DATE:
FROM: Director
Division of
Neuropharmacological Drug Products
TO: Members
Peripheral
and Central Nervous Systems Drugs Advisory Committee
SUBJECT:
As you know, the PCNS
Advisory Committee will meet on 9/25/03 to discuss supplemental NDA 20-717, for
the use of Provigil (modafinil) Tablets in the treatment of Excessive
Sleepiness (ES) Associated with Disorders of Sleep and Wakefulness. This supplement was submitted by Cephalon,
Inc., on
The application
contains the results of three newly conducted randomized controlled trials, two
in patients with Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS; a disease
characterized by collapse of the upper airway during sleep, leading to arousals
during, and disruption of, sleep, with resultant ES during the day) and one in
patients with Shift Work Sleep Disorder (SWSD; a disturbance in people who work
outside normal working hours, resulting in ES at night and poor sleep during
the day, and presumably related to a mis-alignment of circadian rhythms and the
“normal” work/rest cycle). In addition,
the sponsor briefly reports the results of the two trials previously performed
in patients with narcolepsy, and which served as the basis for the current
approval.
You have already
received the briefing document prepared by the sponsor, in which they describe
the results of their trials, and in which they present their argument to
support their proposed indication.
Unfortunately, the Agency reviews of the application are not completed;
therefore, we cannot forward to you our independent analyses of the data. However, we have reviewed the sponsor's
description of the controlled trial data, and are in general agreement with the
results of their analyses.
In this memo, I will
briefly review the data, and outline the issues we would like the Committee to
discuss at the 9/25 meeting.
As the sponsor
describes, they have, in large part related to multiple discussions held with
the Division, chosen to evaluate the effects of Provigil on the excessive
sleepiness seen in patients with three distinct diseases already mentioned
(narcolepsy, OSAHS, and SWSD) as support for their proposed claim. In the first two settings, the excessive
sleepiness occurs during daylight hours, and in SWSD, the excessive sleepiness
occurs during the hours the subject is supposed to be awake, namely, at night,
during what for them is their work time.
Based on the trials in these three settings, the sponsor wishes to be
granted a general claim for "Excessive sleepiness associated with
disorders of sleep and wakefulness".
This proposed general
claim, and the approach taken by the sponsor, are the direct results of the sponsor's
classification of the various sleep disorders.
As the sponsor notes,
the International Classification of Sleep Disorders (ICSD) classifies sleep
disorders into four main categories:
Dyssomnias, Parasomnias, Sleep Disorders Associated with Mental,
Neurologic, or other Medical Disorders, and Proposed Sleep Disorders.
According to the
sponsor, the Dyssomnias are disorders of initiation and maintenance of sleep
and disorders of excessive sleepiness, or both.
The Parasomnias are disorders of arousal, partial arousal, or sleep
stage transition; according to the sponsor, these disorders do not give rise to
complaints of excessive sleepiness. The
third category comprises sleep disorders thought to be secondary to other more
primary disorders, and the fourth category comprises disorders that are not yet
well characterized.
The sponsor believes
that the primary sleep disorders associated with ES can be broken into four
categories: those associated with sleep induced respiratory impairment; those
associated with movement disorders; those associated with disorders of the
timing of the sleep-wake pattern; and those associated with neurologic
disorders (see the sponsor's table, page 17 of their briefing document).
The sponsor asserts
that the pathophysiology of ES is sleep disruption and increased drive for
sleep during wakefulness. Given this
view, they believe it is reasonable to classify the four primary categories of
sleep disorders associated with ES into three categories, defined by the
following primary pathophysiologic mechanisms:
1)
Sleep-wake
dysregulation
2)
Sleep
disruption
3)
Circadian
misalignment
Because of their view
that the conditions included in these three groupings all share a common
clinical picture (namely evidence of disturbed sleep and an increased drive for
sleep during periods that the subject wishes to be awake), they believe that
these disorders can reasonably be considered to be Disorders of Sleep and
Wakefulness.
As can be seen in the
sponsor's Table 1, page 19, they have subsumed various diagnoses under these
three categories. In the first category,
Narcolepsy is apparently the most common diagnosis, in the second category,
OSAHS is the most common, and in the third category, SWSD is the most common
diagnosis. It is for this reason that
they have chosen these conditions to study, and these serve as the basis of
support for their proposed general claim.
The sponsor, therefore, has chosen to support a general claim based on
the demonstration of effectiveness in the most common diseases they believe are
representative of each of the three categories of pathophysiology that produce
ES.
I will very briefly
review the primary findings on the three newly performed studies; please see
the sponsor’s document for a review of the narcolepsy studies.
OASHS
The sponsor performed
two controlled trials in patients with OASHS-Study 303 and Study 402
This was a
randomized, double blind, placebo controlled parallel group study performed at
39 centers in the
The primary outcome measures were the Maintenance of Wakefulness Test (MWT) and
the CGI-C. In the MWT, the patient is
instructed to stay awake in a darkened room.
