on
some vulnerability not to adjust in that 23 percent of the population.
It would be very nice if we can sort of figure out prospectively what is
that vulnerability. We don\'t know the answer to that.

But getting relevant to the question you asked in the second part of
your question, in all of these situations the discontinuation of
medication did not lead across studies to take the medication more
frequently across the 12 weeks, nor did it lead to a discontinuation
syndrome where you wind up with the PSG on the last night being
significantly worse than it was. So, one, medication usage didn\'t
change, and two, PSG didn\'t change.

Very much like Ohayon\'s data, by the way, which I\'m not sure was
presented, of the people who volunteered for the study, only about a
third met diagnostic criteria to get into the study. So it was a very
large number of people who answered the ad. First screening, and then of
those people who came into the laboratory with their criteria. So again,
it\'s not shift work. It\'s somewhere about 15 to 25 percent. Again,
those are the people who sort of take it as the need it, don\'t escalate
it, and don\'t have withdrawal syndromes.

DR. KAWAS: Then can I ask, regarding that vulnerability that you
mentioned, do we know that\'s a biological vulnerability or is that an
environmental difference? Particularly, in light of the fact that you
planned on bringing in individuals that had both chronic and
intermittent shift work and yet you ended up almost completely with
chronic shift workers, does that mean that there\'s some difference
between those two people in terms of all these things we\'re talking
about?

DR. RUSSELL: Dr. Dinges first and ‑‑

DR. KAWAS: I would have thought that an intermittent shift worker would
‑‑ why did they not end up in the study I guess is what I\'m trying to
figure out.

DR. RUSSELL: There are two questions here. I think Dr. Czeisler should
answer the one about the intermittent versus permanent night shift
worker, which is one of your questions.

DR. DINGES: Well, let me just say briefly regarding the biological
vulnerability, we\'ve been studying this trying to understand why people
have such literally an order of magnitude, a 10-fold greater difference,
in response to being kept up at night. What we found fairly consistently
now ‑‑ and this is NIH-supported work ‑‑ is the interclass correlations
when you repeatedly look at these people are very, very high, on the
order of .8, .9. In other words, this is trait vulnerability. It looks
very biologic. It\'s very stable. We don\'t understand. We\'re still
looking for predictors. We\'re trying to understand where does this
begin in life. Are you born with it, et cetera? It may be modified by
development; that is to say, as you get older, we don\'t know if that
characteristic diminishes or gets worse. But this is a very new area of
science, but it looks very biological and we have enough data now to say
that with certainty.

DR. RUSSELL: If Dr. Czeisler could answer the second part of that
question.

DR. CZEISLER: The distinction between what the individuals labeled
themselves as to whether they were rotating shift workers or,
quote/unquote, permanent night shift workers is a bit of an artificial
distinction insofar as, if you could show slide 768, the rotating night
shift workers, quote/unquote, worked an average of 10 nights per month
on overnight shifts, whereas the, quote/unquote, permanent night shift
workers worked an average of 15 overnight shifts per month. So it is not
as if one is working all the time at night and the other is not working
all the time at night, and their distributions very significantly
overlap or substantially overlap I should say. It is a matter of degree.
So that\'s one issue.

The second issue is that the workers, even when they are working 15
nights per month, 15 nights per month they are not working at night, and
we know from extensive studies of shift workers that when they are not
working at night, they invert their schedule and sleep at night. So even
the, quote/unquote, permanent night shift workers are rotators in the
sense that on all of their days off, which is half of the days per
month, they are inverting their schedule and scheduling themselves to be
awake during the day and asleep at night. So all are rotators in that
sense.

Then if we also look at and compare these different groups, as you can
see in the upper panel to this slide, in terms of their MSLT levels,
their KSS scores, and their CGI scores, you can see that the MSLT levels
were comparable between the two groups, the KSS levels were comparable
between the two groups, and the percentage of individuals reporting
themselves as markedly severely ill are very comparable between the two
groups. So we don\'t see that there is any real difference between them
other than their self-identified labels.

DR. KAWAS: Dr. Neubauer?

DR. NEUBAUER: I\'m still wondering who these people are who are defined
in the shift work study as having the shift work sleep disorder in terms
of any sort of criteria. The best example of trying to define a sleep
disorder would be with narcolepsy, and even there, there is some debate
with some patients. And shift work sleep disorder must be at the other
end of the spectrum because even the ICSD criteria are extraordinarily
broad, simply saying that the patient has a primary complaint of
insomnia or excessive sleepiness and that is temporally associated with
the work period.

Well, that\'s an awful lot of people who do shift work, and Dr. Dinges
tells us that he can identify certain individuals who have much greater
difficulty in a laboratory setting with sleep deprivation, but how does
that relate to the real-world population and those people who would be
diagnosed with something called shift work sleep disorder, and how does
that relate to the people that were included in this study?

DR. RUSSELL: In our study, we clearly looked at the ICSD criteria for
shift work sleep disorder but really didn\'t want a population that just
only met the minimum criteria. They had to meet other criteria too. So
that was why, in conjunction with discussions with Dr. Katz, we really
wanted to make sure that these patients were not only significantly
sleepy at night, so we implemented that objectively looking at an MSLT.
But they really truly had objective evidence of disruptive sleep during
the day, so we ran data on PSGs. So in addition to meeting the minimal
criteria in terms of having a complaint of excessive sleepiness, we
obviously were more interested in that component than the insomnia
component there to also have some objective criteria that they were
truly suffering from shift work sleep disorder too.

DR. KAWAS: Just to give us an idea of the magnitude of the clinical
effect in terms that we can relate to, I note on the MSLT that the range
of improvement in all the studies is from .7 minutes to 1.4 minutes. If
somebody did a couple of cups of coffee, what would that be expected to
result in in an MSLT?

DR. RUSSELL: Dr. Walsh? Sorry. Dr. Roth.

DR. ROTH: That\'s a very important question. Let me give you the direct
answer to that. How many cups and whose coffee? But 600 milligrams will
give you that kind of change. CPAP 6 hours a night will give you that
kind of change.

One of the things that some people are perplexed by, especially in the
sleep community, is how does that 1- to 2-minute change give you this
dramatic clinical change. The answer to that actually comes from Dr.
Krohnauer at the Brigham and Women\'s Hospital who has done extensive
research on this. It turns out these tests of sleep tendency are
psychometrically nonlinear. So that 2-minute change going from 2 to 3 is
geometrically much greater than going 15 to 16.

So again, 600 milligrams of caffeine would give you just the same thing.
6-and-a-half hours of CPAP would have given you the same thing. It
translates to big clinical effects probably because these tests, as Dr.
Krohnauer showed, are not linear at that part of the scale.

DR. MIGNOT: If I can comment on this because I agree with what was just
said. I think even though the changes look very small on both the scale
and the MSLT, I think they are clinically significant. It\'s very well
known that in narcolepsy you start from a very sleepy background and
that the tests never normalize completely. I think that may be a message
that\'s important. I think even in shift workers that take modafinil,
they may not be completely normal at night taking the drug. That\'s
another matter. But in terms of improving them substantially, I think
that\'s not an insignificant effect.

Also the fact that two different types of approaches were used, both
sleep tests like the MSLT or the MWT, and Epworth that are known to not
correlate that well actually and showing efficacy on both of the
objective and subjective measures I think is very reasonable.

DR. KAWAS: Dr. Wolinsky?

DR. WOLINSKY: So given those effects of caffeine, how was coffee
ingestion controlled for in these studies and especially in those
patients on modafinil who may have had an increased incidence of
headache? When the modafinil worked, did they stop their coffee?

DR. RUSSELL: Specifically in the shift work sleep disorder study, we had
an entry criteria that on a routine basis these patients shouldn\'t
really drink more than 600 milligrams of caffeine, which equates to 100
milligrams a cup, so 6 cups of coffee during their night shift episode.
In fact, actually the population that were enrolled in the study really
drank only very moderate amounts of coffee. They on average drank 2 cups
a night or whatever. That was the average consumption.

In the laboratory clinical assessments where the MSLTs were done,
caffeine was actually controlled so that neither groups drank coffee
during the nights of their assessments.

DR. KAWAS: Dr. van Belle, and then maybe after that, we\'ll try and fit
in a brief break because I\'m sure some people would like that.

DR. van BELLE: I just have some questions about some of data presented
just to make it clear to me. If I give you the page number of your
overheads, can you give me the actual slide? It would be helpful.

Let\'s go to page 92.

DR. RUSSELL: Is that the right slide?

DR. van BELLE: Yes, that\'s one of them.

I see no statistical test there. So can I assume that these results were
not significantly different between 200 milligrams and placebo?

DR. RUSSELL: Actually in reality the statistical tests haven\'t been
done on the diary data, and we specifically said that in the protocol
and in the statistical analysis plan that on the more exploratory
endpoints, such as the diary data, statistical analyses would not be
run.

DR. van BELLE: Okay, because this is one of the endpoints that has kind
of practical implications in terms of the number of errors that one
would make during the night shift. So that\'s one.

So on page 93, you haven\'t done that either?

DR. RUSSELL: Page 93, which would be during the commute home. No,
statistical tests were not done on this parameter either.

DR. van BELLE: Then there are a whole series of presentations starting
with page 116. Again, was this prespecified that none of, for example,
the CPAP use ‑‑ these tests were not done at all?

DR. RUSSELL: Statistical analysis was done on this I think during the
double-blind treatment period, which you see here. There was no
statistical difference between CPAP usage or ‑‑

DR. van BELLE: That also goes for page 117. There is no trend there?

DR. RUSSELL: There actually is a trend statistically here, yes.

DR. van BELLE: There was a trend, okay.

For page 118, no differences were significant?

DR. RUSSELL: These were not statistically significant.

DR. van BELLE: And 119?

DR. RUSSELL: Likewise.

DR. van BELLE: And 120?

DR. RUSSELL: This was diary data, so no statistical analysis was
performed.

DR. van BELLE: Thank you.

One of the issues that I haven\'t heard discussed yet is a dose-response
kind of issue. You had some trials with 400 milligrams and some trials
with 200 milligrams. The effects are very similar. What are your
inferences with respect to the dose response aspects?

DR. RUSSELL: In terms of between 200 and 400 milligrams, as you rightly
point out, there was no statistical differences between the two doses.
That\'s correct.

DR. van BELLE: So you would recommend 200 if this were to be approved?

DR. RUSSELL: I think in our current label, as it stands at the moment
for narcolepsy, 200 milligrams is the recommended dose, but it does say
that 400 milligrams has been studied, has been well tolerated, but with
no consistent additional benefit beyond 200.

DR. van BELLE: My last question deals with the PVT measures. I\'m not
sure that I have the page numbers here, but the levels in the 305 study
were about four times that in the 303 and the 402 studies. Now, I
understand that part of it is due to the fact that in 303 and 402, the
intervals were 10 minutes, and in the 305 study, the interval was 20
minutes.

DR. RUSSELL: That\'s correct.

DR. van BELLE: But it still strikes me that even adjusting for that, the
305 levels are substantially higher at baseline than in the other two
studies. Can you give me some clinical explanation for that?

DR. RUSSELL: If Dr. David Dinges could answer that.

DR. DINGES: The reason I\'m answering it is because my laboratory
developed the PVT and we spent 15 years validating it.

There are two things to remember in answer to your question. The first
is a clinical issue and that is that the MSLTs and some of the other
data indicated that the shift work sleep disorder patients had a higher
level of sleepiness than did the 303 apnea patients.

But there\'s a second point, and it\'s equally important. As you
increase duration on the PVT, if you have sleepiness, the number of
lapses increase. It\'s not a linear increase. It doesn\'t double. It
goes up very dramatically. Now, you might argue, well, why not do
20-minute PVT\'s in every study? Because this is an onerous task to do.
It\'s very monotonous. It demands sustained attention. It\'s punishing
in that way. We titrated down to 10 minutes because in validity studies
that\'s about the limit of what you can use and still get sensitivity
across a range of homeostatic drive.

