DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PSYCHOPHARMACOLOGIC DRUGS
ADVISORY COMMITTEE
Monday, March 23, 2006
8:00 a.m.
Hilton Hotel
The Ballrooms
Gaithersburg, MD
PARTICIPANTS
Wayne K. Goodman, M.D., Chair
Cicely Reese, Pharm.D., Executive Secretary
COMMITTEE MEMBERS:
Jorge Armenteros, M.D.
Jean Bronstein, R.N., M.S.
Andrew C. Leon, M.D.
Daniel S. Pine, M.D.
Delbert Robinson, M.D.
Philip Wang, M.D., Dr.P.H.
Barbara Wells, Pharm.D.
TEMPORARY VOTING MEMBERS:
Michael Bigby, M.D.
Deborah Dokken, MPA
Richard Malone, M.D.
Cynthia Pfeffer, M.D.
Marsha Rappley, M.D.
NON-VOTING MEMBER:
Dilip Mehta, M.D., Ph.D.
FDA PARTICIPANTS:
Robert Temple, M.D.
Thomas P. Laughren, M.D.
Paul J. Andreason, M.D.
Glenn Mannheim, M.D.
3
C O N T E N T S
PAGE
Call to Order and Opening Remarks,
Wayne K. Goodman, M.D., Chair 5
Conflict of Interest Statement,
Cicely Reese, Pharm.D.,
Executive Secretary 8
FDA Introductory Remarks,
Thomas P. Laughren, M.D. 11
FDA Presentation:
FDA Clinical Review,
Glenn Mannheim, M.D. 16
Modafinil for Treatment of ADHD,
Paul J. Andreason, M.D. 37
Serious Adverse Cutaneous Reactions to Drugs,
Michael E. Bigby, M.D. 64
Sponsor Presentation:
Introduction,
Victor Raczkowski, M.D. 82
Overview of ADHD,
Joseph Biederman, M.D. 87
Clinical Pharmacology and Efficacy,
Lesley Russell, M.R.C.P. 103
General Safety,
Srdjan Stankovic, M.D. 121
Benefit-Risk Conclusions,
Lesley Russell, M.R.C.P. 163
Questions from the Committee to the
FDA and Sponsor 168
4
C O N T E N T S (Continued)
PAGE
Open Public Hearing 210
Committee Discussion 229
Questions to the Committee 257
P R O C E E D I N G S
Call to Order and Opening Remarks
DR. GOODMAN: We expect a few more people
to join us around the table but I want to make sure
that we start on time. Welcome, everyone, to the
Psychopharmacologic Drugs Advisory Committee, or
the PDAC. We have been asked today by the FDA to
advise them on a new drug application for modafinil
in the treatment of attention deficit hyperactivity
disorder, ADHD. Most of the questions, as will be
articulated by the FDA, concern safety issues.
Yesterday there was a meeting of the
Pediatric Advisory Committee which discussed a
range of safety issues concerning medications used
in the treatment of ADHD, the stimulants as well as
Strattera, and actually some data emerged on
modafinil as well during those discussions. I was
present as an observer during those meetings. I am
glad I was there. Some of the members of the
committee that are here today were also present
yesterday so I think a lot of heavy lifting was
done yesterday on some of these important side
effect issues that will help inform us in our
deliberations today.
My remarks are going to be unusually
brief, in part because my voice is strained. My
voice has not been cooperating for the last few
days. In fact, sometimes I am not sure it is my
voice--I don't know what kind of symptom that would
mean. But we have a backup plan. Danny Pine, when
he comes here, in case my voice fails, he will
become my voice.
I also want to put you on notice that
Cicely Reese may deliver at any moment! I am not
kidding! So, we have plans for her transportation
and replacement should that occur. Please bear
with us under these circumstances.
Now I would just like to go around the
table and ask everyone to introduce themselves.
Let's start from the FDA end.
DR. LAUGHREN: Tom Laughren, from the
Division of Psychiatry Products.
DR. ANDREASON: Paul Andreason, Division
of Psychiatry Products.
DR. MANNHEIM: Glenn Mannheim, Division of
Psychiatry Products.
DR. BIGBY: I am Michael Bigby,
dermatologist from Boston.
DR. RAPPLEY: Marsha Rappley,
Developmental Behavior Pediatrics, Michigan State
University.
DR. WANG: Phil Wang, psychiatrist and
epidemiologist from Harvard Medical School.
DR. REESE: Cicely Reese, executive
secretary.
DR. GOODMAN: Wayne Goodman, chair of this
committee as well as chair of the Department of
Psychiatry, University of Florida.
DR. LEON: I am Andrew Leon, professor of
biostatistics at Cornell Medical School.
DR. ROBINSON: I am Delbert Robinson. I
am a psychiatrist at the Zucker Hillside Hospital
and the Albert Einstein College of Medicine.
DR. PFEFFER: I am Cynthia Pfeffer, child
and adolescent psychiatrist at Weill Medical
College of Cornell University.
DR. ARMENTEROS: Jorge Armenteros, child
and adolescent psychiatrist in Miami, Florida.
DR. WELLS: Barbara Wells, I am dean of
the School of Pharmacy at the University of
Mississippi.
MS. DOKKEN: I am Deborah Dokken. I am
the patient family rep. on the Pediatric Advisory
Committee.
DR. MALONE: I am Richard Malone, a child
psychiatrist from Drexel University College of
Medicine.
DR. MEHTA: Dilip Mehta, retired physician
from the drug industry. I am the industry
representative on the committee.
DR. GOODMAN: Thank you all very much. I
think Daniel Pine will be joining us shortly. I
would now like to turn the microphone over to
Cicely Reese to go over some housekeeping,
particularly the conflict of interest statements.
Conflict of Interest Statement
DR. REESE: The following announcement
addresses the issue of conflict of interest and is
made part of the record to preclude even the
appearance of such at this meeting. Based on the
submitted agenda and all financial interests
reported by the committee's participants, it has
been determined that all interests in firms
regulated by the Center for Drug Evaluation and
Research present no potential for an appearance of
a conflict of interest at this meeting with the
following exceptions:
In accordance with 18 USC, Section
208(b)(30, Dr. Wayne Goodman has been granted a
full waiver for his employer's related contract
with a competitor, funded between $100,001 and
$300,000 per year. His employer also has related
contracts with another competitor, funded for less
than $100,001 per year.
Dr. Andrew Leon has been granted a waiver
under 21 USC, 355(n)(4) for his ownership of stock
in a competitor. This stock is valued from $5,001
to $25,000.
A copy of the waiver statements may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building.
We would also like to note that Dr. Dilip
Mehta has been invited to participate as an
industry representative, acting on behalf of
regulated industry. Dr. Mehta's role on this
committee is to represent industry interests in
general and not any one particular company. Dr.
Mehta is retired from Pfizer.
In the event that the discussions involve
any other products or firms not already on the
agenda for which the 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 firms whose products they wish to comment upon.
Thank you.
DR. GOODMAN: Dr. Daniel Pine just joined
us so I wonder if you could introduce yourself.
DR. PINE: Danny Pine, Chief of
Developmental Studies, Mood and Anxiety Disorders
Program, National Institute of Mental Health
Intramural Research Program and I am a child and
adolescent psychiatrist.
DR. GOODMAN: In a moment I will turn over
the floor to Dr. Laughren who will give us the
introductory remarks. I think for all of us who
have read through these briefing materials one of
the issues that emerges, that didn't surface during
yesterday's discussions, are questions about
dermatological reactions. I see that we will also
have the benefit of an intensive review of those
issues as well to help us in our decision-making
today. So, Tom, would you please come forward?
Thank you.
FDA Introductory Remarks
DR. LAUGHREN: I would like to welcome
everyone to today's meeting. Before I introduce
the topics for today's meeting I would like to
acknowledge the service of one of your colleagues
on this committee whose term is ending in June, and
that colleague is Wayne Goodman. This has been a
particularly busy time for the committee, as you
know, and Wayne has, of course, been the chair of
the committee for much of this time. Serving on
this committee, again as all of you know, is a very
demanding and sometimes stressful task and I hope
that you all understand how much we appreciate the
help that you give us.
Now, Wayne told me after the September,
2004 meeting on antidepressants and suicidality in
pediatric patients that he didn't have any friends
anymore in the academic and clinical community. I
just want to assure him that he always has friends
here, at FDA.
[Laughter]
So, thank you, Wayne. This is a small
token of our appreciation.
DR. GOODMAN: Thank you very much. I used
to have a voice before I started this!
[Applause]
DR. LAUGHREN: Now, on to the topic for
today's meeting, we are going to focus on NDA
20-717, supplement 19. This is for modafinil in
the treatment of attention deficit hyperactivity
disorder. As you know, modafinil is marketed as
Provigil to improve wakefulness in adults with
excessive sleepiness associated with narcolepsy,
obstructive sleep apnea syndrome and shift work
sleep disorder. It is a Schedule IV drug and the
recommended dose in these disorders in adults is
200 mg.