At each visit, the patient has four 20 minute sessions performed at two
hour intervals. The score for that visit
is the average of the time it takes for the patient to fall asleep over the 4
sessions (if they do not fall asleep, the time is considered to be 20 minutes).
Secondary outcomes in
this study were the Epworth Sleepiness Scale (ESS; a subjective rating scale
assessing how easily the patient falls asleep during 8 different situations; as
the sponsor notes, a score of 10 or more indicates ES) and the Psychomotor
Vigilance Task (PVT; an objective test in which the subject responds to the
appearance of a visual stimulus; the primary parameter measured in this test is
the number of lapses, defined as brief episodes of nonreactivity; other measures
include the reaction time).
The following chart displays the results of the primary analyses of the Last
observation Carried Forward (LOCF) data set for the intent-to-treat (ITT)
population :
200 mg 400 mg Pbo P-value
(N=88) (N=86) (95)
Change from Baseline
MWT (minutes) 1.6 1.5 -1.1 <0.0001
CGI-C (see
Sponsor’s Table 15, p. 46) <0.0001
The results of the
analyses of the secondary outcomes are as follows:
200 mg 400 mg Pbo P-value
(N=98) (N=92) (N=99)
Change from Baseline -4.5 -3.7 -1.8 <0.0001
ESS
PVT-Change From
Baseline (N=77) (N=76) (N=80)
Median
Reaction Time -20.4 -8.3 1.35 <0.0001
(N=78) (N=76) (N=80)
Number
of Lapses -2.8 -0.8 -0.2 0.0006
An analysis of the patients who were CPAP partially compliant (N=35) revealed no trends for significance on the MWT, and essentially no trends in favor of drug on the CGI-C.
This
was a 4 week, randomized, placebo controlled, double blind, parallel group
study in which CPAP compliant patients were randomized to receive Provigil 400
mg/day (N=77) or placebo (N=80). The
primary outcome in this study was the change from baseline in the ESS; multiple
other secondary outcomes were also assessed, including the CGI and MSLT
(Multiple Sleep Latency Test, a test similar to the MWT, except that subjects
are instructed to not resist falling asleep; it is scored in the same way as
the MWT). The following results were
seen:
400 mg Pbo P-value
(N=75) (n=80)
Change from Baseline -4.6 -2 <0.0001
ESS
CGI-C (See sponsor table 23, page
54) 0.016
Change from Baseline (N=67) (n=77)
MSLT (minutes) 0.99 -.23 0.02
The sponsor performed one controlled trial in patients with SWSD; Study 305.
Study 305
This was a randomized, placebo controlled, double blind, parallel group study
in patients with SWSD performed at 28 centers in the
Secondary measures
included the PVT and the Karolinska Sleepiness Scale (KSS; a 9 point scale in
which the patient rates him or herself from 1 [very alert] to 9 [very sleepy]),
another subjective measure of sleepiness.
In this study,
patients were randomized to either Provigil 200 mg/day (N=99) or placebo
(N=110). The following chart presents
the primary results:
200 mg Pbo P-value
(N=86) (95)
Change from Baseline
MSLT (minutes) 1.70 0.34 0.002
(N=89) (N=104)
CGI-C (see Sponsor’s Table 29, p.
61) <0.0001
The results of the
analyses of some secondary outcomes are given below:
200 mg Pbo P-value
(N=85) (95)
Change from Baseline
KSS -1.5 -0.4 <0.0001
PVT-Change From
Baseline (N=77) (N=83)
Number
of Lapses -4.1 6.1 0.007
The sponsor has submitted the results of three newly conducted clinical trials,
and two previously conducted clinical trials, which they believe provide
substantial evidence that Provigil (modafinil) is effective in the treatment of
Excessive Sleepiness Associated with Disorders of Sleep and Wakefulness. The sponsor’s approach has been to study the
effects of the drug on three different diseases, which they believe are
representative of three categories of sleep disorders associated with ES, which
the sponsor has in turn created and defined by what they presume to be distinct
pathophysiolgic mechanisms. To
summarize, the sponsor has proposed the following pathophysiologic categories,
and has studied the “representative” disease indicated:
Pathophysiologic
Category Representative
Disease
Sleep-wake
dysregulation Narcolepsy
Sleep Disruption OSAHS
Circadian
Misalignment SWSD
The sponsor has
proposed that a demonstration of effectiveness in these three diseases supports
a general claim of effectiveness in the treatment of ES associated with
Disorders of Sleep and Wakefulness.
There is considerable
precedent for the approval of drugs for a given symptom that appears in
multiple clinical contexts. Typically,
the requirements for the approval as a general treatment for such a symptom is
a showing that the symptom is successfully treated in several of those clinical
contexts. A common example would be the
approval of a drug to treat “pain”, based on a finding that pain is
successfully treated in several “models” (e.g., post-surgical, tension
headache, dental pain, etc.). Given such
a showing, the Agency has been willing, in certain circumstances, to grant a
“global” or general claim for the treatment of the symptom. Based on discussions with the Division, the
sponsor proceeded with an attempt to identify representative clinical “models”
in which ES occurs; the clinical program described represents their approach to
the problem.