But one point I\'d like to make about it, in case it doesn\'t get said.
The reason that we\'re interested in these lapses is the sleepier you
are, you have more of these and they get longer. Now, the real-world
relevance of this, the reason that we like this metric in my laboratory
is driving down the highway at 60 miles an hour in a 12-foot wide lane
with an 11-foot wide breakdown lane, the standard U.S. highway, at a 4
degree angle of drift, which is what drowsy driving crashes occur at, 4
to 10 degrees, you only need a 4-second lapse to be completely off the
road. You need a 2-second lapse to hit the car that\'s broken down in
the breakdown lane or less. You get the idea here that these lapses
really do matter in everyday life, and the more you have of them and the
longer they get, the greater risk posed to you when you\'re attempting
to do something, particularly a vigilance-dependent task like driving.

DR. KAWAS: Thank you.

I think we should take a 15-minute break. So we\'ll reconvene at 11:30
with the continuation of the questions and discussion.

(Recess.)

DR. KAWAS: Thank you. We\'re reconvening this session of the Peripheral
and Central Nervous System Advisory Committee for the FDA discussing
Provigil for excessive sleepiness.

At this point, I\'d like to begin the discussion of the committee on
some of these issues. We\'ve been given two major lists from the FDA,
which are partially overlapping lists, on questions that they want
discussed. On one of the lists, we will be taking a formal vote on the
specific questions. On the other list, we have questions for discussion
that I think will actually lead very straightforwardly, hopefully, to
the voting questions. So I\'d like to open the floor for discussion from
the committee members about some of the issues.

I want to remind you that one of the major issues involved in this
committee deliberation, which is really quite different from virtually
any committee that I\'ve been a part of, is that we are talking about an
indication for a symptom across a wide variety of diseases and not
specifically for the treatment of a specific illness as defined in some
way pathologically and clinically. So the floor is now open for anybody
who would like to begin telling us some of their thoughts on this.

Our questions for discussion begin with are the selected primary
endpoints, that is, the MSLT, the MWT, combined with the CGI-C, used in
the two new pivotal trials, which are the trials that are for sleep
apnea and shift workers, appropriate for the identification of a
therapeutic effect. We\'re going to rely very heavily on some of our
sleep experts particularly for some of these questions. So please share
your thoughts with us.

DR. NEUBAUER: Well, I think certainly the MSLT and the MWT are very
appropriate because these are both clinically and in research our best
way to identify sleep propensity. There is some thought that, well,
let\'s look in the real world at numbers of accidents, numbers of
mistakes at work, and they\'re really sentinel events, which would be
extremely difficult to capture in terms of an endpoint for a study. So I
think that these particular standard measures are very appropriate and
very familiar to us.

DR. KAWAS: And the effect size is the next question for discussion, but
I think you can interject it here. The effect size in the two new
pivotal trials. Do you have any thoughts on that?

DR. NEUBAUER: Well, the effect size in the change with the MWT and the
MSLT I think is a very problematic issue. We\'ve heard this morning
already that 1 or 2 minutes of change in the MSLT or the MWT may be more
significant than it looks like numerically and that also may be
different during different ranges, that is, if somebody is going from 2
to 3 minutes on either of those tests up to something in the teens. But,
nevertheless, the changes aren\'t big and they\'re still within the
ranges where we would consider for people to be impaired.

DR. MIGNOT: Yes. I think I already mentioned this earlier. I think I
feel comfortable about also the MSLT and MWT. They have been used both
clinically and in other drug studies and in a number of settings.

I think, indeed, I would have been not so comfortable if only the MSLT
or the MWT had been used because there is increasing evidence that
sleepiness is not just the MSLT or the MWT and that there is a
subjective aspect to it which doesn\'t exactly capture the same
construct. For example, there are a number of studies that have shown
that the Epworth Sleepiness Scale, which reports how sleepy people feel,
doesn\'t correlate always very, very well with the MSLT and MWT. It
correlates but not as well as you may predict. But in this trial, they
have used both subjective and objective measures for sleepiness, and I
feel confident they reflect the outcome.

Now, in terms of the size of the effect, I think I would also agree. I
think even though they look small, there is indeed, for example,
meta-analysis that has looked at the effect of CPAP on sleep apnea that
was done recently and shows that the effects that you get on the MSLT
are indeed relatively small as well. I think that small magnitude of
effect is clinically significant based on other interventions that have
been used in sleep medicine.

I would, however, point out that definitely I think these drugs do not
normalize completely sleepiness in these disorders, and I think that\'s
this indication and I think that\'s important to note whether it\'s
narcolepsy or shift work, et cetera.

DR. KAWAS: Thank you, Dr. Mignot. Actually that\'s a very good point.

DR. NEUBAUER: If I could follow up a bit. I remain worried, though,
particularly with the shift work patients that while there may be a
statistically significant increase, still when we think about the MSLT,
it\'s easy to think broadly of somebody having an average sleep latency
under 10 minutes as being sleepy and somebody with an average sleep
latency under 5 minutes, which would be typical with narcolepsy
patients, for those people to be profoundly sleepy. And while with the
modafinil, their subjects clearly did better ‑‑ they went from 2.1 to
3.8 on the MSLT ‑‑ still they\'re in that range of profound sleepiness,
and I wonder if we would be giving them a false sense of security to
think that here they\'re sleepy, they\'re taking a medication, and
they\'re still in that range where there would be considered to be some
impairment.

DR. WALSH: I\'d like to address that point, if I could. The patients we
studied that had a mean latency of approximately 2 minutes or so during
the night shift were individuals with shift work sleep disorder. If you
look at individuals, for example, in the simulated shift work models
where you don\'t pick them to have the shift work sleep disorder, they
average in studies approximately 6 minutes or so on the night shift. So
the closer we can get them to \"normal,\" the better from my
perspective. Once again, at that end of the scale, a minute-and-a-half,
2-minute, 2-and-a-half-minute improvement in the MSLT I think most of us
would agree does have true clinical significance.

DR. KAWAS: Could you please give us your name and title?

DR. WALSH: Jim Walsh and I\'m from St. Louis University.

DR. CZEISLER: May I also make a comment about that? Dr. Charles Czeisler
from the Harvard Medical School.

I think that one of the things that\'s clear from what Dr. Walsh said is
that these patients don\'t represent ‑‑ we all, if we stay up all night
to work, will be sleepy, but these patients are profoundly sleepy. These
patients with shift work sleep disorder are sleepier than even the
narcoleptic patients. So they represent a very vulnerable subset. I
think what speaks to the clinical significance of the improvement is the
reduction during the 80 minutes that we tested them during the night,
the reduction in the number of lapses as compared to the placebo-treated
group of an average of 1 lapse every 2 minutes. These people are doing
everything from driving to operating power plants and so on. If you
think of the impact of somebody working all night and having a reduction
in their lapses of attention on average of 1 every 2 minutes, that could
be a very profound and have important safety implications as well.

DR. KAWAS: Dr. Krahn.

DR. KRAHN: I think that it is important to keep in mind the patient
perspective. We have a subjective scale that\'s a clinician-rated one,
and I hope that the patient perspective is something that\'s kept in
this picture. I think that the endpoints used in these studies is
satisfactory, but there is room for improvement in the future with just
having a more direct patient report, as well as some of these other
secondary endpoints we\'ve been hearing about, perhaps being employed in
future work a little bit more so.

DR. KAWAS: Thanks.

Just to focus us a little bit on question number 2 with regard to the
magnitude, the agency has noted that the magnitude of change in the drug
group as compared to the placebo group in the MSLT in the shift worker
study appears to be particularly small as compared to the magnitude of
change in the MWT for both narcolepsy and the apnea studies. I would
also point out that in regard to the apnea studies, the significance of
the MWT really largely is dependent on the fact that the placebo group
declined significantly in this 12-week study, generating a large part of
the difference between the two groups.

So the agency has requested that we comment on this, the difference in
magnitude in the different studies. Dr. Mignot?

DR. MIGNOT: Again, I want to stress that the MWT and the MSLT are
measuring two different things. The MSLT is the ability of allowing
yourself to sleep. You are in a dark room and it\'s how fast you fall
asleep when you want to sleep. Whereas, the MWT is how hard, when you
try not to sleep, you don\'t fall asleep. I think to have merged the MWT
effect and the MSLT is a bit misleading in a way because I think they
measure slightly different things.

In fact, in general, when you look at drug effect on the MWT, they have
larger effects than on the MSLT, and a very small effect on the MSLT is
much more significant and would translate in a larger effect on the MWT.
In fact, you see that too in the, for example, sleep apnea studies in
the meta-analysis of Dr. Patel where they have looked at the effect of
CPAP treatment on MSLT and MWT. The magnitude of the effect on
sleepiness as measured on the MWT was larger than on the MSLT. I think
it partially answers your question that the difference in these studies
are partially due to using the MSLT versus the MWT.

DR. KAWAS: In casual observation, it looks like the difference in the
two studies is about a twofold difference. You tend to get about a
2-minute change for every 1-minute change in the MSLT. Is that ‑‑

DR. MIGNOT: Yes. I have to look here, but I think indeed in that
meta-analysis, it was about right.

DR. KAWAS: I also note that the 200 milligram dose in the narcolepsy 302
study is not even significant even though it\'s one of the largest
effect sizes.

DR. WHITE: I\'d just like to comment. I\'m David White from the Harvard
Medical. It was our meta- analysis that looked at this.

If you look at the effect size, the effect size, forgetting the placebo
group, on the MSLT and MWT were bigger even on CPAP. If you get a
1-minute change on CPAP and you put on top of that a 1-and-a-half to
2-minute change that they observed with modafinil, the effect size is
larger than CPAP, and you\'ve already got the CPAP in place, which
suggests to me that the effect size, although again the numbers are
relatively small, is clinically meaningful.

DR. KAWAS: Okay. That serves as a good introduction for question number
3 for discussion which has to do with CPAP.

In the pivotal sleep apnea trial, the sponsor has studied both patients
who were either partially CPAP-compliant or CPAP-compliant. Most
patients were in the CPAP-compliant category. We\'re interested in
knowing if the committee agrees with the sponsor\'s definition of
compliance. That\'s the first part of this question. I think we have to
rely very heavily on our sleep experts here for their thoughts.

If the committee concludes that the drug is an effective treatment for
patients who are fully compliant, we\'ll discuss where we go from there.

DR. KRAHN: The definition used by the sponsor is certainly one that\'s
widely used. I think many clinicians feel that that degree of usage
still indicates room for improvement on the part of patients. So I think
there is some discomfort in general with that definition, although it is
a widely used one for research studies in other settings. But that
represents a lot of room for patients to use CPAP more on a single night
or more consistently.

DR. KAWAS: In a previous life, I had some sleep experience. The one
thing that was very apparent to me was that CPAP is not particularly
well-liked by patients in many ways. Just like we\'d all rather have a
pill to lose weight than exercise, I think that if patients with apnea
were given the opportunity, they might not look at this as an additional
therapy or an adjunctive therapy but actually as a replacement therapy.

Do our sleep experts have any thoughts on this?

DR. MIGNOT: I think my concern would be more to make sure that people
that have sleep apnea know that they have sleep apnea and are treated. I
think what would be more worrying is people with sleep apnea would take
a drug like this without knowing they have sleep apnea.

DR. KAWAS: Right. That\'s a very good thought.

Yes, Dr. Krahn.

DR. KRAHN: I also believe it will be important that patients\' use of
CPAP be monitored so that neither clinicians nor patients forget about
the importance of CPAP and its demonstrated role in reducing other
things like high blood pressure. I think that would have to be
emphasized and be a very important issue.

DR. KAWAS: Dr. Neubauer?

DR. NEUBAUER: I think part of the good news here is that at least
looking at the studies, most of the patients were using the CPAP about 6
hours and it would be much more worrisome if it was down around 4 hours.
Clinically if a patient comes in saying, at least with evidence from
their equipment, that they\'re just using it for 4 hours and they\'re
complaining of sleepiness in the daytime, we\'re certainly going to work
very hard to increase that compliance and see what we can do to have
them be able to tolerate it for a longer period of time rather than
turning to some other measure to maximize daytime alertness.

DR. KAWAS: But as the sponsor very appropriately and rightly pointed out
to us, the individuals in the study were not typical of individuals out
in the community in the number of hours per night that they actually
used CPAP. In fact, they used CPAP more than we typically see.

Furthermore, as the FDA would like us to comment on, if somebody is
fully compliant on CPAP, do we think that this drug is an effective
treatment for them, as well as partially compliant or not compliant?
Have we had enough ideas from the data we\'ve seen to discuss this
rather thorny issue?