Now, Cephalon has provided us data in
support of a claim for the safety and the
short-term effectiveness of modafinil in the
treatment of ADHD at a slightly higher dose, at a
dose of 340 mg per day in children less than 30 kg
and 425 mg per day in children greater than 30 kg.
This supplement was submitted in December of 2004
and, as you know, we issued an approvable letter in
October of last year.
Though we did issue an approvable letter,
the letter addressed three concerns that we wanted
to have further addressed. One of those was
serious skin rashes; a second was psychiatric
adverse events; and, finally, there were three
patients with transaminase elevations for which we
wanted additional data.
The sponsor responded to our approvable
letter, in November of last year, and today you
will hear from several FDA staff. You will hear
from the primary reviewer, Glenn Mannheim who, as
you know having seen his review, has recommended
against approving this drug based on his concerns
about rash and several other adverse events.
You will also hear from Dr. Paul Andreason
who will provide some additional comments on
safety. Our presentations are going to focus
entirely on the safety issues because we agree with
the company on efficacy. But you will hear from
the company on efficacy and, as well, you also have
our reviews.
In addition, we have obtained advice on
the dermatologic problems from our own internal
consultants from Dermatology. You have their
reviews, and Dr. Markham Luke, from the Dermatology
Division, is here to address any questions you
might have. In addition, we have Dr. Michael
Bigby, who is the chair of the Dermatology Advisory
Committee, who will be making a presentation on
serious drug-related rashes and he will be
participating in the discussion as well.
Now, I want to be clear that the Division
of Psychiatry Products has not reached a conclusion
yet about this application. We have these concerns
and that is precisely why we are coming to you to
ask for your advice. After you have heard the
findings and the arguments we are going to ask you
to vote on two questions. The first question is
focusing on efficacy questions, whether or not you
believe that the company has demonstrated that this
product is effective in the treatment of ADHD.
Secondly, we will ask you to vote on the question
of whether or not it has been shown to be
acceptably safe in the treatment of this disorder.
In addition, we are going to be asking for
your comments on several other issues related
mostly to rash. First of all, if the drug were to
be approved for this indication we would like your
advice on a risk management plan. We would like
your advice on labeling, particularly for rash.
Finally, we would like your advice on any
postmarketing studies that you think might be
useful to further clarify this problem. I think I
will stop there and Dr. Mannheim will be presenting
his findings. Thank you.
FDA Presentation
FDA Clinical Review
[Slide]
DR. MANNHEIM: As Dr. Laughren explained,
I reviewed the initial submission for modafinil for
this indication. I will review with you today the
information specific to safety.
[Slide]
Here is an outline of what I will be
covering. I will be reviewing a little bit of the
background and history of modafinil; an overview of
the safety database; common adverse events in
Cephalon's clinical trial; other adverse events of
significance; psychiatric adverse events; and, most
importantly, rashes and what I think the potential
public health impact may be. Then I will give you
some closing comments, and I will be followed by
Dr. Andreason.
[Slide]
In 1998 modafinil was approved as a
wakefulness-promoting agent in adults with
excessive daytime sleepiness associated with
narcolepsy. Additional indications were granted by
FDA in 2003 for excessive daytime sleepiness
associated with obstructive sleep apnea/hypopnea
syndrome and shift work sleep disorder.
The important thing that I would like you
to notice from this slide is the dose. The
recommended dosing was 200 mg once a day which,
based on a 65 kg adult, comes to about 2.67 or 2.7
mg/kg. I want you to remember those numbers since
we will come to it in other slides.
Recommendations were to give modafinil, Provigil,
as a single morning dose for narcolepsy or
obstructive sleep apnea or for shift work sleep
disorder one hour prior to the start of the work
shift. No additional benefit was shown for doses
more than 200 mg.
[Slide]
The current application is for use of
modafinil in children and adolescents with ADHD.
Two doses have been proposed by Cephalon. For
children less than 65 lbs or 30 kg, they would be
getting a single daily dose of 340 mg. For
children or adolescents more than 65 lbs or 30 kg,
they would be getting a dose of 425 mg a day.
Now, remember the number 2.6. For the
highest dose in children, on a milligram/kilogram
basis, the children would be getting 21 mg/kg or
about 8 times higher than the adult dose. For
those over 65 lbs or 30 kg the highest dose would
be 5.3 times higher than the adult dose. Cephalon
is recommending that children or adolescents start
the drug at initial doses of 85 mg and slowly
titrate up, based on tolerability, by incremental
steps of 85 mg to the targeted dose of 340 mg or
425 mg a day.
[Slide]
This shows the population which was
studied in the submission. It was children and
adolescents 6-17 years of age with DSM-IV ADHD who
attended a full-time school. These were moderately
to severely ill children. They had minimal
learning difficulties. As it relates to adverse
events, children with psychiatric comorbidities
were excluded. Stimulant non-responders were not
allowed in the trial. Those with abnormal
laboratory or medical conditions one month prior to
the start of the study were also excluded.
[Slide]
There are three studies which are called
the pivotal studies for this. Study 309 and 311
were 2 9-week, double-blind, flexible dose, weekly
titration studies. Study 310 was a 7-week,
double-blind, fixed dose study, followed by a
2-week randomized withdrawal to modafinil or
placebo. Children less than 65 lbs went on 340 mg
a day and those over 65 lbs went on 425 mg a day.
[Slide]
This slide shows the total number of
subjects and doses used in the Phase 3
double-blind, placebo-controlled trial. Of note,
420 subjects were treated with modafinil and 213
subjects were treated with placebo. The important
thing to note here is the numbers 102, 256 or 358.
Children and adolescents only received the proposed
labeled efficacious doses.
[Slide]
This slide comes from Cephalon's briefing
document which was submitted for your consideration
by Cephalon. It summarizes the pediatric trials.
The 420 comes from the Phase 3 double-blind
exposure. The number I want to show here is the
number 933 because this constitutes the core safety
database of this supplemental NDA. This slide
indicates that additional 303 children were exposed
to modafinil in an open-label ongoing Phase 3
trial. About 400 other children for obstructive
sleep apnea and narcolepsy are the legacy studies.
As far as the purposes of this submission,
we are only considering the number 933 since we
don't have an integrated safety database for the
other 689 children and they were not part of this
submission. It certainly would be reassuring if
there were no adverse events in these subjects but
we really don't know at this point.
[Slide]
This slide is a little busy and I
apologize for that. It shows exposure to modafinil
and modafinil metabolites and compares it with what
one sees in clinically used doses in adults with
those proposed for children. What I want to bring
your attention to is the exposure of the modafinil
sulfone as measured by the total exposure area
under the curve. In adults, with an initial dose
of 200 mg, the average area under the curve is 38
or close to 40. Going to the highest child,
receiving 425 mg, the area under the curve of the
sulfone is about 250. This is 6.5 times higher
than the exposure seen in adults. Going to the
lowest dose of children receiving 340 mg, the
average area under the curve is around 630. This
is 16 times higher than that seen in adults with
clinical dosing. This cannot be explained by
differences in dosing on a milligram/kilogram
basis. These are clinically used doses and with
them one sees that the sulfone metabolite is much
higher compared to adults.
[Slide]
Now we are going to look at the adverse
event data.
[Slide]
The incidence of common treatment-emergent
adverse events in the Phase 3 double-blind,
placebo-controlled trial is listed. Of note,
insomnia occurred in 27 percent of subjects on
modafinil and 4 percent of subjects on placebo.
Anorexia occurred in 16 percent of subjects on
modafinil and 3 percent of subjects on placebo.
Perhaps associated with that, there was weight loss
in 4 percent of subjects on modafinil and 1 percent
of subjects on placebo.
[Slide]
Notable psychiatric adverse events include
psychosis in 0.5 percent, as listed here, and
suicidal events in 6 subjects, 0.6 percent. The
suicidal events included 5 ideations; 1 attempt.
None were completed. Yesterday Dr. Mosholder
reported on a pooled analysis of the ADHD trials
and that suicidal behavior was infrequent among the
non-medicated ADHD placebo subjects.
[Slide]
Other clinically significant adverse
events which were noted in this trial consisted of
gastric or duodenal ulcers in 2 subjects. One case
of note was a child who was admitted to the
hospital with a moderate metabolic acidosis who had
an H. pylori infection.
There were 9 cases of syncope in the total
exposure. Of note is a child who, according to the
vignette information, had a 40-minute bradycardia,
hypotensive syncopal episode and one week later an
EKG was performed which showed AV dissociation with
adjunctional rhythm. There were 24 children who
were quoted as having asthma.