However, in order for
us to conclude that these data do, in fact, support such a general claim, we
must conclude that the clinical “models” chosen here adequately represent the
universe of clinical conditions subsumed under the sponsor’s proposed
overarching category; that is, Disorders of Sleep and Wakefulness. It is worth noting that the sponsor’s classification
of sleep disorders is their own creation, based on their view of the
pathophysiology underlying various clinical conditions. It is fair to say that the underlying
pathophysiology of sleep disorders is not completely understood, and therefore we
would be interested in knowing whether or not you believe that the sponsor’s
approach to classifying these diseases is appropriate. Further, even if their grouping of diseases
is felt to be appropriate, we need to ask if a demonstration of effectiveness
in the three diseases studied reliably permits the inference that Provigil will
successfully treat ES in all of the other conditions not studied. For example, does a showing of effectiveness
in Narcolepsy allow us to predict that Provigil will be effective in Recurrent
Hypersomnia, or does a showing of effectiveness in OSAHS permit us to conclude
that Provigil is effective in Restless Leg Syndrome, or does a showing of
effectiveness in SWSD permit us to conclude that Provigil is effective in
patients with Time Zone Change Syndrome?
It will be necessary for us to conclude that this is so before we grant
a global claim of the sort proposed by the sponsor (other possibilities exist:
it is, of course, possible that one could conclude that the classification
scheme is appropriate, but that in only one or two of the categories was the
disease studied a valid “model”). If the
Committee concludes that the data do not support the sponsor's proposed, or any
other, global claim, do the data support any other (perhaps disease specific)
claim?
There is at least one
other general question we would like the Committee to discuss.
The sponsor has
chosen to assess Provigil’s effect on the objective measures MWT or the
MSLT. These measures are widely used in
the field, but it is worth asking if the sponsor should have, instead, assessed
the drug’s effect with more direct, or perhaps face valid, measures of
sleepiness . For example, one could
imagine that, instead of the laboratory based MSLT or MWT, one could count
episodes of falling asleep during the day in patients with narcolepsy, or motor
vehicle accidents during the day in patients with OSAHS, or number of
work-related accidents while patients with SWSD were working. We are very interested to hear the
Committee’s views on this issue.
We have additional questions
related to the specific results in the specific disease studied.
In the OSAHS studies,
the changes from baseline between drug and placebo in sleep latencies were
quite small; although analyses of the global measures and other secondary
measures also yielded statistically significant between-treatment differences,
we can fairly ask if the differences seen are clinically meaningful. Further, the vast majority of the patients
were CPAP compliant, at least as defined by the study protocol. As a result, we have no useful information
about the effects of Provigil in OSAHS patients who are not compliant with
CPAP. If the Committee concludes that
the drug is effective in patients with OSAHS, is it appropriate to include in
the approval patients who are not CPAP compliant? In addition, it is possible
that, in these latter patients, a decrease in ES during the day may predispose
these patients to remain CPAP non-compliant (that is, in these patients, their
primary complaint might be ameliorated); we are interested in the Committee’s
views on these, and related, issues and questions (such as, if these patients
remain CPAP non-compliant, is this an unacceptable outcome).
In the SWSD studies
too, the numerical results on the MSLT are small; again, even though analyses
of the other outcomes demonstrated statistically significant between-treatment
differences in favor of Provigil, we must ask if these results can be
considered to document a clinically meaningful benefit in these patients.
Although the sponsor’s intention was to enroll mostly patients who worked a
night shift only a few nights/month, the study enrolled almost entirely
patients who essentially worked the permanent night shift. Although I noted the “representativeness” of
the chosen disease to serve as a model for other diseases above as a general
issue, it is worth noting it here to be discussed in this context. Specifically, we need to know whether the
Committee believes that the results obtained in these “permanent” shift workers
can generalize to those with much more intermittent shift work (we are also, of
course, still quite interested to know if the Committee also feels that SWSD is
a reasonable model for the other so-called disorders of Circadian
Mis-alignment).
In addition, patients
with SWSD have great difficulty sleeping during the daytime. If Provigil decreases their ES during the
night (when they are supposed to be awake), it is fair to ask if this effect
has any deleterious effect on the patient’s attempts to sleep during the day, and
whether the sponsor has adequately assessed this possibility. Indeed, we would be interested in the
Committee's views on whether or not the sponsor has adequately evaluated the
effects of Provigil, either in the short or long-term, on appropriate sleep in
any of these populations.
Of course, we are
interested not only in the Committee’s views on the issues raised here, but
also in any other issues you feel are pertinent. I look forward to seeing you later this
month, and I thank you for your efforts.
Russell
Katz, M.D.