DR. HERSHKOWITZ: Can I make a comment about that, one of those
questions? The fully compliant issue has more to do with the fact that
some sleep experts are of the opinion that if there\'s true full
compliance, there shouldn\'t be any sleepiness, and if there\'s residual
sleepiness, the patient has an alternative diagnosis.

The partially compliance question has more to do with concern about ‑‑
or the noncompliance, that is, perhaps the physician isn\'t pushing
compliance sufficient, which I think was commented by one of the
panelists.

DR. KATZ: Claudia, the particular question that we\'ve asked in this
list of discussion topics related to noncompliance has to do with ‑‑
because there is so little information from the trials about how the
drug works or doesn\'t work in noncompliant or partially compliant
patients, the question is if you think it\'s been shown to work in sleep
apnea, what can we say, if anything, about its effects in patients who
aren\'t really very well compliant. Is it appropriate to include them in
the conclusion that the drug is effective or can we not say anything
about those patients, that sort of thing?

DR. KAWAS: Any thoughts from the committee on this issue? It was pointed
out by the agency that stratification on the MWT efficacy data and to
people who were partially compliant indicated little or no effect of
Provigil. Obviously, we don\'t have any data at all on people who are
not compliant with CPAP.

Yes.

DR. ROTH: The most relevant data is if you look at narcolepsy, you wind
up with a mean MSLT of about 2, and we saw what the effects are.
Patients who are totally nonusers of CPAP will wind up with a comparable
MSLT. So there\'s no reason to believe that the response in a nonuser
will be the same.

But Dr. Katz raises an interesting question: should we say anything
about that? The concern, which I think is again related to what Dr.
Mignot said, is one shouldn\'t be using it unless one is, in fact, using
the primary therapy and it\'s not intended as an alternative therapy.

So will it work? Yes, it will work because the level of sleepiness will
be that which we see in narcolepsy, and you\'ve seen several studies to
show that it works and it\'s indicated for that.

Should it be used in that condition? I would have to agree with Dr.
Mignot. No, it shouldn\'t. In other words, I think that\'s what we want
to say is if you\'re not being optimally managed with CPAP therapy, then
you shouldn\'t.

In terms of fully compliant patients, the best answer we have there is
the data in children who have sleep apnea, secondary to hypertrophied
tonsils and adenoids, and there after surgery their apnea goes away
totally and you still get refractory symptoms. So even fully compliant,
some individuals get refractory symptoms.

DR. KAWAS: Thank you, Dr. Roth.

Dr. Mignot?

DR. MIGNOT: Yes, I would agree with that. It will work, I\'m sure, and
in fact it may be a bit part of the worry.

I guess in general the question is I think people need to have a sleep
evaluation so that you know that these patients, if they have sleep
apnea, are treated. I would be also concerned, for example, people could
be concerned in the shift work area where people could have sleep apnea
and being a shift worker, for example. I think it would be very
important to make sure that whoever is suspected of sleep apnea is
treated for the primary diagnosis before using the drug.

DR. KAWAS: That\'s very easy for us to say here. Do you have any
suggestions, though, on how to make that actually translate into
clinical practice?

DR. MIGNOT: They can be studied or there can be a screening tool.

DR. KAWAS: Dr. Wolinsky.

DR. WOLINSKY: So this is not a cottage industry for me, but it would
seem that given the range of conditions that were displayed so nicely
for us, that those which are disease-associated probably require chronic
therapy and those that are something that\'s not necessarily ‑‑ may
possibly be trait-associated but also
normal-conditions-of-life-associated probably don\'t need chronic
therapy, one wonders whether or not there should be a suggestion ‑‑ I
don\'t know what actually can go into the labeling ‑‑ that patients on
chronic therapy need to be evaluated in a sleep lab.

DR. KAWAS: I think in many ways we\'ve actually been discussing also
question number 4 right now which is the gold standard of treatment for
apnea is CPAP and it may ameliorate some of the secondary morbidities
such as hypertension. The division is concerned that symptomatic
treatment may decrease CPAP compliance, and I think that there has been
some concern ‑‑ correct me if I\'m wrong ‑‑ on the part of the committee
that there is some truth to that.

I think there has been even more concern, if I\'m hearing correctly,
that individuals who need CPAP will never find out that they do because
of symptomatic treatment.

Yes, Dr. Krahn.

DR. KRAHN: I think technology makes this easier. For patients who have
an established diagnosis of obstructive sleep apnea, there are many more
ways to monitor their compliance now than there were 10 years ago, and I
think that it\'s important that compliance monitors and the like be
utilized to determine that they are using CPAP as much as possible
before a trial of an alerting agent is added. So for the patients where
the diagnosis is understood, that should be part of the recommendation.

DR. KAWAS: Most patients right now with sleep apnea, as I understand it,
have not been diagnosed anyway. So when the diagnosis is not understood,
it actually affects even more people than what we\'re concerned about in
those who already have it.

I guess I don\'t understand completely the long-term sequelae of not
diagnosing these disorders, but I am under the impression that there\'s
concern that the long-term sequelae without diagnosis and treatment may
be an issue.

Question number 5, has the sponsor adequately ‑‑

DR. WHITE: Can I comment on that last one? I don\'t mean to interrupt
you. Sorry.

The company is not advocating just treating generic sleepiness. 80
percent of sleep apnea patients are not diagnosed. That\'s the current
estimate on the street right now. But they don\'t present as shift
workers or they don\'t generally present as shift work disorder. They
don\'t present as narcoleptics because every narcoleptic is diagnosed
formally in the sleep laboratory or certainly should be. So for an apnea
patient to simply be treated with modafinil without making the diagnosis
would imply the doctor is just taking a sleepy patient and putting him
on a drug to prevent sleepiness without doing any workup or evaluation
whatsoever. And that is not in any way what the company is advocating
relative to the use of this drug.

DR. KAWAS: Dr. Katz.

DR. KATZ: I had a question for the company about the long-term data with
regard to CPAP compliance. We saw in the controlled trials, which are
short, that there was no decrement in compliance. And there was sort of
a histogram presented for data out to a year I think, and there was a
slight decrement which was said to be consistent with what\'s reported
in the literature about decrements over time in compliance.

But I had a question about this specific cohort that was studied. How
long were patients on CPAP before they got into that long-term
extension? I assume a lot of those were in the controlled trial. Do you
know what the average, let\'s say, the mean duration of CPAP use was
before the trial? I have a reason for asking that, which I\'ll get to.

DR. RUSSELL: All the patients who went into the open-label extension had
obviously been on the double-blind ‑‑

DR. KATZ: No, no, no. I\'m asking how long had they been on CPAP before
they got into the double-blind on average. Years?

DR. RUSSELL: We\'d need to try and find that out.

DR. KATZ: The reason I\'m asking is because I don\'t know the literature
about long-term compliance. I assume they followed cohorts forward in
time, at best I suppose. But the cohort you\'re following from the time
that you started following them, they had already been on CPAP for
years. I don\'t know if that\'s true but let\'s, for argument\'s sake,
say that\'s true.

So what I\'m trying to figure out is if you took a cohort who had
already been on CPAP for years and then you followed them forward in
time, would they also have a decrement in compliance? In other words, if
they\'ve been on it for years already, they\'ve sort of declared
themselves as users, let\'s say, and they may not have the same
decrement in compliance over time as a de novo cohort followed forward
from the day they started CPAP. So if that isn\'t too tortured.

DR. WHITE: That\'s a very fair and astute question actually, and
there\'s not a lot of data on it. The longest CPAP follow-up study to
date was done in Scotland by Neal Douglas. It was a 3-year follow-up
protocol. Clearly the rate of decline in CPAP use is steeper at the
beginning of the time you use CPAP and flattens out over time, but even
out 3 years, it was still deteriorating somewhat. Now, I\'ve not gone
back and looked at that study to see exactly how much did the
deterioration out 2 or 3 years correlate with what was seen in the
Provigil study, but deterioration in CPAP utilization does continue at
least out 3 years, and we don\'t have any data longer than that.

DR. RUSSELL: Just to clarify, for the people going on the protocol, it
was a minimum of 2 months. They had a diagnosis of a minimum of 2
months, but the range was actually from months to many years pre-study.
So you have a real wide range of people with a diagnosis ranging back
years as well.

DR. KAWAS: So the minimum was 2. The range was infinite. Do we know a
mean or median or anything like that that would give us an idea of the
distribution between those two points?

DR. RUSSELL: No, I\'m afraid we don\'t.

DR. KAWAS: Has the sponsor adequately demonstrated that Provigil does
not interfere with normal scheduled sleep, daytime sleep during shift
work, for example, or nighttime sleep in obstructive sleep apnea?

Here I think the sponsor showed us some data along those lines. How
convinced is our committee, recognizing fully that anyone who\'s in a
study doesn\'t necessarily represent the real world out there in a
variety of different ways, but we had some data to look at?

DR. NEUBAUER: Although the stated elimination half-life I believe is 15
hours, still it seems to be reasonable in not promoting problems with
insomnia or disrupted nighttime sleep in the studies and in clinical
experience with the narcolepsy patients as well.

DR. KAWAS: Finally, most patients studied in the pivotal shift worker
study were permanent non-rotating shift workers. With this is mind, is
it appropriate to generalize treatment to all shift workers, including
rotating shift workers?

DR. MIGNOT: Based on my understanding of the interaction of the
homeostat and the circadian clock mechanisms that were eloquently
presented, I don\'t see this being a real problem personally. I don\'t
see why the drug would be less efficacious in permanent versus
temporary.

DR. NEUBAUER: I agree that it probably doesn\'t make too much difference
in a general sense because people can be sleepy at nighttime from
permanent night shift or occasional night shift or rotating schedules.
It doesn\'t really answer the question of whether or not there is a
special population of highly sensitive individuals who have more
difficulty. An awful lot of people doing rotating night work or shift
work and other schedules are still going to have difficulty with
sleepiness. So I think it will be hard to tell who those people are who
would be most appropriate from a particular physiological vulnerability
as opposed to that which all of us would experience with a rapidly
changing or a slowly changing schedule.

DR. KRAHN: I do think that we have to be careful because there isn\'t a
lot of data available about the rotating night shift worker. So although
scientifically we can see the issues are fairly similar, there hasn\'t
been a lot of data for us to look at concerning that important segment
of our population. So I feel somewhat cautious about that group.

DR. KAWAS: I\'m still having trouble wrapping my brain around some of
this. So for me personally, the rotating shift workers really aren\'t
problematic. I almost view them as just another version of jet lag. They
intermittently try to shift into a completely new schedule. And for that
matter, maybe even the jet lag people aren\'t that much of a concern for
me.

But what does concern me still is that we\'re talking about treating a
symptom without understanding one of the many possibilities that may
lead to this symptom. When we treat pain, we know the pain is from
post-op, we know it\'s from dental, we know it\'s from whatever, and our
treatment of the pain does not keep us from treating the underlying
illness.

In this case, it seems to me that we\'ve got a potentially large issue
here for the majority of people getting a potentially serious symptom
treated and that their underlying disease might even be exacerbated by
ameliorating this symptom, just in the same way that if we treated pain
in an appendix or something, we would be doing the patient a disservice
in the long run.

Can I get some of the committee members to weigh in on this area for us?

DR. MIGNOT: I think the difference with pain ‑‑ and I think pain may not
be the perfect example ‑‑ is that everyone experiences sleepiness,
whereas not everyone experiences pain, and I think that\'s something to
keep in mind.

DR. KAWAS: Could you take that a little step further? I mean, keeping it
in mind, then what does it make you think about the whole issue? Not to
put you on the spot or anything.

(Laughter.)

DR. MIGNOT: I think since everyone can experience sleepiness, the need
for defining the symptoms, evaluating the symptom is very important.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: I think that because sleepiness is a normal state of being
and there certainly are some people who have excessive sleepiness
that\'s pathologic, this is going make it harder for the practicing
clinician to decide when to prescribe a medication, and I think that\'s
going to be the challenge. Many physicians don\'t have a lot of
education in sleep medicine and they\'re going to be presented with
patients who are sleepy, and it is going to be difficult for them to
know where the threshold should be to prescribe a medication for
sleepiness associated with a sleep disorder. For something like shift
work sleep disorder, we have heard that that is distinct from shift
work, but how possible will it be for the ordinary clinician to make
that distinction? I have some concerns about that.