Of note is a subject in one of the pivotal
trials, 310, who, 8 days after being started on
modafinil at a dose of 340 mg collapsed at school
during gym, stopped breathing momentarily and was
given an inhaler and began breathing normally.
This was diagnosed as an acute asthma attack and
the child was discontinued from the study on day 9.
There were 3 subjects who had dehydration,
and of note is a subject in the open-label
continuation trial who, on day 147 of treatment,
was admitted to hospital with severe dehydration,
moderate ketoacidosis and hypoglycemia which was
found secondary to a strep. throat.
Sixteen subjects had laboratory evidence
of hepatocellular injury based on transaminases
being greater than 3 times the upper limit of
normal. Of note, there were no cases of jaundice
or liver failure, or no significant bilirubin
elevations.
[Slide]
Now I am going to talk to you about the
rashes but I am not a dermatologist and I am
relying on FDA's dermatologist, Dr. Porres who did
a consult, and someone from FDA from Dermatology is
here to answer some questions.
When you look at all the subjects who were
exposed, rashes were present in 5 percent of all
subjects compared to 4 percent that you saw in the
Phase 3 double-blind, placebo-controlled trial
versus 2 percent in placebo. Only 1 subject
dropped out in the double-blind, placebo-controlled
Phase 3 trial, which was an 8-week, study, because
of a rash.
When you look at all the studies,
including the open-label safety study, 101 subjects
dropped out because of an adverse event, of which
26 percent were noted to have a rash in their
vignettes although it may not have been coded as a
reason for discontinuation. In one-half of these
subjects, or 13 subjects, the rash was coded as a
primary reason for discontinuation. The rashes
varied in spectrum of severity. Eight with rash
also had fever; 2 with rash had elevated liver
function tests, one with a transaminase of 17 times
the upper limit of normal.
[Slide]
I am now going to discuss some of the
serious skin rashes, primarily the erythema
multiforme, Stevens-Johnson which, from my standing
as a pediatric neurologist are usually
hypersensitivity reactions to drugs. There were 2
rashes which were thought to be erythema
multiforme, Stevens-Johnson.
One subject had peeling and blistering
over the entire body, with lips and urinary tract
involvement, in study 311. The drug was stopped
but the rash progressed to involve peeling,
blistering, mucosal involvement over days. In
another subject in study 207 the drug was stopped
but the rash progressed. The child was
hospitalized.
Other rashes of note included a child in
study 207 with vesiculobullous cheeks with severe
lip blisters. In study 312 another subject had a
rash where there is no clear description but the
rash was obviously severe enough that he was
treated with systemic steroids, prednisone and
given Benadryl. The rash recurred when restarted
at 85 mg on day 34. There are two cases of
positive, you know, rechallenge.
[Slide]
Other skin reactions of note--there were
possible allergic events in about 22 of the
subjects out of the total exposure of 933 subjects,
at 2.4 percent. They included hives, urticaria;
facial edema; pruritus; allergic reactions; red
lips; eczema with increased LFTs. There were some
non-allergic events of alopecia, tongue blotches,
Herpes zoster, plantar warts and ringworm.
[Slide]
Now I would like to give some more details
about the index cases here. Case number one was a
young girl with an unremarkable medical history who
had attention deficit disorder. She was started
and then titrated over 2 weeks to a target dose of
either 340 mg or 425 mg a day, but it differs in 2
different vignettes. Two days later, on day 16,
the child developed a fever of almost 102, sore
throat, mild rash which was described as red bumps.
The next day the child was seen in the emergency
room. My understanding is they thought the child
had strep. throat and they gave one dose of
amoxicillin which was subsequently stopped. The
next day, day 18, the modafinil was stopped. Over
the next 4 days the rash worsened and progressed.
There were multiple pruritic areas over the arms
and stomach. On day 22 the rash progressed to
involve the face. On day 23 mucosal involvement
was said to be present in 2 areas. It burned when
the child urinated so there was involvement of the
urethra. The child had swollen and crusty lips.
At some time later--the exact course is uncertain
from the vignettes--there was extensive skin
peeling involving the palms and soles. No new
lesions were said to be present by day 30 and the
event was said to be resolved. By day 31 or day
26--it differs in 2 vignettes--the child was given
1 more dose of modafinil by the mother for unclear
reasons and the itching returned. On day 44 the
child was withdrawn from the study and the vignette
indicates the Stevens-Johnson syndrome resolved but
the erythema multiforme continued.
[Slide]
This case involves a young child with
inattentive deficit disorder who also had Turner's
syndrome and bed-wetting, who was on somatotropin
for the Turner syndrome for 7.5 years prior and
desmopressin for the bed-wetting for 4 months
prior. She was started, titrated on modafinil 200
mg a day for week 1 of the study and then 100 mg a
day for week 2 of the study. By day 4 she
developed fever, abdominal pain and diarrhea. This
lasted for 9 days. By day 14 the child was seen in
the emergency room for pruritic urticaria involving
the face and chest. The drug was stopped. The
child was treated with diphenhydramine. The rash
worsened by day 15. The child was then
hospitalized with a provisional diagnosis of
Stevens-Johnson. The child was seen by a
dermatologist who found no evidence of mucosal
involvement but was diagnosed as a moderate
morbilliform rash. The child was treated with
hydroxyzine. This rash resolved in 1 week. This
case was accepted by Cephalon as being compatible
with Stevens-Johnson syndrome.
[Slide]
Another subject of note is a young boy who
was started on modafinil at 400 mg a day for 2.5
weeks, and on day 14 developed fever and a moderate
rash on the cheeks. The rash progressed. By day
17 there was severe blistering on the lips. The
rash was described as vesiculobullous. On day 19
the modafinil was stopped. The time course of
everything else was not specified in the vignette
and no more information is available. The child
was treated with cephalexin for the rash and
Tylenol with codeine for fever and pain.
[Slide]
Dr. Porres, of the Division of Dermatology
at FDA, reviewed the 21 cases identified in my
initial review and the entire safety database of
this submission. He divided the cases into three
categories, definite cases representing erythema
multiforme, Stevens-Johnson. There are 2 subjects
there or 0.2 percent; subjects who had a history
consistent with early prodromal erythema multiforme
and Stevens-Johnson, there were 3 subjects, 0.32
percent; and then there were 7 additional subjects
who had a history suggestive of prodromal erythema
multiforme, Stevens-Johnson. So, 10 more subjects
plus the 2 subjects, or 12 subjects, so this is a
total of 1.25 percent of subjects with definite and
potential erythema multiforme, Stevens-Johnson.
[Slide]
When one looks at the postmarketing
experience with modafinil, there were 6 reports of
serious skin reactions. All occurred in adults 18
and over. There were 5 biopsy confirmed cases of
erythema multiforme, Stevens-Johnson. Four were
hospitalized and 1 died, but this case was really
confounded by other medications and medical
conditions. There was 1 dermatitis bullous.
Because of the under-reporting, the true number of
cases is probably likely to be greater. But the
take-home message that I would like to say is that
this slide shows that biopsy confirmed
Stevens-Johnson syndrome occurred in adults at
lower exposures than those received by children.
[Slide]
Erythema multiforme or Stevens-Johnson
syndrome is generally thought to be
hypersensitivity reactions to drugs.
[Slide]
One of the cases which was really
interesting involved a child who developed
urticaria, facial edema, fever and a 17-fold
elevation in transaminase between 10-14 days after
starting the drug. The child had a history of
allergy to sulfamethoxazole trimethoprim.
Sulfamethoxazole is a sulfonamide and is one of the
drugs known to cause Stevens-Johnson. It is
structurally similar to modafinil sulfone, which
raises the question of a possible cross-sensitivity
to the sulfone metabolite.
[Slide]
What is the potential public health impact
of these findings? Two recent estimates of the
background rate for erythema multiforme,
Stevens-Johnson was 1-2/million/ year. In this
submission there were 2 subjects with erythema
multiforme and 10 other possible cases of a
significant rash. The total range of risk is
anywhere between 0.2 percent to 1.3 percent.
[Slide]
A recent CDC study estimated that 2.5
million children, ages 4-17, were on ADHD
medication. Now, if we assume that only 10 percent
of these children will try modafinil at some point,
then we ask the next question, how many cases would
result.
[Slide]
We estimated that there would be a range
between 500 and 3,000 cases which will occur based
on the 0.2 percent to the 1.3 percent incidence
among the 10 percent who are switched to modafinil.
Based on the known mortality associated with
erythema multiforme, Stevens-Johnson, we would
expect from 15 to over 400 deaths to occur. We
conclude that even though a crude estimate can only
be made at this time, a potential exists for a
significant number of cases to occur post-approval
since ADHD is so prevalent.
[Slide]
The question is can one label for this?
Can we prevent this? Dr. Le Grenade and her
co-authors at FDA recently published a paper on
Stevens-Johnson syndrome and toxic epidermal
necrolysis in association with selective COX-2
inhibitors. I quote from her and I italicized
certain areas: There is no satisfactory method for
determining who is at greatest risk for developing
drug-associated Stevens-Johnson syndrome and toxic
epidermal necrolysis and hence of preventing it,
short of avoiding drugs altogether. There has been
a single study suggesting that early withdrawal of
the agent at the first sign of illness may improve
the outcome. Although this intuitively makes
sense, this study needs to be replicated. Even if
it is proven correct, its practical application
will be limited because it is very difficult to
identify the very earliest lesion in a timely
manner because of the rapidly progressive nature of
this illness and the non-specific features of its
prodrome.
In the cases observed with modafinil in
this submission in children no deaths occurred.
The rash progressed after the drug was stopped and
the children recovered. It may not be so next
time.
[Slide]
ADHD is a serious condition--I will give
you closing comments--it is a serious condition
which is usually not considered to be associated
with a fatal outcome. Exposure to a sulfone
metabolite is significantly greater, up to 16 times
more in children than in adults. This raises
questions about the relevancy of the adult safety
experiences to pediatric use.
[Slide]
The relationship of this metabolite to
rash is purely speculative but it has structural
similarities to drugs known to cause erythema
multiforme and Stevens-Johnson syndrome which can
be fatal.
The incidence of erythema multiforme,
Stevens-Johnson syndrome observed in these studies
is, at a minimum, hundreds of times the background.
The age ranges of the rashes appear skewed towards
subjects less than 12 years, those having a higher
sulfone exposure. Doses lower than 340 mg have
been shown to limit efficacy, hence, dose reduction
is not a reliable option.
[Slide]
Although some cases with rash got better,
there were 2 positive rechallenges and one case
progressed after discontinuing the drug. One
subject with rash was hospitalized but there was
disagreement about the diagnosis. One child with a
history of reactions to sulfa drugs developed a
hypersensitivity reaction with transaminase
elevation 17 times the upper limit of normal, with
urticaria, fever and facial edema 10 days after
starting modafinil, which raises the hypothesis of
cross-sensitivity with sulfa drugs.
[Slide]
Psychosis and suicidality, although not
standardly significant, were more frequent in
subjects on modafinil than with placebo. Insomnia
was present in 27 percent of subjects on modafinil
versus 4 percent in placebo, and anorexia occurred
in 16 percent of subjects on modafinil versus 3
percent on placebo in the double-blind, Phase 3
trials.
[Slide]
This review was very much a team effort of
my many colleagues at FDA, some of whom I am
blessed to call my friends. Thank you.
DR. GOODMAN: Before you step down, could
you review any cardiovascular effects, effects on
heart rate and blood pressure?
DR. MANNHEIM: Dr. Andreason is going to
do that.
Modafinil for the Treatment of ADHD
DR. ANDREASON: Good morning.
[Slide]
My name is Paul Andreason and I am the
Acting Deputy Director of the Division of
Psychiatry Products. I would like to talk to you
this morning about modafinil in the treatment of
ADHD.
[Slide]
Dr. Mannheim has outlined the concerns
that he has about modafinil in the treatment of
ADHD, and I think what we are faced with as we look
especially at the skin rashes is what I like to
call incongruity of data. I will get into that in
a little bit. I would also like to acknowledge the
Neurology Products Division where the drug
resides--it is kind of its home since it was
approved there first--and the safety team for
helping us out with the background rates for
Stevens-Johnson and looking at the adverse event
reports through the Adverse Event Reporting System
and their epidemiologic expertise.
Glenn did the primary review on the first
submission. June Cai helped out with the review of
the response to the approval letter. In the
Division of Dermatology, I would like to thank Joe
Porres and Markham Luke, who is here with us
today--Markham is here with us today. Joe took
another job and he is not with the Division of
Dermatology right now. Then, in the Division of
Drug Risk Evaluation, I would like to thank Andy
Mosholder and Kate Gelperin who, as part of their
presentation yesterday, did an analysis of the
psychiatric adverse events that are associated with
modafinil use.
[Slide]
Just as a quick review of how we workup
safety problems with drugs or safety profiles of
drugs, I should say, when we look at a drug we look
at deaths, serious adverse events, adverse
dropouts, potentially clinically significant labs,
ECG and vital signs and then we develop information
on comparative common and drug-related adverse
events, all these things from controlled trials.
We also do special searches, especially in this
case with modafinil and many psychiatric
drugs--well, all psychiatric drugs, for psychiatric
adverse events; in this case, for Stevens-Johnson
syndrome and neutropenia because these were things
that kind of popped up; and then the recent
interest in blood pressure, pulse and
cardiovascular adverse events. Then with the
response to the approvable letter we get a safety
update. In that safety update we focus on serious
adverse events and deaths, if they occur. We
develop our profile of the common and drug-related
adverse events from the controlled trial data, as
well as the comparative information on labs, ECGs
and vital signs.
[Slide]
Modafinil is a marketed product and we got
some information from Verispan about the exposure
to modafinil at this point. These are numbers not
in patient-years but in unique patients. At all
ages at this point between the years 2002 to 2005
there were 1,087,000, roughly 1,088,000 exposures
in all ages, and for children ages 0-17 there were
roughly 36,000 exposures.
I kind of want you to keep that in mind
because this is the first piece of what I would
call inconsistent data about rash. It is almost
unheard of to see cases of Stevens-Johnson syndrome
in controlled trial data and here we have at least
nominally 2 cases that have been identified as
such. At that kind of a rate you would expect to
see something in the adverse event reporting data.
Dr. Mannheim said, well, based on these numbers,
these would be the projected number of cases that
we would see after marketing. The piece of
incongruity here is that the drug is already
marketed. We have 36,000 exposures in the age
ranges that were studied, and in the 0-12 group
right around 11,000 and we have no AERS-reported
cases.
Now, one of the cases from the controlled
trial data actually is a duplicate case. It got
reported in AERS but there are no spontaneous
reported cases. So, given that kind of projection,
I would expect to see some cases reported in AERS
and we haven't seen that yet.
[Slide]
This is, again, a review of patient
exposure in the controlled trial database. In the
safety update we did get some information on
serious adverse events and dropouts, as well as
deaths, and Stevens-Johnson syndrome would be
considered in that group. So, as more and more
information comes in, you know, that denominator of
cases reported per amount of exposure changes,
however, even with 2 cases in 1,600 that would
still be a large number.
[Slide]
I think the problem that comes about when
we look at Stevens-Johnson--and we will hear more
from Dr. Bigby in a moment about how that
ascertainment is made--is that in these two cases
one was hospitalized and one was not. Neither of
them were in a burn unit or the ICU and we don't
have biopsy information on those kids.
[Slide]
These are tables that you have already
seen. It reviews the numbers of patients exposed
in the three pivotal trials.
[Slide]
Now, this is a table that shows you the
common adverse event profile. Our usual definition
of common and drug-related is adverse events that
occur at least 5 percent of the time and occur at a
rate that is twice placebo. In italics you will
see that anorexia and insomnia meet that criteria.
There are a couple of other adverse events that are
close but don't quite make that cutoff. This is
the table actually that is proposed in labeling and
is the usual kind of table that we have in
labeling.
[Slide]
Just as a quick overview of the safety
results from the controlled trials, there were no
deaths and, of the adverse events of note, there
were these 2 cases that were identified as either
Stevens-Johnson or erythema multiforme. There were
no new cases of leukopenia in the AERS system
update, and we could see no real signal for
leukopenia in the controlled trial data.
As far as psychiatric events, there were 4
suicide-related adverse events, no completed
suicides. I will talk more about those in a
moment. There were none in the placebo group.
As far as mean blood pressure changes,
modafinil actually showed a slight decrease
compared to placebo in mean blood pressure.
However, the numbers of patients that met the
outlier criteria of systolic blood pressure of
greater than 130 and an increase in greater than 20
mmHg were 9/420 for modafinil and 1/213. With
pulse there was no difference in the mean value
either, and the numbers for outliers are 6/420
versus 2/213. The 6 versus 2 in those 2 groups is,
in my opinion, not terribly different. There was
some weight loss, 0.7 kg weight loss with modafinil
versus 1.0 kg mean weight gain in the placebo
group.
So, did that answer your question about
blood pressure?
DR. GOODMAN: Yes.
DR. ANDREASON: Great!
[Slide]
As far as psychiatric adverse events, this
is drawn from one of Andy Mosholder's slides from
yesterday. These were the comparative numbers with
patient-year exposure, and these are real years.