DR. KAWAS: Dr. Czeisler.

DR. CZEISLER: Yes. Dr. Czeisler from the Harvard Medical School.

I think that the most important thing is that physicians be educated as
to the diagnosis and treatment of sleep disorders so that that primary
treatment is the first step that is taken. I would draw the analogy with
insomnia. This field of sleep disorders medicine has been encouraging
the education of physicians so that they treat the underlying cause of
the insomnia.

But I would say that the issue that the committee has before it is not
that dissimilar from the use of hypnotic medications for insomnia. In
fact, I would argue that the symptom of excessive sleepiness is much
more homogeneous than the symptom of insomnia with respect to what
causes it. Yet, many, many different compounds have been approved and
are used for the treatment of insomnia and, by the way, in shift
workers. Shift workers are given hypnotic compounds because of
difficulty with insomnia during the day. People are given hypnotic
compounds for treatment of insomnia associated with loss of a loved one,
with the situation with travel across time zones, many of the things
that we are talking about, and the agency has repeatedly approved the
use of compounds without requiring the specific understanding of the
pathophysiology of each of the insomnia conditions.

And this is the flip side of that whole question, and it is the
treatment of the symptom of excessive sleepiness which we know much more
about what generates it than we do of the symptom of insomnia and which
the company has demonstrated with these studies is effectively treated
with modafinil.

DR. KAWAS: Thank you.

Dr. Neubauer.

DR. NEUBAUER: I agree entirely with Dr. Czeisler\'s comments, although
I\'ll point out that while the hypnotics may be useful in treating
insomnia and represent a fairly general treatment, with using a
stimulating medication in the daytime to counter excessive sleepiness,
there may be greater danger of missing what the underlying problem might
be. Now, effectively educating all doctors about sleep medicine would
allow them to properly diagnose people.

But if this approval for disorders of sleep and wakefulness opens up the
door considerably for the range of sleep complaints that might be
treated, there are many insomnia patients, for instance, who will come
in complaining of being sleepy in the daytime, putting together their
daytime symptoms and their nighttime symptoms, and I wonder if, fairly
quickly, they may be given symptomatic treatment with a medication like
Provigil without adequate evaluation as to whether or not it might be
apnea. There are many patients out there who are not overweight and
snoring loudly or at least have a bed partner to identify that. We see
many patients coming in complaining of insomnia who turn out to have bad
apnea, and of course, we\'re in a good position to be able to evaluate
that. I would worry about somebody too quickly being given a stimulant
to treat that symptom, their being happy with the results and go on for
a long period of time without effective evaluation and treatment.

DR. MIGNOT: I think the parallel with insomnia is a fairly good one. I
think there are similar problems with treating insomnia patients
indiscriminately. Clearly depression has been a very longstanding
example of that where insomnia can just be a sign of depression, and if
it\'s treated symptomatically, it\'s a catastrophe. Similarly, I think
sleep apnea as well. I agree with Dr. Czeisler.

DR. KAWAS: I want to poll the committee a little bit. It\'s 12:15 and
although normally we would break for lunch now, it looks to me like
we\'re moving along at a rapid clip here, and I wondered if the
committee would like to break for lunch of if you\'d like to try and
work through and see if we can get this done in a reasonable period of
time and break for good.

Any thoughts, feelings? I heard one go for it. I think many people are
trying to get a plane out, so I think that would be a vote in favor of
continuing. Is that interpreted correctly? Okay, let\'s get started and
see what happens then.

The questions for the advisory committee to vote on.

DR. WOLINSKY: Madam Chairman?

DR. KAWAS: Yes.

DR. WOLINSKY: Before we get into the voting questions, there\'s an issue
that I know is bothering me and maybe some others that wasn\'t addressed
in terms of potential toxicity for good reasons I suspect because this
is a drug which is already licensed. And I didn\'t go back and read the
package insert. So could the sponsor enlighten me about the pregnancy
category for this drug and its recommendations for use in breastfeeding?
Because if we go to more general use of the drug, I suspect we might
have an interest in that.

DR. NEUBAUER: I wonder if we could add drug-drug interactions to that
list as well.

DR. RUSSELL: It\'s currently listed on the package insert as a pregnancy
category C and therefore, the benefit of use in pregnancy should
outweigh its risks. That\'s how it\'s currently written in the label,
and we don\'t propose that any change in that labeling should occur as a
result of this potential expanded approval.

DR. NEUBAUER: So it got to category C because there was some preclinical
concerns for abortogenic effect or teratogenic effect, or how did it get
to C?

DR. RUSSELL: In fact, I\'ll ask my toxicology colleague to explain the
toxicology finding.

DR. McCORMICK: Hello. My name is George McCormick. I am the Vice
President of Drug Safety and Disposition with Cephalon, Incorporated.

The company received a pregnancy category C rating based on results of a
segment 2 rat study, and a segment 2 study is also known as a teratology
study. In this study, the pregnant animals or presumed pregnant animals
are dosed during the period of organogenesis, at which time the
offspring are delivered by cesarean sectioning and are examined for
skeletal or soft tissue malformations.

In the study that we\'re referring to, there appeared to be a slight
increase in the incidence of hydronephrosis, as well as a delay in the
ossification of certain vertebrae in some of the offspring. I would like
to note that this study was conducted under non-GLP conditions, but it
was the study that was incorporated into the Provigil NDA. The pregnancy
C was recommended from the agency, and we accepted that category.

However, as part of our phase IV commitment, we repeated the teratology
or segment 2 studies in both species of rats and rabbits. In this study,
we used significantly higher doses under GLP conditions, and in that
study there was no evidence of any teratologic response in the animals.

The findings that I referred to, the hydronephrosis and the delay in
ossification, are frequently referred to as developmental delays rather
than true teratogenic responses. This may have an effect on the time
that the offspring are taken away from the pregnant animals. Therefore,
they should not be viewed as teratologic manifestations, but that is why
we have the C category rating.

DR. KAWAS: Any comments on drug-drug interactions for Dr. Neubauer\'s
question?

DR. RUSSELL: Yes. Currently written in the label, it is noted that
Provigil has been shown in vitro to induce hepatic metabolizing enzymes,
specifically CYP3A4, and also is a reversible inhibitor of CYP2C19, and
in one study has shown in vitro to be a suppressor of 2C9. There are
currently appropriately worded cautions regarding co-administration of
drugs that are either CYP3A4 as a substrate, and in 2C19, it appears to
be that those people who are also CYP2D6 deficient, which is roughly 7
to 10 percent of the population, if they were administered a drug
that\'s a substrate of that enzyme, which would then use the CYP2C19 as
an adjunctive pathway, may have higher levels than you would otherwise
expect. So that\'s all worded in the label at the moment.

DR. KAWAS: For those of us who are completely naive, can you tell us
what drugs would fall in that category or give us some examples?

DR. RUSSELL: For the CYP3A4, it appears to be clinically significant
interactions may occur really with those compounds that use CYP3A4 as a
substrate which have high first-pass metabolism and compounds that fall
into that category include things like cyclosporine.

For the CYP2D6 deficient population, which I said is around 7 to 10
percent of the population, you might be concerned about things like
tricyclic antidepressants.

DR. AZARNOFF: What about MDR1 transporters in the intestines?

DR. RUSSELL: There\'s nothing there.

DR. KAWAS: Did that take care of your question, Dr. Neubauer? Okay.

Before we move on to the votes, we\'re running ahead of schedule, but
the public forum, which is scheduled for 1 o\'clock, we\'re going to try
and put in next. To begin with, I need to read a statement from the
agency.

Both the Food and Drug Administration, the FDA, and the public believe
in a transparent process for information gathering and decision making.
To ensure such transparency at the open public hearing session of the
advisory committee meeting, the FDA believes it\'s important to
understand the context of an individual\'s presentation

For this reason, FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral presentation to advise the
committee of financial relationships that you may have with the sponsor,
its product, or if known, its direct competitors. For example, this
financial information may include the sponsor\'s payment of your travel,
lodging, or other expenses in connection with your attendance at the
meeting. Likewise, FDA encourages you at the beginning of your statement
to advise the committee if you do not have any such financial
relationships.

If you choose not to address this issue of financial relationships at
the beginning of your statement, it will not preclude you from speaking.

We have two people who have requested speaking during the public forum.
The first one is Richard Gelula. Is he available? He\'s Executive
Director of the National Sleep Foundation.

MR. GELULA: Thank you and good afternoon. My name is Richard Gelula.
I\'m Executive Director of the National Sleep Foundation, a
not-for-profit organization established in 1990 by the organization now
known as the American Academy of Sleep Medicine.

I know the panel has received my remarks and I\'m going to skip over
some of the description of the foundation and our activities and just
jump to the disclosure statement, though I will also say the remarks
I\'m about to give are about 10 minutes in length and there is
apparently some overlap with prior presentations, but with a different
focus and viewpoint.

The work of the foundation is supported by contributions and grants from
a variety of sources, including individual donors, patients, memberships
of nearly 600 sleep center affiliates, project grants from several
federal agencies, foundations, and corporate contributions or
sponsorships from a range of industries. Of the latter, within the last
year, Cephalon joined other contributors to be an unrestricted sponsor
of our National Sleep Awareness Week program and of our fund raising
dinner. Their contributions amounted to less than 4 percent of our total
income. We have not received travel reimbursement or any other
compensation from any source to appear here today.

All of our work is guided by a 25-member board of directors. Our
standard is to solely rely upon scientifically validated information or
scientific consensus for our public guidance or policy positions. We
accept no grants that are not unrestricted, meaning the foundation
creates all the content of our educational materials independently.

Our purpose in briefly addressing the panel today is to advocate for
only one thing: a greater concern and focus on the key problem of
sleepiness. Although our concern pertains to the panel\'s consideration,
we are not testifying with specific regard to modafinil. While we are
aware of the benefits the medication has produced, we leave it to those
most familiar with the clinical data to comment on its safety and
efficacy for the new indication.

We address sleepiness because both observation and research have shown
that it is a lead symptom for compromised attention and alertness,
cognitive and mood disorders, and illness. Sleepiness is clearly the
harbinger of danger for those with critical attention responsibilities,
including all 190 million drivers in the U.S.

I don\'t mean to take away from the seriousness of this consideration,
but I\'m going to point out that it is for good reason that hearings
such as this are not conducted between midnight and 8:00 a.m. They\'re
conducted during the daytime, and that is when most of us have our
optimal alertness.

The view of the National Sleep Foundation is that sleepiness, though
widespread, is no mere social artifact, something we should joke about
and accept. It should be recognized as a serious signal that every
individual and authority in our society understands as a risk factor and
precursor to accident, injury, destruction, and death.

Clearly, sleepiness in our society is a byproduct of a number of
different phenomenon with a range including reckless behavior, poor
sleep hygiene, lifestyle choices on one hand, and economic and social
forces, medical treatment and illness on the other hand, conditions that
people can\'t always change.

At the National Sleep Foundation, we seek to establish a widespread
dialogue about sleepiness within and among key institutions, including
the workplace, health care, schools, criminal justice, and among
community and civic organizations, and we are working to do this.

We also seek to establish a dialogue about sleepiness between doctors
and patients so that the work can begin of distinguishing whether
sleepiness is an indicator of disease, whether it results from economic
and social factors, or whether it is due to personal choice. And such
distinctions should not only be made, but they should be treated
differentially as well. But currently these distinctions are, in truth,
generally not made at all.

Dr. Carl Hunt, Director of the National Center for Sleep Disorders
Research at the National Heart, Lung, and Blood Institute, made this
point this week in a statement reported in the New York Times. He said
‑‑ and I quote ‑‑ \"People today are so accustomed to being sleepy
because they don\'t get enough sleep, that when they develop a real
sleep disorder, they don\'t recognize it as a medical problem.\"

Another way of saying this is that the prevalence of sleepiness due to
poor sleep hygiene degrades our understanding of its significance and
the threat it poses, and it masks pathology resulting from disease or
societal forces such as employment patterns and institutional schedules,
all of which may be unavoidable for the individual patient. Our
objective at the National Sleep Foundation is to encourage greater
clinical consideration of the root cause of sleepiness so that it can be
treated differentially and effectively. We advocate for this because
sleepiness is a morbid condition with a high risk of mortality to self
and others. In some circumstances, such as for people whose work is in
transportation, nuclear power, industrial operations, armed services,
medical care, public safety, and other professions, the inattention that
accompanies sleepiness ‑‑ or actually falling asleep on the job ‑‑ can
have dire effects on the health and safety of people in entire regions,
communities, and within families. This makes sleepiness a significant
public health issue.