They are not multiplied. So, with 33 patient-years
exposure in placebo you have no cases of mania or
psychosis or suicide-related adverse events. But
there were 5 cases of aggression, spontaneously
reported aggression. Zero cells are kind of tough
to deal with when you are doing statistical
analysis, but oftentimes you can use a Fisher's
exact test to get at least some idea of whether or
not something is statistically significant. I will
show you that for the suicide-related adverse
events on the next slide.
You will notice that numerically the cases
of aggression are slightly less with modafinil than
they are with placebo. As Dr. Mosholder stated
yesterday, that was not a significant difference
but it is not, by the same token, greater. In the
open-label data it shows that the rates are lower.
That doesn't necessarily mean--well, let me put it
this way, these are patients, once they reach
open-label, who have tolerated the drug and I think
that probably the best comparison for this is the
controlled trial data.
[Slide]
These are the results of the Fisher's
exact test for suicide-related adverse events. You
see here that you have the 4 cases in the modafinil
and that is compared to no suicide-related adverse
events in the 660 in placebo. So, that ends up
with a 2-tail value of p of 0.31 and 1-tailed p of
0.22.
[Slide]
Just to give you kind of a comparison
with, say, Strattera that has received labeling for
suicide-related adverse events, with Strattera
there were 6/1357 versus 0/851. Because of the
increased sample size, those numbers ended up being
statistically significant. There were 5 cases of
ideation and 1 attempt in the FDA defined cases. I
would like to note that Eli Lilly has slightly
different numbers because they had a slightly
different definition of the suicide-related adverse
events. They had 7 versus 1 out of 1357 and 851
respectively. That p value ended up being 0.07.
Traditionally, for safety-related topics we don't
necessarily use a p of 0.05 like we do for
efficacy. We use a p of 0.1. So, using a cutoff
of a p of 0.1, the 0.7 would still be statistically
significant. And, Strattera has a boxed warning.
Now, with the modafinil there are 4/664
versus 0/308. This is not statistically
significant by Fisher's exact and all were cases of
ideation and 3 of the cases actually resolved
without discontinuation of the drug. The sponsor
proposes warning language in labeling as opposed to
boxed language.
[Slide]
As far as the cases of severe rash that
are identified as Stevens-Johnson syndrome, we will
hear more about that, again, from Dr. Bigby, and
Dr. Markham Luke is here today to talk about the
cases individually if people have questions on
those.
The problem that we have with almost any
adverse event report ascertainment, there was no
histopathology with either of these cases. With
Stevens-Johnson syndrome admission to burn units
and ICUs is common. One of the kids was
hospitalized but not in an ICU or burn unit. The
other child was treated as an outpatient. You have
heard about the cases. I can go back to those if
anyone has any questions. Again, there were no
children in the postmarketing Adverse Event
Reporting System, other than the one case that is
the duplicate from the controlled trial.
There were 4 adults in the AERS
postmarketing database, and it turned out that 3
had confirmatory histopathology and the other one
was erythema multiforme without histopathology.
There were no adults with Stevens-Johnson
identified in the adult controlled trial database.
[Slide]
So, what we are left with from this
controlled trial database, along with the
open-label material that goes with it, is 2 serious
cases, one admitted to the hospital, neither to the
ICU or burn unit; none in the placebo group; 10
dropouts due to rash versus no dropouts due to rash
in the placebo group. Spontaneous adverse events
in the controlled trial, about 4 percent for
modafinil versus 1 percent for rash, for all kinds
of rash.
But then, the incongruity here is that
there are no other children with either
Stevens-Johnson syndrome in the postmarketing
adverse event database with about 36,000 kids
exposed. Again, with that kind of exposure and the
projected numbers of cases of SJS, based on 2/933
or even 2/1,600, one would expect to see more in
the Adverse Event Reporting System.
[Slide]
So, just to compare and contrast labeling
with Lamictal that carries a boxed warning for
Stevens-Johnson syndrome, in that boxed warning
there are some fairly hard numbers. For example,
they did a prospective registry study and there was
one death due to Stevens-Johnson syndrome with
Lamictal out of 1983 patients. There was also
information on rates in adults with different kinds
of diagnoses, for example, 8/1000 in children with
Lennox Gasteau and 3/1000 adults. Then in the
bipolar population it was 1.3/1000 adults on
adjunctive therapy for bipolar disorder. So, those
are some fairly hard numbers.
On the modafinil side, the sponsor
proposes warning language and I have listed under
here the points to compare and contrast with
Lamictal. There are no deaths reported. Actually,
on one of the slides that Dr. Mannheim presented,
he said there was one death. That case was a
fellow who came in to the hospital and had a
subarachnoid hemorrhage and was treated with
several drugs, one of which was phenytoin, known to
be associated with Stevens-Johnson syndrome. He
developed Stevens-Johnson syndrome as part of the
course of his hospitalization and apparently was
treated with modafinil prior to that
hospitalization. So, I think that case is terribly
confounded and I wouldn't count that as drug
related, or I don't think we could count that one
as a good drug-related case. So, based on my
exclusion of that case, there would be no deaths so
far due to Stevens-Johnson.
The child cases were not severe enough to
require burn unit or ICU. Now, again back to this,
there are at least 2 nominally identified cases out
of the 933 in the submission that were identified
but there is no biopsy confirmation. Back to the
other part of the incongruity, there are 36,000
exposures already with no cases. Then back to the
other side, you have 3 confirmed cases of adult SJS
in the postmarketing but that is with 1.5 million.
So, that is getting close to the background.
Depending on how you factor in under-reporting, you
know, there could be association and increased risk
for Stevens-Johnson.
[Slide]
So, I guess in the end the question that
you need to think about is if there is an increased
risk of Stevens-Johnson syndrome associated with
modafinil, what would be an acceptable risk. And,
if modafinil were considered for approval, what
kind of risk management program would you want to
implement, and how should the concern about serious
skin rashes be addressed in product labeling.
Again, you have the examples of labeling and I can
go over those a little more if you would like.
And, should there be a requirement for
postmarketing studies, if approved, to better
understand the skin rashes?
There was one slide, as a bit of a
digression that Dr. Mannheim showed about liver
enzymes, he included GGT in a slide, along with ALT
and AST as a percentage of increased liver enzymes
under the heading of hepatocellular injury.
Usually we look at ALT, AST and bilirubin as signs
of hepatocellular injury and don't necessarily
include GGT. Excluding GGT, there were 3/420 cases
of elevation of ALT and AST of greater than 3 times
the upper limit of normal, for a percentage of 0.7.
In placebo there was 1/213, for a percentage of
0.5, and I don't see that as meaningfully
different.
So, that concludes my remarks about
modafinil and I would be happy to entertain any
questions.
DR. GOODMAN: Thank you. I understand
there is going to be a change of technology before
the next presentation. Is that correct? Yes? So,
why don't we start doing that but I wonder if you
can stay for questions that this committee may
have. Let me start that off.
Of the 35,000 or so children who have been
exposed to modafinil postmarketing, how many of
them were on the doses that are proposed to be used
in ADHD? I would suppose further that that would
be mostly for Mexico where it is already approved.
DR. ANDREASON: I am not sure. By the
way, those numbers are for the United States only.
DR. GOODMAN: So, if they are for the
United States only let me go back and rephrase it.
How many of them would be in the dose range that is
proposed for ADHD?
DR. ANDREASON: Yes, we tried to track
that down and found that it was impossible to get
that kind of information. I think the only thing
you could do would be to assume that they had
received the maximum recommended dose, which was
only 200.
DR. GOODMAN: We have one of our committee
members that I would like to see introduce herself,
Jean Bronstein.
MS. BRONSTEIN: Good morning. I am Jean
Bronstein. I am a nurse and consumer
representative for the committee, and I apologize
for being a little late. But I do have a question.
I am trying to understand some 300 patients, I
believe, that have dropped out of the study, and I
am wondering if the rash numbers are also
representative of all patients having dropped out
of the study at some point. Is that clear?
DR. ANDREASON: The patients who dropped
out due to rash are included in those numbers, yes.
MS. BRONSTEIN: They are? Thank you.
DR. GOODMAN: Any other questions around
the table or are we ready to proceed with the
presentation?
DR. WANG: It is actually a follow-up to
Wayne's question. In the negotiations for these
pivotal trials how were the doses chosen? Why was,
you know, 300 mg, 400 mg chosen? For the
wakefulness indication it is 200 with no additional
benefit.
DR. LAUGHREN: Paul, you may be able to
say more about this, but my understanding is that
there was a Phase 2 study, a fixed dose study that
looked at different doses, I think running from
100-400, that basically showed effects only at the
higher doses and that was the basis for focusing on
the higher doses in the pivotal trials.
DR. ANDREASON: I am sorry, I thought you
were looking at Cephalon when you asked that
question. But, yes, that is correct. Two of the
studies were flexible dose studies in the pivotal
trials and one of them was a fixed dose study.
DR. WANG: There is no data in here to
suggest something that you have raised, Dr.
Mannheim, that there is no potential benefit to
trying lower doses. They don't look to be, you
know, sort of clinically efficacious, which these
data don't suggest.
DR. MANNHEIM: My understanding from the
earlier Phase 2 trials was that lower doses didn't
work and they had to get to these doses in order to
show efficacy in ADHD. Cephalon can respond to
that.
DR. GOODMAN: Yes, maybe we can hear more
about that from the sponsor during their
presentation. We have Dr. Leon and then Dr. Mehta.
DR. LEON: I would like to follow-up on
the number of exposed. Is that based strictly on
the 7- or 9-week clinical trials out of which maybe
about 40 percent dropped out? Or, does that
include the follow-up as well? Is there slide on
person-week exposure?
DR. ANDREASON: Oh, as far as the number
of patients that are exposed for an adequate amount
of time to count, I think what we came up with was
as an estimate that was around 600. Again, if you
say 2 cases out of 600, that makes the rate of it
seem even higher. Then, it even makes it seem more
implausible that we don't see anything in
postmarketing. So, I think you are right, if
Stevens-Johnson is something that shows up in the
first 2-8 weeks of treatment the numbers in the
controlled trials would be right around 600. The
900 includes patients that dropped out. It
includes patients that were in Phase 2
studies--excuse me, I take that back. The 933
includes patients that were in the open-label
trials, so patients that were exposed for much
longer.
When we looked at postmarketing data and
estimates of exposure we didn't look at
patient-year exposure because we wanted to focus on
the fact that Stevens-Johnson we probably likely to
show up in the first 2-8 weeks and if we looked at
patient-year exposure the rate of background would
start to drop with extended exposure if you looked
at patient years instead of unique patients. That
is why we chose to look at it that way.
DR. GOODMAN: Dr. Mehta?
DR. MEHTA: Is the dose of the drug
relevant to the occurrence of Stevens-Johnson
syndrome? I would have thought that this is a
sensitivity reaction so it doesn't matter what came
out of the drug that is used, that is, the dosage
is irrelevant for the occurrence of SJS.
DR. ANDREASON: You will see from the
presentation coming up from the company that it
didn't appear that the sulfone metabolite was
increased any higher, than in other patients that
didn't have rash, in the 2 patients that were
identified as having rash. The expert is here to
talk about that.
DR. BIGBY: Can I just make a quick
comment about that?
DR. GOODMAN: Go ahead.
DR. BIGBY: It shouldn't make any
difference in terms of the incidence of the rash.
I think you are correct in that regard. The only
way that I think it could affect the disorder is in
outcome in terms of at a higher dose it will take a
little bit longer to be cleared from the body so
that the prognosis might be worse if you start with
a higher dose because it may take longer to be
eliminated.
DR. GOODMAN: Dr. Malone?
DR. MALONE: I just had a question about
dosing. The stimulants are also used for daytime
sleepiness disorders. Is the dose used for ADHD a
lot different than the dose used for daytime
sleepiness?
DR. ANDREASON: Yes, it is higher.
Daytime sleepiness and obstructive sleep apnea
doses are 200. Right, Glenn? Then, for ADHD it is
300 and 425.
DR. RAPPLEY: No, I think he is asking
about comparing the other stimulants? So, are the
doses for Adderall or Ritalin higher for ADHD than
they are--
DR. ANDREASON: I am sorry, I don't have
that right at the top of my head.
DR. GOODMAN: Dr. Pfeffer?
DR. PFEFFER: I have a question about the
pharmacokinetics of this drug, with the dose being
so much higher in children, especially younger
children, how is the drug metabolized? Also, is
there a way of understanding if there are children
who are slower metabolizers of this drug and,
therefore, this is higher? Can we understand that?
Is there a way of understanding also if there are
certain children that might be assessed in terms of
the metabolism and understand that relative risk?
DR. ANDREASON: I can't really answer that
question. I think we have somebody who can answer
that question. Let me preface it by this though, I
don't necessarily believe that ruling out the
sulfone would be necessarily a guarantee of safety.
In my opinion, I think the sulfone may be a bit of
a red herring. I think with Lamictal we have no
real idea why SJS occurs and it is much more common
in kids than it is in adults. If they could come
up with some kind of marker that would show what
the risk was, that would be wonderful. I don't
think in this case the sulfone reaches that kind of
state. First of all, we have to identify whether
or not there is a signal. Then, if one came to the
conclusion that there was a signal, I still don't
think that the sulfone would give us any assurance
of safety regardless at this point.
DR. GOODMAN: Dr. Temple and then I want
to go to Dr. Bigby's presentation.
DR. TEMPLE: I just wanted to observe that
on the dose relatedness matter it is sort of
unusual to have almost an order of magnitude
difference between what one group gets and what the
other group gets. So, a lot of our experience with
drugs will be looking at, you know, one- or
two-fold differences and things like that. I am
not sure one really could say that a marked
difference in blood levels or exposure might not be
related to rate. It could.
DR. ANDREASON: Ron Cavanaugh was the
human biopharmacologist on this.
DR. GOODMAN: But then definitely Dr.
Bigby.
DR. CAVANAUGH: Thank you. I agree with
Dr. Andreason that at this point for the sulfone we
really don't know any relationship for certain. It
is purely at this point a plausible hypothesis. It
is very structurally similar to the one drug which
causes the highest incidence of Stevens-Johnson,
blethamide, which is slightly different than many
of the other sulfonamides in that it has a third
oxygen in addition to the nitrogen and the sulfone.
Modafinil also has that third oxygen in the same
position. We do not know. Basically, the only
reason we looked at the sulfone was because of the
dramatic higher amounts, as well as when Glenn
asked me about the sulfone I immediately thought
Stevens-Johnson and immediately thought
sulfonamide. So, at this point we don't know.
In terms of the kinetics, from what I have
seen, the metabolism does not seem to be
particularly well defined. So, I really do not
know at this point, you know, anything in terms of
could specific metabolic pathways result in higher
sulfone concentrations in some kids versus others.
The concentrations that I see, and it is very poor,
do not lead me to believe that the sulfone
concentrations in these particular children--and
there was only one child who had any measurement of
the sulfone who had any of the Stevens-Johnson or
other severe dermatologic reactions, and that
sample was taken several days after the drug was
discontinued. If I back calculate, it basically
seems that for that one child the concentration was
in the approximate range.
In terms of dose response, which was
raised, we really have too few numbers here. You
are also dealing with, you know, population numbers
and you are dealing with 0.1 percent difference,
0.2 percent differences. There is no way you can
be certain.
In terms of a dose related to hapten and
degree of what is the likelihood of Stevens-Johnson
or a hypersensitivity of any sort, I am not an
immunologist; I do not know. One of the reasons we
focused on AUC is because that gives you an idea of
total exposure. When someone has already developed
hypersensitivity and they have already had a
history with a sulfonamide, they can get
Stevens-Johnson with the very first dose of a drop,
and there have been deaths in cases like that.
Really we are more talking about the
development of hypersensitivity, and what you are
developing as it being a hapten, my understanding
is that it is the combination of, you know,
developing hypersensitivity to the combination of
the drug bound to certain proteins, or other things
in the body. So, with the higher exposure you are
going to get more of this binding and, therefore,
more antigenic exposure. The numbers are so small,
we don't know. Also, with longer duration you
would expect more stimulation.
I would really refer you to an
immunologist. I really don't know, but the whole
issue of dose response and everything else in terms
of developing hypersensitivity, to me, is not
clear.
DR. GOODMAN: Thank you. Thank you for
being patient, Dr. Bigby. We are running behind
schedule but the way I hope we may be able to make
up some time is that I am going to cut lunch and I
don't think we have that many public speakers. But
I am determined to end at least at our scheduled
time. During the sponsor presentations I would ask
the committee members to restrict their questions
to ones of clarification.
Serious Adverse Cutaneous Reactions to Drugs
DR. BIGBY: Good morning.
[Slide]
I am always impressed when I come down to
sort of work in FDA committee meetings about the
seriousness of what goes on here, and also the
dedication that people have to trying to make
rational decisions, and I hope my comments are
helpful in your deliberations.
[Slide]
What I was going to talk about is serious
adverse cutaneous reactions to drugs, and in order
to do so I am going to cover three things. One is
how to identify a drug eruption as a drug eruption
and pin it down to a specific drug. We will look
specifically at common eruptions, the serious
eruptions, and I will end by showing you some
things that are commonly mistaken for drug
eruptions.
This is sort of a gold standard for
determining that a rash is due to a drug. First
you have to be sure that the rash you are looking
at is a morphology that can be caused by drugs.