For example, just one worker on an overnight shift, a nurse working
double shifts, a truck driver getting his perishable load to destination
by morning, or even an intern or resident working around the clock in
their training, for any of them a single brief episode that experts call
micro-sleep can kill them and also take away the lives of any of us or
any of our loved ones as we make our way to work or to school in the
morning. This is no fantasy. It is happening daily across America.

I\'m going to skip again and just say we conducted the first-ever
National Summit to Prevent Drowsy Driving at the National Academy of
Sciences and in partnership with the National Academy this past
November. We heard testimony from people who were affected as
perpetrator, as victim in a variety of ways, and we heard from experts
as well. Our findings reinforce the view that today the medical
perspective on sleepiness as a pathological conditions is entirely
inadequate. This has occurred for many reasons, but that is not the
topic or the focus of today\'s meeting.

Overall, we need to recognize that sleepiness is a medical concern, one
that is not entirely unlike the problem of controlling contagious
diseases because its morbid and potentially mortal effects extend to the
public health and can have their greatest peril for other individuals
and communities who are not necessarily sleepy themselves. These
secondary patients and victims are endangered because of their contact
with others who are, to extend the analogy, not only sleepy but also
contagious.

To foster a more aggressive medical approach that is commensurate to the
level of individual and community risk caused by undiagnosed and
untreated pathological sleepiness, we feel that doctors and the patients
too who are treated for sleepiness that is not responsive to behavioral
change or other treatments need access to and deserve safe and effective
treatment options. New treatment options ideally will have useful
characteristics, including ability to foster alertness, low risk for
abuse, side effects, addiction, or tolerance, and do not make other
disease symptoms worse, do not worsen them, and they should not disrupt
or degrade the quality of sleep.

Successful treatment of sleepiness and its causes has enormous positive
effect. We clearly see this among patients who are diagnosed and treated
for sleep disorders. Patients with obstructive sleep apnea who are
successfully treated with continuous positive air pressure devices and
who do not suffer residual sleepiness are frequently heard to say, it
changed my life. They regain vitality, interests, social relations, have
restored libido, more positive marital and home like, become more
productive at work, and begin exercise programs.

A second example now, combined pharmacotherapy and behavioral therapy
permits people with narcolepsy to manage their symptoms and lead
apparently normal lives. Previously for many, their pathological and
unpredictable sleepiness made normal manifestations of life, including
education, employment, career, driving, and social relations an
impossibility. I would note today that you can have your driver\'s
license withdrawn in many States if you have untreated or unresponsive
narcolepsy, but no one has suggested taking away the driver\'s license
of shift workers or people being treated for cancer or other diseases
where fatigue is a byproduct.

Such pathological sleepiness and compromised alertness do not
necessarily stem from sleep disorders alone, and others are similarly
affected. Circadian effects, whether due from disrupted sleep schedules,
jet lag, or shift work, may cause the same manifestations. Disease and
medical treatments are another common source of sleepiness, particularly
in aging Americans.

Again, the National Sleep Foundation just held a terrific two-day
workshop on sleep, health, and aging where this was pointed out in
presentation after presentation. This was conducted in partnership with
the National Institute on Aging.

These conditions and certain economic and social factors are not always
options that people can change or they are not necessarily responsive to
behavioral or environmental alterations. We must also recognize that
people who suffer from profound sleepiness and its effects and who do
not even like to work overnight or who recognize how it endangers
themselves or others will continue to choose shift work and overnight
work if the choice is between shift work and unemployment.

In conclusion, we feel that sleepiness is a very important public health
challenge and is deserving of a robust medical response. We feel this
response should differentiate the causes of sleepiness and match
treatment to the cause. We don\'t suggest that people who are behaving
recklessly be treated by their doctors with modafinil or, just the same,
that an overnight truck driver try to treat his sleepiness with
caffeine. Both need the appropriate intervention, and the medical
response should be fully commensurate to the risk that untreated
sleepiness can pose to the health and safety of all the people in the
communities in which our patients live. I think this panel needs to
consider the community and public health perspective of this issue. This
is how we would frame the context of your decision today, and I thank
you.

DR. KAWAS: Thank you.

Is Christin Engelhardt available? She is Executive Director of American
Sleep Apnea Association.

MS. ENGELHARDT: Good afternoon. My name is Christin Engelhardt, and I am
the Executive Director of American Sleep Apnea Association, a nonprofit
organization dedicated to seeing that all with sleep apnea are diagnosed
and treated properly. Thank you for letting the ASAA present its view on
Cephalon\'s application at today\'s hearing.

In the interest of full disclosure, I first want to acknowledge that the
ASAA has received some support from Cephalon for our activities over the
last four fiscal years but only less than \$4,000 per fiscal year. All
activities, such as exhibiting at medical meetings and National Sleep
Awareness Day, have been initiated by the ASAA, never by any company. I
personally hold no stock in Cephalon or any other company in the sleep
field other than what may be in the retirement mutual fund.

Sleep-disordered breathing, including sleep apnea and upper airway
resistance syndrome, is a common disorder that affects millions of
Americans of all ages. Yet, it is relatively rarely diagnosed in part
because the most common symptoms, snoring and falling asleep easily
and/or sometimes inappropriately, are not recognized by society as
symptoms of a potentially serious medical disorder. Consequences of
untreated sleep apnea may be significant and include sleepiness, high
blood pressure and other cardiovascular disease, morning headaches,
feelings of depression, impotence, and memory problems. Once diagnosed,
the patient can be prescribed a course of treatment. Treatment options
include oral appliances, weight loss, positional therapy, surgery, and
the use of a continuous positive airway pressure, or CPAP, device.
Medications may also be prescribed for central sleep apnea. Which
treatment option is best for the patient depends upon the severity of
the sleep apnea and other aspects of the patient\'s medical history.

As you have heard, the gold standard and most consistently effective
therapy is the CPAP machine. CPAP works by pushing air, via tubing that
connects the CPAP to an interface that touches the patient\'s face,
through the airway passage at a pressure high enough to keep the airway
passage open during sleep. The pressure is set according to the
patient\'s sleep apnea. Pressure that is too low will not be as
effective in eliminating the apneas and hypopneas. While effective, CPAP
may be difficult to use. Hence, published compliance rates may be
suboptimal. Of course, adherence to any therapy for any chronic disease
is typically suboptimal. For example, adherence to pharmacological
therapy is approximately 50 percent. Moreover, it is possible and
important to improve adherence to CPAP. Our publication, If Your Patient
is Not Complying with CPAP, was written for professionals precisely for
this purpose. And I should note that Cephalon has, through support of
our presence at medical meetings, helped us to distribute this to
physicians and other health care professionals. Education of the patient
can also help improve compliance.

Comfort is often an issue with CPAP, and sadly patients may not get all
the equipment and/or assistance they need to utilize this effective
treatment all night, every night. For example, patients need access to
all available options in the mask and machine features so they can find
the best one for them, hence the ASAA publications, Choosing a CPAP and
Choosing a Mask and Headgear, among others. There are many masks on the
market now and manufacturers constantly work to develop more comfortable
masks, but there is no one best mask or machine. Each patient has
different personal preferences.

In addition, some patients need to be desensitized to the mask. It often
takes a skilled and experienced health care professional to enable a
patient to adhere to CPAP therapy. Yet, unfortunately, it can be
difficult, if not impossible, for all patients to gain access to this
expertise. Even patients who are assertive and persistent have been
known to give up on the treatment before they find a comfortable option.

Thus, proper treatment of sleep-disordered breathing does not always
follow the diagnosis. The ASAA finds the state of affairs unacceptable.

The three main causes of sleepiness are sleep deprivation, endemic in
this country, untreated sleep disorders, and circadian rhythm
misalignment caused by factors such as jet lag and night work. Alcohol
and certain medications may also cause sleepiness, as can depression and
certain illnesses. Numerous studies show that untreated sleep apnea
causes sleepiness and that CPAP, even when not used all night, every
night, reduces sleepiness. Likewise, there are studies that show that
patients with inadequately treated sleep apnea are likely to remain
sleepy. One may also have treated sleep apnea and be sleepy from sleep
deprivation or night work. Studies also show that patients who appear to
have well-treated apnea may also have residual sleepiness. Regardless of
the cause, sleepiness can have adverse consequences and requires
attention.

Modafinil was originally approved by the Food and Drug Administration to
improve wakefulness in patients with excessive daytime sleepiness
associated with narcolepsy. It has also been investigated, as you have
heard, to treat residual sleepiness in patients with treated sleep
apnea, defined in one study as using CPAP on a regular basis at least 4
hours a night on 5 nights per week, not all night, every night.
Modafinil has been shown to be safe in clinical studies and in clinical
use. It is thought to be safer than amphetamines which have also been
prescribed for residual sleepiness in sleep apnea. But still it is not
benign. No drug is.

As noted earlier, some sleep apnea patients experience residual
sleepiness despite getting sufficient sleep and having effective therapy
for apnea. Because of this, based on the limited available data, the
American Sleep Apnea Association can support the narrow use of modafinil
in patients whose sleep apnea is being treated appropriately and
sufficiently and whose other causes of sleepiness, including sleep
deprivation, insufficient CPAP pressure, or mask leak, have been
addressed or excluded. It is worth noting that to our knowledge, no
published study looked at the role of sleep deprivation in the
sleepiness. Yet, the ASAA believes that modafinil has a role, albeit a
minimal one, in managing sleep apnea, and the absence of a relevant
indication for the drug can be a barrier for patients to get insurance
coverage for medically necessary medication.

Still, we cannot emphasize enough that prior to prescribing medication
for sleepiness after a patient has begun treatment for sleep apnea, the
physician must examine and address all possible causes of the patient\'s
sleepiness, particularly CPAP adherence. As Dr. Jed Black wrote in his
editorial, Pro: Modafinil Has a Role in Management of Sleep Apnea,
published in the American Journal of Respiratory and Critical Care
Medicine, one unpublished study found that two-thirds, or 31 out of 46,
of CPAP patients who were sleepy after being on CPAP for at least 6
months were no longer sleepy \"following 30 days of subsequent upgraded
CPAP use.\" At the same time, 15 of the 46 subjects still had residual
sleepiness and underwent a trial of modafinil. It, however, must be
remembered that this pharmacological approach treats only the symptom of
sleepiness, not the underlying cause of sleepiness. It does not prevent
apneas and the consequential oxygen desaturation and sleep fragmentation
that may lead to cardiac disease and other health problems.

So while it may be easier for physicians to prescribe and for patients
to take modafinil, both must know that taking modafinil does not render
CPAP unnecessary. This point must be made clear on the labeling and in
any advertising, particularly as one study found a statistically
significant reduction in CPAP use among subjects given modafinil
compared to the control group.

In addition, in cases of extreme sleepiness thought to be from untreated
sleep apnea, modafinil may have a short-term role to minimize the direct
risk of sleepiness until definitive treatment is initiated and found to
be effective. While we are aware of no formal studies on the use of
modafinil as bridge therapy, the doctor must make a clinical judgment on
the potential benefits and risks of prescribing modafinil and of not
prescribing modafinil. Sleepiness does carry risks. Yet, modafinil must
not be seen as a panacea. The drug must not hinder appropriate diagnosis
and treatment of the underlying cause of the sleepiness.

The ASAA is clearly committed to seeing that modafinil, should it be
approved for additional indications, be prescribed appropriately. We
believe Cephalon as the manufacturer must vigilantly educate the public
and prescribing physicians about the appropriate role of modafinil. The
ASAA remains willing to continue to work with Cephalon and with other
interested parties on our common goal of helping people with sleep
disorders.