You have to exclude alternative causes. You have
to examine the relationship between the exposure to
the development of a rash in terms of the time
interval; note the response to drug withdrawal,
i.e., the rash will go away.
For many drugs there is information known
about their proclivity to produce rashes, so what
the frequency of rash is for a particular drugs.
Then, in those rare cases where you actually do
have a re-exposure, to determine what happens on
re-exposure so you can be positive that it is a
drug rash and looks like an eruption that is a
classic eruption for drugs. You have excluded
alternative causes; the interval from exposure to
the development of a rash is correct in terms of
what is known about that drug and that eruption.
It goes away. Often I think the mistake people
make about the response to withdrawal is that you
expect it to go away very quickly when you withdraw
the drug. For most eruptions that is not the case
and the rash will actually take much, much longer
than most people think to go away after you
withdraw the drug. Then, oddly enough, re-exposure
doesn't always produce the rash but when it does,
then you can be absolutely sure that you are
looking at a definite cause. Where some of these
things are missing, are judged to be probable or
unlikely or not due to the drug at all.
[Slide]
Very quickly, we are going to look at
these three common drug eruptions: exanthem which
is the most common, urticaria and fixed-drug
eruption. This is a patient with a widespread
exanthematous drug eruption. It usually starts
within the first 3 days after exposure to the drug.
For some drugs like antibiotics and allopurinol
that exposure window can be up to about 2 weeks.
The rash is best described as small, erythematous
papules that may coalesce. These patients have
pruritus but they are not generally ill. Mucous
membrane involvement is rare. It is a benign
condition in that as the drug is withdrawn the
patient gets better. They can often later in the
course of the disease desquamate but they don't
develop blisters and they don't have epidermal
detachment.
[Slide]
There is very good data about this type of
reaction. It has been studied in several
prospectively collected data sets. One was the
Boston Collaborative Drug Program. There is data
on I think something like 35,000 exposures over
about, you know, a 10-year period, collected in
many hospitals.
[Slide]
You can say with fair certainty that there
are certain drugs that have higher rates than
others, and in this list the highest tends to be
antibiotics. The highest rates are for amoxicillin
and co-trimoxazole.
[Slide]
It is also helpful to know that there is a
large list of drugs that are almost never
associated with reactions. So, if a patient is on
multiple drugs, which they often are, it is useful
to refer to this type of list to exclude the ones
that are least likely to be the culprit.
[Slide]
Urticaria you all know how to recognize.
It is areas of swelling. There are usually plaque
type lesions, and the key about urticaria is any
individual lesion generally will last for less than
24 hours. Here is one of the perfect examples. If
you identify the cause and you withdraw it patients
will often have urticaria after such an exposure
for weeks and even months even though you have
identified the correct drug and withdrawn it.
[Slide]
The list of drugs that cause urticaria is
very similar to the ones that produce exanthem.
[Slide]
Lastly, this is a fixed-drug eruption. A
fixed-drug eruption is a really peculiar thing in
that it tends to occur only on certain areas and to
recur in those areas on re-exposure. It is the one
instance where people will often be re-exposed
because it is not so clear to the providers that
this was, in fact, a drug eruption. The other
reason that this is quite relevant is that the
histopathology of a fixed-drug eruption is very
similar to what you see in erythema multiforme and,
to a lesser degree, in Stevens-Johnson syndrome and
toxic epidermal necrolysis.
[Slide]
Again, if you look at the drugs that cause
fixed-drug eruptions, there is a lot of overlap
between the drugs that most commonly cause all of
these types of eruptions.
[Slide]
The three serious drug reactions that I
want to talk about are the ones that I think are
the most relevant to this question that you are
asking today, and that is toxic epidermal
necrolysis, Stevens-Johnson syndrome and the drug
hypersensitivity syndrome.
[Slide]
Of all of the things which I have to say
today, this is the slide that I want you to
remember the most. These are two patients that I
saw personally. These are people with toxic
epidermal necrolysis. The most obvious and
important thing about these patients is, number
one, that they are sick. They often have multiple
mucous membranes involved. In severe cases not
only are the sort of distal mucous membranes
involved, but it can affect the trachea and even
the bronchi.
The second most important thing is that
they have widespread areas of cutaneous involvement
and, in the case on the right, they often shed
full-thickness necrotic skin over very large areas,
and they have basically the equivalent of a
widespread burn. The summary of toxic epidermal
necrolysis in terms of its clinical features is
also a prodrome of fever and malaise. This usually
lasts one to two days. The eruption is
predominantly on the face and torso. The lesions
are best described as pruritic plaques. They can
have bullae. Multiple mucosa are commonly
involved. Patients with toxic epidermal
necrolysis, however, do not have true target
lesions. Probably by the best definition of toxic
epidermal necrolysis, it has to involve at least 30
percent of the body surface area, and the mortality
for such described toxic epidermal necrolysis is
quite high, around 30 percent. The majority of
deaths are due to either infection or problems with
respiratory distress that are either due to
pneumonia or to the fact that the airway linings
are involved.
[Slide]
As has already been mentioned, it is a
relatively rare phenomenon so that in most
population studies the incidence is about one case
per million patient years; 95 percent of the cases
clearly have a drug etiology, and there are certain
drugs for which the incidence is much higher.
[Slide]
Based on a case-controlled study that was
published in the New England Journal ten years ago,
this was a study that carefully ascertained cases
in France, Germany and Italy and to drug exposure
histories from patients in three age and gender
matched controls, and came up with an estimate of
the number of cases per million exposures that one
would see per week. It was highest for
sulfonamides. If you do the arithmetic, this turns
out to be something in the order of 1 case in
200.00 or 250,000 for some of these drugs.
[Slide]
The drugs commonly associated with TEN are
listed here. Again, these lists are very similar
to the ones that cause benign eruptions and the
same sort of drugs keep showing up: sulfonamides,
hydantoins, some but not all of the nonsteroidals
and allopurinol.
[Slide]
This is a patient with Stevens-Johnson
syndrome, Stevens-Johnson syndrome and toxic
epidermal necrolysis are dissimilar disorders in a
continuum. The difference between Stevens-Johnson
and TEN is one of degree of epidermal detachment.
The symptoms are very similar. There is prodrome
often of fever and malaise. The lesions are very
similar. In Stevens-Johnson syndrome the area of
involvement is usually defined as being less than
10 percent. It has a much lower mortality.
The other interesting thing is that if you
look at the etiology of Stevens-Johnson syndrome,
it can be attributed to drugs in only about 50
percent of cases. Now, that seems to be in
congress with TEN and SJS being part of a spectrum.
I think the problem is that there is a lot of
confusion about mixing up cases of erythema
multiforme, which I think is a quite separable
disease, with Stevens-Johnson syndrome. I think
that explains why drug etiology is less commonly
identified. I will have more to say about erythema
multiforme at the very end.
[Slide]
Again, the incidence is about one per
million per year, drug induced in about 50 percent.
There is a higher incidence with some drugs and it
is that same list of drugs, you should note.
[Slide]
Now, what I was saying about the
relationship between SJS and TEN, TEN is defined as
those cases where the area of involvement is more
than 30 percent. SJS is less than 10 percent.
Then, there are people who are kind of in the
middle, between 10-30 percent, that are called
SJS/TEN overlap. The other thing to note is that
erythema multiforme is not mentioned anywhere on
this slide or in my previous comments because, as I
said, I think it is a distinct disorder.
[Slide]
The last serious reaction that I wanted to
talk to you about is the hypersensitivity syndrome.
That is what this slide is an example of. It looks
very similar to exanthem except for two things.
When you have seen a few of these patients it
always strikes you that the color in the
hypersensitivity syndrome is a much brighter and
darker red and the amount of confluence of the rash
is much higher.
[Slide]
Symptomatically, these people have
exanthem. They have fever, lymphadenopathy, often
have hepatitis, some of them have arthritis. This
is a disorder that has a significant mortality. It
is not clear how patients should be treated and,
again, the list of drugs that cause this that are
already known and sort of identified as such is
very similar to the list of drugs that cause drug
rashes in general.
[Slide]
This is a slide from a paper that was done
by Roujeau and Stern, in the New England Journal,
and it is a very busy slide. The only thing I want
you to note is that the fatality rate for the
hypersensitivity syndrome is about 10 percent. For
TEN it is about 30 percent. For Stevens-Johnson
syndrome, because of the area of involvement and
severity it is much less; it is lower.
[Slide]
Finally, exposure to rash for TEN and SJS
is in the order of weeks, so 1-3 weeks is noted in
the third column in this slide. Skin biopsies are
very helpful because in TEN and SJS they tend to
show full-thickness epidermal necrosis, detachment
of the skin at the dermal/epidermal junction, and
often there is very, very little inflammation in
the dermis associated with the rash.