Again, thank you very much for this opportunity to speak to the panel
today, and I do just want to note that we\'ve limited our comments to
the use of modafinil for sleep-disordered breathing given the mission of
the American Sleep Apnea Association. Thank you.

DR. KAWAS: Thank you, Ms. Engelhardt.

Anyone else who would like to speak in the public forum section?

(No response.)

DR. KAWAS: Okay, this section is now over.

Since we\'re going to try to do without a lunch break, it\'s been
requested that we have another bathroom break. So if we can have a very
quick break, I\'m going to start sharply in 10 minutes.

(Recess.)

DR. KAWAS: We\'re reconvening this session which hopefully will not
extend to a dinner break, but I can tell everyone is hungry. So if it
comes down to everyone wanting a break for lunch, please holler and let
me know.

I\'d like to reconvene this session and open with a final opportunity
for anybody on the advisory committee who has any other questions,
comments, or thoughts, questions either for the sponsor or for the
agency, to take this opportunity now before we proceed to the formal
vote for the different questions that they\'ve given us. Yes, Dr. Krahn.

DR. KRAHN: I have a question for the agency. If Provigil gets this
indication, I\'m concerned that it will be used in a very widespread way
for patients who may have shift work issues rather than shift work sleep
disorder. I\'m wondering what suggestions or comments you may have on
ways to limit its usage to ensure that it is provided to patients who
have appropriate needs and not used in a more widespread way.

DR. KATZ: Usually in a case like this, we would basically rely on
labeling to describe in whom the drug is safe and effective, who should
get it. We can\'t be completely directive, but we can spell all this out
in labeling and not just professional labeling for the prescriber but
patient labeling, the so-called patient package insert which is
something that can be given to the patient each time they get a
prescription filled, which will tell them this shouldn\'t be taken for
just routine ‑‑ you stayed up a couple of nights and now you\'re sleepy,
but if you have sleepiness, you should go to the doctor, get it worked
up, that sort of thing. So labeling in various forms I think would be
mostly what we would do.

In certain cases you can attempt in labeling to more formally restrict
who can prescribe it and this sort of thing, but I don\'t think we would
anticipate that sort of thing here. The drug has been out on the market
for a number of years. We obviously want to hear what you think, but so
far we haven\'t thought that there is a particular safety concern which
would usually drive that sort of thing. So a lot of information to the
relevant parties.

DR. MIGNOT: And how effective is this information?

DR. KATZ: I\'ll let Dr. Temple answer that.

DR. TEMPLE: This is under the general heading of risk management, which
everybody is busy worrying about now, and the conversation often turns
to the risk management tools that you have. Well, the physician
labeling. That\'s one tool. We know that doesn\'t always work. The next
thing you think about is a combination of making sure promotion is
appropriate, which we try to do, and perhaps directing information to
the patient specifically. If you were to ask me how well we know those
things work, I will tell you I don\'t know the answer to that. But
patient labeling is certainly used widely. Many of the sedative
hypnotics have labeling that says don\'t use this too long, be careful,
watch out if you\'re going to drive a car, stuff like that. And you can
think of things you could do here that would do that, reminding people
that sleep apnea isn\'t cured by something that takes care of your
daytime sleepiness. There are other problems associated with it and you
really better see a doctor about it and get the right machinery and
stuff like that. So those things could be considered.

If there\'s something we\'re really, really worried about, we sometimes
have limited distribution systems. It\'s not easy to think of doing that
without some quite dramatic cause for drugs already on the market
without it for a long time. But troublesome drugs like thalidomide and
things like that have special distribution systems and other drugs too.
That\'s relatively extreme. It\'s relatively disruptive and you need a
pretty good reason for doing that.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: I guess my concern about Provigil is that patients may really
go in to their physicians requesting it and they may desire it to reduce
their need to sleep at night. So they may view it as replacement for the
normal amount of nighttime sleep. And how are we going to put in place
some safeguards to reduce its misuse in that way?

I do think that it\'s different than a sleeping pill. Many patients want
to sleep at night, but it replaces something that\'s missing and they
don\'t want to sleep more than they should be. Here a person may want to
enhance a physiologic state and have, let\'s say, 20 hours of alertness
in place of what is more normal. That\'s why I think that this is an
important issue for Provigil with an expanded indication.

DR. KATZ: Besides the approaches we\'ve already talked about in terms of
labeling and describing in labeling, again to focus back on the
professional labeling, there can be language in that instructing the
physician that a diagnosis has to be made that this should be only be
used in patients who have had a formal diagnosis.

The other thing that has been done in the past are educational campaigns
where companies produce documents that can be designed to be sent to the
physicians, as well as the patients, explaining in greater detail who
this should be used for, what it is capable of doing, what it is not
capable of doing, and not in terms of treating the underlying illness,
that sort of thing. So, again, it\'s more avenues of information.

Short of that, I\'m not sure. Again, as Dr. Temple said, unless there\'s
a real known significant risk to the treatment, more restricted
distributions would be, I think, problematic in this case.

DR. TEMPLE: You can be fairly sure that none of the attempts to
encourage proper behavior will be fully effective. Fully might be even
over-optimistic or less than fully might be an over-optimistic
statement.

But it\'s not an easy answer. If you read the papers, apparently a lot
of people are existing on less sleep than they need already, which is
one of the reasons there are dangerous drivers and things like that.
It\'s not completely obvious whether off-label use that helps them deal
with their bad behavior is worse or better than not doing anything.
Those are not easy questions. If they\'re driving next to me, I think
I\'d prefer they be on it.

(Laughter.)

DR. TEMPLE: So as a general matter, we don\'t believe that we can
control what physicians and patients do fully. If it\'s a teratogen, we
take very excessive, very strong steps to try to make sure nobody gets
the wrong drug. If it\'s other things, we don\'t do as much, but we try
to get it right through labeling and patient labeling and making sure
promotion doesn\'t over-promise and things like that.

DR. MIGNOT: Just to follow up on this question, I think one of my
concerns was especially for shift workers that may have sleep apnea
additional to their shift work. Sleep apnea is so common that I\'m just
worried that something like this could occur where a patient would have
both disorders. It\'s a bit difficult to ask us to somehow vote on this
I think without knowing what the label will say, in a way, because I
think that\'s really going to be critical that people are really warned
that they shouldn\'t use it as a replacement for CPAP for treatment of
sleep apnea.

DR. TEMPLE: We\'re listening to that concern. Speaking for Russ, we know
that the labeling should be clear on that.

It\'s not out of the question, you know, that more people who notice
that they\'re sleepy will actually get to their doctors for sleep apnea
as a result of better information. There\'s not a lot of ways to get
that information to people, and a commercial sponsor with an interest is
one way of getting it. So it could even be good.

DR. KAWAS: Do we have any other questions or comments or queries from
the advisory committee? If not, we\'ll move on to the questions for a
vote.

(No response.)

DR. KAWAS: No, okay.

Question number 1, using the International Classification of Sleep
Disorders, which actually divides sleep into dyssomnias, parasomnias,
sleep disorders, and proposed sleep disorders, the sponsor has defined
disorders of sleep and wakefulness associated with excessive sleepiness.
Does the committee agree with this designation?

I think the way we\'re going to do this today is we\'ll start at one end
of the table and let each person vote. We\'ll switch the order
periodically just to build up the suspense.

(Laughter.)

DR. KAWAS: So, Dr. Azarnoff, would you like to start?

DR. AZARNOFF: I don\'t believe I have a vote.

DR. KAWAS: Oh, I apologize.

Dr. Ebert.

DR. EBERT: I\'m going to take the approach to this one from primarily an
academic standpoint and say that I vote yes.

DR. KAWAS: Dr. Mignot?

DR. MIGNOT: Yes.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: Yes.

DR. KAWAS: Dr. van Belle?

DR. van BELLE: I defer to the experts in this. I\'m not an expert so
I\'m not voting either for or against.

DR. KAWAS: Abstain.

DR. van BELLE: I\'m abstaining. Thank you.

DR. KAWAS: Okay.

Dr. Wolinsky?

DR. WOLINSKY: Yes.

DR. KAWAS: I vote yes at least in the sense that there\'s excessive
sleepiness and all of those conditions.

DR. KAWAS: Dr. Kattah?

DR. KATTAH: Yes.

DR. KAWAS: Dr. Neubauer?

DR. NEUBAUER: I vote yes.

DR. KAWAS: So the vote is all yes and 1 abstain.

Second, the sponsor believes that the above group can be divided into
three categories based on presumed cause of the excessive sleepiness.
The categories are: sleep-wake dysregulation, sleep disruption, and
circadian misalignment. Does the committee agree with this
classification?

Dr. Neubauer?

DR. NEUBAUER: I\'ll agree, yes.

DR. KATTAH: Yes.

DR. KAWAS: Yes.

DR. WOLINSKY: Yes.

DR. van BELLE: Abstain again.

DR. KAWAS: Abstain.

DR. KRAHN: Yes.

DR. MIGNOT: Yes.

DR. EBERT: Yes.

DR. KAWAS: The third question, does the committee agree that the
disorders studied by the sponsor, which are narcolepsy, obstructive
sleep apnea, and shift work sleep disorder, are representative of the
three categories described above?

I guess we\'ll start with Dr. Ebert.

DR. EBERT: That they\'re representative of the categories described
above, I would say yes.

DR. KAWAS: I\'m sorry. I should have said this first. One of the
questions in my mind is what do we mean by representative here? Does the
agency have any guidance to give us on that? I mean, my inclination
right now is to say no, they\'re not representative. They\'re the most
common, for sure, but there\'s a big difference between obstructive
sleep apnea and periodic leg movements, for example, potentially. So in
what way do you want us to discuss the representativeness?

DR. KATZ: Well, again, the next question sort of asks the \$64,000
question, or more.

(Laughter.)

DR. KATZ: But what we\'re really trying to get at is whether or not the
approach that the sponsor has proposed and has undertaken is adequate.
In other words, if the drug is studied in shift work sleep disorder, can
we therefore generalize and say, well, this drug works in disorders of
circadian misalignment? That\'s what we mean by representativeness. So
that\'s what we mean. Again, the fourth question which asks overall do
the data support the claim incorporates that concept, but that\'s what
we mean. If you show it works in one disorder, which they have done, in
each of the three categories, does that mean that the drug will work and
we can reliably conclude that the drug will work in all disorders in
that category.

DR. TEMPLE: This also comes slightly in two flavors also. Sometimes the
potential reality of it helps focus.

The indication is written broadly and maybe they could say this works
for circadian abnormalities. But the other possibility is that you might
see conceivably a specific claim for jet lag which has never been
studied. So, on the one hand, there\'s the sort of general idea which
someone might conclude applies to jet lag but not a specific claim, I
work in jet lag. And the other is, you get those specific claims even
though you haven\'t specifically studied them.

This comes up a lot of other times. We insist that there be data on both
men and women, old and young, black and white, and the labeling all says
it seemed to work basically similarly. But if somebody set out and did a
campaign, I work in patients over 65, without specific studies of that,
that might make us nervous. So it\'s nuanced and not entirely
satisfactory because we do want broad information. This has a little bit
of that.

So as you go through this, you might think about how you feel about
that. Even if you think the broad claim is supported, how do you feel
about specific conditions under that claim that have not actually been
studied. I mean, you might think it\'s okay. I\'m not trying to tell you
what to think.

DR. KAWAS: Great. I think actually that helps me somewhat. I hope the
committee feels the same way.

On that note, Dr. Ebert, would you like to vote?

DR. EBERT: Given the slight change I think in the term
\"representative,\" what I\'m hearing now is that we\'re saying that
that disease would infer that it would apply to all conditions within
that category, I would like to change my vote to no.

DR. KAWAS: Thank you.

Dr. Mignot?

DR. MIGNOT: I still have a question about this specific issue. It\'s
impossible to really predict all. Obviously, diseases are heterogeneous
and I don\'t think you can ever have something that\'s all. You could
say almost all, but you cannot say all. For example, periodic
hypersomnia or certain forms of idiopathic hypersomnia may be described
later as having a sub-cause that will not respond to modafinil. If it
was \"almost all\" ‑‑ \"representative\" is the broader term for the
large majority of patients ‑‑ I would say yes. But if it\'s \"all\" ‑‑
completely all ‑‑ I don\'t think that\'s possible to really answer. I
want to know if you mean ‑‑

DR. KATZ: Well, what we mean by the question is driven by what the
sponsor is proposing. The sponsor is proposing that the drug be approved
for excessive sleepiness associated with disorders of sleep and
wakefulness. If such a claim is granted, the implication is that it
works to treat excessive sleepiness in disorders of sleep and
wakefulness which, as they\'ve defined it, includes that whole list of
disorders that are subsumed under the three categories they\'ve created.
That\'s all. I mean, it\'s inclusive. The implication is that because it
worked in shift workers, it will work in the six other conditions that
are subsumed under circadian misalignment. I don\'t think there is, for
the purposes of labeling as they\'ve proposed it ‑‑ the indication as
they proposed it, I don\'t think it\'s some. I think the intention is
for the conclusion to apply to all conditions subsumed under this
broader heading.

DR. MIGNOT: I\'m sorry to ask this question again, but maybe if you were
pooling patients, like if you do a clinical trial and you say they are
all disorders of ‑‑ you know, it\'s a statistical argument really ‑‑ all
disorders of sleep that have sleepiness and you pool them all and you
have 10,000 of them, and then you will see a statistically significant
effect, then the answer would be yes because, of course, there will be
some patients that will not maybe react to the drug.

DR. KATZ: Well, it depends. You could do a large study and have only 2
patients with restless legs, and you\'d be hard-pressed to say, well, it
applies to restless legs.

But here, the situation is much more stark. I didn\'t add up the total
number of disorders that are included here under disorders of sleep and
wakefulness, but it\'s a large number. They studied three. And they are
asking us to conclude that based on the findings in those three specific
conditions, that the drug will be effective in all the others. That\'s
really the whole question, much of what we\'ve been discussing today.

So now we have to decide whether or not we think that\'s valid. You have
unanimously concluded that disorders of sleep and wakefulness associated
with excessive sleepiness is a real thing and that the three
subcategories that the sponsor has subsumed those disorders under is
real, meaning presumably that they share a common pathophysiology or
something. Now we have to decide whether or not we think that those
three indications support all the rest.

That doesn\'t necessarily mean in labeling we would list all of those,
but I don\'t know what we would do in labeling yet, as far as that goes.
But the implication will be that this drug works to treat the sleepiness
associated with this entire list of disorders. At least that\'s the way
I interpret their proposal.

DR. TEMPLE: There are also potential nuances. We haven\'t figured out
what the labeling should be. But, for example, one could also
conceivably use the broad language and then say, the drug was
specifically studied in the following conditions and not others. This
isn\'t to say we would ultimately conclude that\'s the right thing to
do, but there\'s really no limit to how you do those things and not a
lot of precedent, I have to tell you, either.

DR. KATZ: Right, but even such an approach where you just list ‑‑ I
would sort of anticipate that\'s probably close to what we might do,
just say here\'s the overall claim, here are the conditions it would be
studied in. In fact, we would do something very close to that in any
event because there\'s a part of labeling where we describe the trials
that served as the basis for the approval. And those are the trials that
were done, so those are the trials we would describe. You could put it
in the indication section. Anyway, it would certainly be somewhere in
labeling.

Nonetheless, the overall claim, which is what we\'re talking about here,
or indication, presumably applies to the entire universe of disorders in
those categories.

DR. MIGNOT: I vote yes.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: No. This discussion has been very helpful, and I realize
labeling might help address this issue, but I think that it\'s hard to
highlight three disorders and say that that represents all the other
disorders.

DR. KAWAS: Dr. van Belle.

DR. van BELLE: Well, I\'m going to say something about this.

First of all, the word \"representative\" has a very specific
statistical meaning; namely, \"representative\" means randomly selected
from a population. Well, clearly that was not the case here.

On the other hand, there was discussion with the FDA about what would
constitute representative conditions according to these three categories
I think. In fairness to the sponsor, I think we should work from that.

So in statistics, there is another way to sort of get out of the
representativeness and to simply talk about a convenience sample. So to
my mind, these three studies represented three convenience samples from
each of those three areas. So if you allow me to substitute the word
\"convenience\" sample for representative, then I do think that the
sponsor has, indeed, satisfied the condition.

DR. KAWAS: Please.

DR. KATZ: I really don\'t want the primary issue to get lost in the
language. You can call it representative. You can call it anything you
want. It\'s the fundamental concept that really matters, which is again
if they show it works in these disorders, can we conclude that it will
work in all the other disorders with excessive sleep, with the larger
category that they defined. I don\'t care if we call that representative
or not, but that\'s really the fundamental issue that we\'re grappling
with in this question.

DR. van BELLE: But the analogy by Dr. Temple earlier today about, for
example, pain, that not every possible condition for pain is studied and
yet approvals are given for conditions of pain. That must be based on
studies very similar to this situation here.

DR. TEMPLE: Well, and a history that goes back 60 years too which is a
little different.

DR. KATZ: So do we have a vote?

DR. KAWAS: Yes, I need to make sure I understand Dr. van Belle\'s vote
on question number 3.

DR. van BELLE: Yes, in the way that I\'ve defined the representative.

(Laughter.)

DR. KAWAS: Got it.

Dr. Wolinsky.

DR. WOLINSKY: I actually see the fundamental issue as a little bit
different than what I\'m hearing espoused on that end of the table.
First of all, I think that within any one of the three conditions that
have been tested, the patients are representative of the response. As
best I could tell from the data presented, not every patient got a
response.

I also understand from the data that was presented that there was no
claim that there was any specific treatment of the underlying disease
but just an amelioration of symptoms which were relatively common to a
broad variety of diseases that could be specified. I felt that the data
presented in the classification system was such that, in fact, these are
three conditions, each one representative of an example of that
classification system.

If I thought they were treating diseases, I would have to say no, but
they are treating symptoms, so I have to say yes.

DR. KAWAS: I think that was a yes.

DR. KATZ: Yes, that\'s what I wrote down.

(Laughter.)

DR. KAWAS: And my vote is going to be no. Although I agreed with the
categories, you can keep categorizing things, and the three categories
on presumed cause of the excessive sleepiness was an acceptable division
for me, but that didn\'t mean, to my mind, that we have a common
pathophysiology. From that standpoint, I feel strongly that I think the
sponsor made some very wise choices in what they chose to study, i.e.,
they studied the most common disorders in each of those categories.

But at this point I feel that seeing evidence, for example, that this
may reduce the excessive sleepiness of obstructive sleep apnea and may
be reasonably safe for people with obstructive sleep apnea, it doesn\'t
tell me anything about its efficacy or safety, for example, in central
apnea. It doesn\'t tell me anything about its behavior in other diseases
like periodic leg movements. It may work in narcolepsy, but I don\'t
feel that I have enough information to assume that it would work in
periodic hypersomnolence. The information from my perspective doesn\'t
give me enough information about efficacy or safety in the other
diseases in the category, for the most part.

Dr. Kattah.

DR. TEMPLE: Can I ask something? Is this a matter of the number of
models? If there were more models, could you ever be convinced, or is it
just that you think really you just can\'t know until you study it in
any setting?

DR. KAWAS: I think in some settings and some places where the diseases
are better understood pathophysiologically, it might be numbers. But in
this case I think we\'re grouping a very diverse group of conditions
under each of the three categories, and to my mind the pathophysiology
of those are likely to differ so substantially that I\'d be concerned
about what effects it would have in these conditions. Does that answer
your question?

DR. TEMPLE: Yes. I think you\'ve reached the conclusion that the
treatment here should not be considered a mere symptom, if you like, but
something that may have something to do with the pathophysiology of the
disease. I think that\'s the differences that we\'re seeing. I mean, if
you believe it\'s just a symptom, then you wouldn\'t worry about having
every conceivable disease. If you\'re not so sure about that, then you
really sort have to go one by one. I think that\'s what the differences
are.

DR. KAWAS: That capsulized it well, yes.

DR. KATTAH: I guess as the comments are going around, the more I hear
about it, the more I think that we\'re looking at sleepiness as a
comprehensive term, and in that sense, then the answer will be no
because it doesn\'t encompass common pathophysiology, and it has not
established all cases of daytime sleepiness. So in that sense, I will
say the answer will be no.

DR. KAWAS: Dr. Neubauer?

DR. NEUBAUER: I vote no. It\'s really more of a technical issue than a
practical one because I think that probably there are final common
pathways related to sleepiness that modafinil has a potential to help
with. The only thing that troubles me here is the selection. We have
narcolepsy on the one hand, which is clearly a disease. We have
obstructive sleep apnea hypopnea syndrome, which is a syndrome, and then
there is the shift work disorder, which is really nothing that\'s very
well defined at all.

I wouldn\'t have a problem if it was just shift workers who were sleepy.
Now, whether or not to treat them would be another issue, but at least
in terms of saying they\'re representative of these categories, the
sleepiness and insomnia that\'s part of the experience of many shift
workers, would be very reasonable here.

But the interpretation that we\'ve heard here is that a special subset
of shift workers who have something else wrong with them, who have some
other underlying vulnerability that is only brought forth under the
circumstances of their doing the shift work. In fact, if that\'s the
case, then those people with this particular vulnerability actually
would belong in a different category which would be the sleep-wake
dysregulation, more like the narcolepsy patient, but something that is
only brought out under those circumstances. So it\'s nothing that\'s
intrinsic to shift work itself if that\'s the population we\'re told is
studied here.

DR. KAWAS: Remind me. Your vote is no.

DR. NEUBAUER: No, correct.

DR. KAWAS: I\'m trying to figure out the tabulation here, and it looks
to me like 3 yeses and 5 noes, with all kinds of qualifications.

Actually, if I may go back to your question, Dr. Temple. For example,
knowing that it works in shift workers, for example, who have a kind of,
in their own way, a regular schedule, it doesn\'t tell me what it will
do for a delayed sleep phase person where their sleepiness is always at
a different time of day. The disorder has completely different
underpinnings even though it fell into the same category, and I think
this might have been Dr. Neubauer\'s point, whether or not they\'re
environmental or disease or intrinsic-induced. You know, you put a bunch
of things in the same category.

Question number 4. Does the committee agree that the sponsor has
submitted substantial evidence of effectiveness for the indication for
the treatment of excessive sleepiness associated with disorders of sleep
and wakefulness?

Would you like to start, Dr. Neubauer? We should start in the middle of
the table sometime. Actually I will. How about if I start with Dr.
Wolinsky? We need to liven up things here.

DR. WOLINSKY: Well, I assume that this vote should wind up being very
similar to the last vote, otherwise my logic fails me. But I will add a
little different comment. I think that the clinician, armed with the
data that we\'ve seen, approaches patients with this category of
symptoms as what I would call and others have called an n of 1 study
with a quick vote back as to whether or not there was effectiveness. So
I say yes.

DR. KAWAS: Dr. van Belle?

DR. van BELLE: Yes.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: No, again because of the global nature of the indication.

DR. KAWAS: Dr. Mignot?

DR. MIGNOT: Yes.

DR. KAWAS: Dr. Ebert?

DR. EBERT: No. I feel that although I think the drug is effective in
treating the symptoms, my concern is that the approach to the symptom
will overshadow the need for a diagnosis. Again, as Dr. Krahn mentioned
earlier, in many cases this drug may be prescribed by primary care
physicians that may feel that they\'re approaching the symptom and have
not done a complete job of approaching the diagnosis.

DR. TEMPLE: That\'s a somewhat different ‑‑ not that it\'s not a
legitimate concern, but it\'s quite a different concern. So we need to
understand what you\'re saying. Are you saying, oh, yes, it probably
does work anytime where a person is sleepy, but I\'m worried about using
it so broadly? That\'s sort of an answer of yes, but I don\'t want to
approve it for that, which is not the same as saying, no, I don\'t
believe it, which for example Dr. Kawas has been saying. So it would
help us if you distinguished which of those things you\'re saying.

DR. EBERT: What I\'m saying is I\'m concerned whether it\'s from a
detailing standpoint or from an approach that if a patient presents with
that symptom, that as we mentioned by many people here, perhaps the
patient has sleep apnea, and rather than working that patient up and
trying to fully use front-line therapy such as CPAP, that instead we
would be approaching it more from a symptom standpoint. It would bypass
a full diagnosis.

DR. KATZ: But just to follow up on what Dr. Temple said, should we take
from that that you think, though, that the effectiveness ‑‑ forget about
approvable because I don\'t think the question actually asks about
approvable. We usually don\'t. We just ask if there\'s substantial
evidence of effectiveness. So do you think the data support the claim?
As I say, put out of your mind for the moment that this is related to
approval.

DR. EBERT: Okay. Well, again, to me the term indication, as you probably
are alluding to, is synonymous with approval. So I understand what
you\'re saying. If we were to take that word out of the question, I
still think, again similar to what my vote was in number 3, that
there\'s not enough information to make the broad application to a
variety of diagnoses.

DR. KAWAS: So that\'s a no. Right?

Dr. Kattah?

DR. KATTAH: Yes.

DR. KAWAS: Dr. Neubauer?

DR. NEUBAUER: No. And I say that with some reservations because I think
that modafinil does have a lot of potential in a broad range of
categories, and it really comes down to what you mean by effectiveness
because they have submitted substantial evidence of clinical
improvement, which really might be very important for a lot of people.

However, my real reservation relates to the shift work sleep disorder
studied because while the clinical improvement associated with 1 or 2
minutes on the MSLT may be great, how can we say that it is effective
for that population when the treated subjects still had an MSLT of 3.8?
These are people that we would be worried about being out on the road
driving and this is when they\'ve had the medication. So I\'m reluctant
to say that it is truly effective for that population even though there
is a clear clinical improvement.

DR. KATZ: Again, just as a typical matter, the treatments that in
general we approve certainly are no cures. There\'s no obligation that
they be cures. The treatments that we ordinarily approve on average have
relatively small treatment effects. That doesn\'t mean you couldn\'t
conclude that in this particular case that would be the wrong thing to
do. Of course, you could do that. But just as a general background, we
recognize that the treatments that are approved in our division and in
most divisions are symptomatic treatments.

It\'s not unheard of to have similar situations to what you have here
which is that patients enter a trial based on some severity. They\'re
treated. The drug is better than placebo and they still probably could
meet the criteria to enter the trial, but nonetheless, they\'re better
than they would have been had they not had the treatment. In general, in
that sort of setting, we decide that\'s good. Of course, a mean effect
hides a distribution of effects and some people may have large effects.

So the fact that the symptom hasn\'t been eradicated is perfectly
consistent with how drugs are approved traditionally. But again, in any
individual case, you could decide that that\'s just not good enough.

DR. KAWAS: Are you comfortable with your decision?

DR. NEUBAUER: I am.

DR. KAWAS: Good.

I believe that the sponsor has submitted substantial evidence of the
effectiveness for the indication of excessive sleepiness in three
situations which are obstructive sleep apnea, shift worker sleep
disorder, which is a subset of shift workers, and for narcolepsy, but
not for the general treatment of all the groups of disorders that they
put into that category. So my vote is no.

So that makes the vote total here, I think, 4 and 4. I\'m sure that
helped.

(Laughter.)

DR. KAWAS: For our sleep experts, for whatever it\'s worth, they were
also divided between the two votes with one of them on the yes side and
two on the no side.

Has the sponsor demonstrated that Provigil can be used safely for this
broad indication?

Dr. Kattah?

DR. KATTAH: I think that in narcolepsy ‑‑ well, that\'s not an issue
right now ‑‑ it has done this and also in the shift work sleep disorder.

In the group of patients with sleep apnea, I\'m somewhat concerned. I
raised the question about the headache. If you look at the two trials,
303 was 12 weeks and 402, 4 weeks. There was a twofold incidence of
headache in the group with sleep apnea, and I wondered if that might
relate to increasing intracranial pressure. I know that there is a high
incidence of pseudotumor cerebri in sleep apnea, and if we see now an
increment in the headache, given the short duration of the trial, it
makes me think that there could be perhaps a mechanism whereby changes
in blood pressure may be occurring at the same time accounting for this
increased incidence of headache.

And my answer will be yes for the shift work sleep disorder, but not in
the sleep apnea. I would want to have more information and longer
follow-up.

DR. KAWAS: Thank you. I\'m not sure how to count that in the tab, but
it\'s a good thing that\'s Ms. Patel\'s job I hope.

Dr. Neubauer?

DR. NEUBAUER: Yes.

DR. KAWAS: Dr. Wolinsky?

DR. WOLINSKY: Yes.

DR. KAWAS: Dr. van Belle?

DR. van BELLE: Yes.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: Yes.

DR. KAWAS: Dr. Mignot?

DR. MIGNOT: No. Yes, I still have the same concern I guess. My concern
is that it doesn\'t treat all the symptoms of sleepiness and it really
depends on what will be written or how the drug will be prescribed in
terms of not efficacious enough maybe in some patients that will have
sleep-wake ‑‑ you know, that will be a shift worker and take modafinil
and thinking that they\'re perfectly safe, where they are not. I think
also we really need to make sure that patients with sleep apnea not
untreated take the medication. Maybe some of that can be addressed by
the labeling, and I would trust the FDA to look at this issue very
carefully. But as it is now, I don\'t think I can make a yes without
looking at what will be done to ensure that this is not the case.

DR. KAWAS: Dr. Ebert?

DR. EBERT: Yes.

DR. KAWAS: And I think my vote is no. I\'m certainly comfortable,
however, that the sponsor has demonstrated adequate safety for the
indication in the three diseases that they studied. I just can\'t
comfortably generalize that based on what we discussed earlier.

Now, we have two more questions that we were supposed to discuss if we
voted yes on questions 1 through 5. I\'m not exactly sure ‑‑

DR. KATZ: If you didn\'t vote yes. In other words, the point of these
two questions is if you don\'t think it should be approved for the broad
indication, do you think it should be approved for anything? It\'s
already approved for excessive sleepiness associated with narcolepsy. So
does the committee think that there\'s sufficient data to get the
individual conditions that actually were studied into labeling?

DR. KAWAS: So would you like to hear from everybody or only the
individuals who said no?

DR. KATZ: That\'s a good question. Everybody, although I suspect we
could predict the answer for the ones who said yes, but let\'s hear from
everybody.

DR. KAWAS: Okay, excellent. So the first of those questions is, has the
sponsor provided substantial evidence of effectiveness to support the
use of Provigil in the treatment of excessive sleepiness in patients
diagnosed with sleep apnea?

Can we start with Dr. Krahn?

DR. KRAHN: Certainly. Yes.

DR. KAWAS: Dr. Mignot?

DR. MIGNOT: Yes. I would add diagnosed and treated because they were
treated with CPAP, and I think that\'s important to mention that.

DR. KAWAS: So for the apnea patients, if they\'re already on CPAP.

DR. MIGNOT: Yes.

Dr. Ebert.

DR. EBERT: Yes, with a similar statement as an adjunctive therapy to
CPAP.

DR. KAWAS: Excellent.

Dr. van Belle.

DR. van BELLE: Yes.

DR. KAWAS: Dr. Wolinsky?

DR. WOLINSKY: Yes.

DR. KAWAS: And I say yes.

Dr. Kattah?

DR. KATTAH: Yes.

DR. KAWAS: And Dr. Neubauer.

DR. NEUBAUER: Yes.

DR. KAWAS: We\'ve got a unanimous yes.

The final question.

DR. KATZ: Before you get to the final question, typically if we were
dealing with a new chemical entity that had not been approved for
anything, a finding of substantial evidence would require that there be
independent replication in the disease in question. So that means
usually at least two so-called adequate and well-controlled trials
supporting that.

There is one trial in shift work. On the other hand, it occurs in the
context of two trials in narcolepsy and two trials in sleep apnea. So
I\'m just throwing that out as something that people, before they give
us their advice, might want to think about.

DR. KAWAS: I think that\'s a crucial point. Thank you.

Yes, Dr. Hershkowitz.

DR. HERSHKOWITZ: Yes, can I just make one point? With obstructive sleep
apnea, the test itself was not specifically designed to be what one
would consider a pivotal trial. It wasn\'t quite designed the way we
suggest. It had a single primary endpoint which was a subjective
endpoint, and it was a somewhat small study. I know this is related to
the past issue that you voted on, but I just wanted to get it out for
the record.

DR. KAWAS: Dr. Katz?

DR. KATZ: Just to follow up on what I had said and I said this finding
in a single study in shift work occurs in the context of multiple trials
in other presumably related settings, it\'s not uncommon for us to
approve a new indication on the basis of a single trial in the context
of multiple other trials on related endpoints, like for example, a drug
might be approved initially to treat partial seizures on the basis of
multiple adequately controlled trials. If a sponsor wants to get a drug
approved for generalized seizures, it might be acceptable for them to do
only one trial in generalized seizures, and we sort of borrow strength,
to use a term, from the previous data, and we say, well, it\'s not
exactly the same. That\'s why they had to do another trial, but it\'s
related. So we sort of consider the whole package of evidence.

So I\'m just trying to give you a regulatory or a historical context for
your decision on the last question. Right, we even have a guidance which
talks about when a single trial would be acceptable as substantial
evidence. It\'s this sort of thing.

DR. MIGNOT: Should we revote considering this?

DR. KATZ: Well, no. So far you haven\'t voted yet on the one that only
had one study. I just want to make sure you know these things before you
vote on that last question.

DR. KAWAS: Do you want to reconsider your vote on the previous after
this discussion?

DR. MIGNOT: No. Sorry.

DR. KAWAS: There were two sleep apnea studies. We never really discussed
the effect in both of those in particular, but there were two sleep
studies that were nominally positive, although not set up by typical
pivotal trial criteria.

Dr. Azarnoff, did you have some questions or comments you\'d like to
make?

DR. AZARNOFF: I was just going to repeat what Dr. Katz told you, that
single trials are approvable with supporting data.

DR. KAWAS: There is a very clear set of guidelines from the FDA, as I
recall, on when a single trial is acceptable. Do you think it would be
of some benefit to tell the committee members what those are? My recall
of them is not good enough to do that for the group.

DR. TEMPLE: I\'m not sure I\'m going to remember all of them, but I\'ll
remember some of them. This generally refers to situations where you\'re
looking at a claim for a drug that already has some kind of claim and
you bring forth other data. The examples that are given are where you
have data at one dose, you don\'t usually need two studies at another
dose. We might rely on a study of a drug alone and only ask for a single
study where it was to be used in combination. If the conditions are
closely related, a subject to be considered, you might move to a closely
related disease with just a single study. That happens in oncology all
the time. Different stages of the disease or severity of the disease,
you don\'t usually need two studies to move from one to the other. It\'s
examples like that.

DR. KAWAS: Thank you.

On that note, Dr. Ebert, would you like to begin?

DR. EBERT: Yes. I\'ll vote yes. I think that again the emphasis here is
on treatment of a symptom not on the amelioration or the elimination of
the disease, and given the fact that the drug has had a similar effect
on that symptom for the other diseases that have been discussed, I feel
comfortable with that indication.

DR. KAWAS: Dr. Mignot?

DR. MIGNOT: Providing that there is some very strong labeling regarding
the possibility of having shift work disorder and sleep apnea, for
example, which I think is going to be extremely common, I would vote
yes.

DR. KAWAS: Dr. Krahn?

DR. KRAHN: Providing that there\'s very strong labeling that is for
shift work sleep disorder rather than shift work, I\'ll vote yes.

DR. van BELLE: Yes.

DR. KAWAS: Dr. Wolinsky?

DR. WOLINSKY: Yes.

DR. KAWAS: Given that from my perspective the criteria is two
independent studies and we only have one, I vote no.

Dr. Kattah?

DR. KATTAH: Yes.

DR. KAWAS: Dr. Neubauer.

DR. NEUBAUER: No, because I think the conceptual issues of exactly what
constitutes the shift work sleep disorder, as opposed to those
individuals who are doing shift work and experience some sleepiness, and
also back to the question of the effectiveness that I discussed earlier
with these people still being in a range of very profound sleepiness.

DR. KAWAS: Thank you.

So the tally on this is 6 yeses and 2 noes.

Any other questions, things, discussions, queries you would like us to
address?

DR. KATZ: I can\'t think of anything.

DR. KAWAS: I hereby declare lunch. This meeting is adjourned.

(Whereupon, at 1:54 p.m., the committee was adjourned.)