[Slide]
Finally, I would like to conclude by
showing you examples of things that are often
called drug eruptions but are not, primarily
erythema multiforme. Now, erythema multiforme--you
can't make that diagnosis unless patients have
typical target lesions. Typical target lesions
have three rings, either a dusky or bullous center,
an area of erythema around that and then a
surrounding area of edemous skin. You can often
actually have rings beyond that but if you have the
three rings it is I think easily identifiable as
erythema multiforme.
In terms of the distribution, another
thing that is helpful is that erythema multiforme
predominantly affects the face and the extremities.
The torso is much less commonly and much less
extensively involved. The majority of cases of
erythema multiforme are actually associated with
infection, herpes simplex being the most common one
and, although it can be caused by drugs, drugs are
a much, much less common etiologic factor for
erythema multiform.
The other thing is that erythema
multiforme, by and large, is a benign disorder.
Patients recover and deaths are extremely rare for
erythema multiforme. I think people shouldn't
combine erythema multiforme, even erythema
multiforme major with mucosal involvement with
Stevens-Johnson because I think they are distinct
entities.
Grover's disease is another one that looks
to the world like a drug eruption. It tends to
occur commonly in hospitalized males on their back
and, you know, a lot of the times we get called for
drug eruptions and it turns out to be just this
scenario, elderly men with Grover's disease
predominantly on their back.
Lastly, extensive cases of pityriasis
rosea can be mistaken for drug eruptions. The key
there is that, you know, the history is usually
pretty classic. The distribution is classic as
well and if you have the herald patches, as noted
in the right-hand slide, there is not a lot of
confusion.
The last two things on this list, the
viral exanthem and graft versus host disease, no
one can really distinguish those from drug
exanthems or several other drug eruptions and it is
a matter of great difficulty.
[Slide]
That is where I will stop. Thank you.
DR. GOODMAN: Thank you. Questions from
the committee? Dr. Pine?
DR. PINE: I guess I am struggling a
little bit, kind of like Dr. Andreason was. On the
one hand, you know, the rashes were very concerning
that were described. On the other hand, there are
no cases in the spontaneous reporting. I was just
wondering, given your background as somebody who
sees this kind of thing every day presumably, or
frequently, what was your impression when you
reviewed the cases in terms of how convincing they
were, number one and, number two, when you combine
that with what you would expect to see how
concerned, as a dermatologist who spends a lot of
time thinking about this, were you about the data
that you saw and the cases that you saw?
DR. BIGBY: I think that the 7 year-old
child that was described, to me, was a probable
case of SJS that was drug related. After looking
at the material, I think that the drug is going to
be, and probably already is, associated with sort
of an excess of cases of SJS/TEN.
DR. PINE: Thanks.
DR. GOODMAN: Dr. Rappley?
DR. RAPPLEY: I looked over 26 cases, I
think it was, that had rash and I noted that many
of those cases presented on a continuum that
included fever, pharyngitis, rash, and it went from
very mild to very severe. That is something in
pediatrics that we see as a reaction with
immunosuppression or reaction that, you know,
reminds of Kawasaki's--not exactly but it makes me
think of that. It reminds me of drug reactions.
It reminds me of neutropenia. So, my question is
do you see that as a continuum, those symptoms as
related?
DR. BIGBY: I am actually not sure I
understand your question. I mean, of the material
that I saw, I think that there was one case that
probably had SJS. I think that the other sort of
| rashes described- | |
|---|---|
| DR. RAPPLEY: | So, you don't see that as a |
| continuum? | |
| DR. No- | |
| DR. RAPPLEY: | You see Stevens-Johnson as a |
| very discrete- | |
DR. BIGBY: Yes, right. You know, I think
that eruptions are sort of specific things to
dermatologists and these things don't sort of fit
together as a gestalt for a kind of reaction to
that drug, no.
DR. RAPPLEY: Okay.
DR. GOODMAN: What I would like to do is
take an unscheduled quick break, seven minutes.
Before we do that, just an admonishment, I would
like to remind the committee that, in the spirit of
the Federal Advisory Committee Act and Sunshine
Amendment, discussions about today's topic should
take place in the forum of this meeting only and
not during lunch breaks or in private sessions. We
ask that the press honor the obligations of the
committee as well. If you will allow the committee
members to exit the room first to take their break,
we will reconvene in seven minutes. Thank you.
[Brief recess]
DR. GOODMAN: We are resuming now with a
series of presentations from the sponsors. Please,
committee members, restrict any burning questions
to those of clarification. I think that we will go
to lunch at 12:30 instead of 12:00, which means
that we save time for more detailed questions of
the sponsor after the public presentations. Please
go ahead.
Sponsor Presentation
Introduction
DR. RACZKOWSKI: Good morning.
[Slide]
Dr. Goodman, members of the advisory
committee, Dr. Laughren, FDA representatives,
ladies and gentlemen, today we will be discussing
the application for Sparlon tablets for approval
for treatment in pediatric patients with ADHD.
[Slide]
My name is Victor Raczkowski and I am the
vice president for worldwide regulatory affairs at
Cephalon.
[Slide]
Our proposed indication for Sparlon is for
the treatment of ADHD in children as well as
adolescent patients. We filed our application in
December of 2004 and we received an approvable
letter about ten months later. We submitted a
complete response then to the agency in November of
last year.
[Slide]
Sparlon contains the active ingredient
modafinil which is also contained in Provigil
tablets. So, modafinil is not a new chemical
entity. Sparlon tablets have been formulated to
facilitate administration to pediatric patients.
That is, on a milligram/kilogram basis of modafinil
they are smaller than Provigil tablets. They come
in dosage that ranges in strength from 85-425 mg
and are intended for once daily administration in
the morning.
[Slide]
Provigil has been marketed in the United
States since 1999 and is currently marketed in 28
countries worldwide. Provigil is a wakefulness
promoting product and it is approved in the United
States in adults with excessive sleepiness
associated with narcolepsy, obstructive sleep
apnea/hypopnea syndrome or shift work sleep
disorder. We have estimated exposure globally
through the end of February 2006 as being
approximately 780,000 patient-treatment years, of
which 30,000 patient-treatment years are in
pediatric patients. Modafinil is also listed in
Schedule IV of the Controlled Substances Act.
[Slide]
You have been asked to address a number of
questions today and the two voting questions are on
the efficacy and safety of Sparlon. We hope to be
able to show you with our data today that not only
is Sparlon effective for the treatment of ADHD, but
it has also been shown to be acceptably safe for
the treatment of ADHD in pediatric patients.
[Slide]
We have also been asked to address the
dermatological safety of Sparlon tablets. Just by
way of orientation, this slide represents cases of
SJS in pediatric patients in clinical trials as
well as in our postmarketing experience. Other
speakers are going to go into this in much more
detail. This is just to orient you that an earlier
review by our experts indicted that there was one
case of probable SJS in our clinical trial program
out of 1622 patients exposed. However, that case
is of uncertain etiology. In addition, if the
committee has questions or interest in the clinical
course of that patient, we do have the investigator
here at the meeting today who can describe the
clinical course of that patient.
In our pediatric postmarketing experience
we have seen no pediatric cases of SJS in over
30,000 pediatric patient-treatment years.
[Slide]
We will have a number of presentations
today, beginning with an overview of attention
deficit hyperactivity disorder by Dr. Joseph
Biederman. That will be followed by a review of
both the clinical pharmacology and efficacy by Dr.
Lesley Russell. Dr. Srdjan Stankovic will then
provide an overview of the safety and then Dr.
Russell will conclude with an overall benefit-risk
assessment.
[Slide]
We have a number of consultant experts in
the field with us today representing various
disciplines including psychiatry/ADHD, dermatology,
addiction medicine, cardiology, child development
as well as epidemiology. I would just like to
highlight one name since dermatology is a major
issue in today's presentation, we do have an
individual, Dr. Neil Shear, with us today who has
published extensively in peer reviewed journals on
SJS as well as other dermatological disorders. I
would also like to note, as you can see on this
slide, that we have a number of investigators with
us today.
[Slide]
With that, I would now like to introduce
Dr. Joseph Biederman, who is professor of
psychiatry at Harvard Medical School. Dr.
Biederman?
Overview of ADHD
DR. BIEDERMAN: It is a pleasure to be
here. I would like to offer you a very brief
overview of ADHD as a very serious illness of
genetic etiology affecting the brain that has a bad
prognosis. I strongly believe that without
understanding the assessment of benefit-risk
alternative treatment is impossible.
[Slide]
First of all, I think that it is important
to note that ADHD is a highly heterogeneous illness
like all psychiatric illnesses. We know that genes
are important, as I am going to show you in
moment--perhaps the most important risk factor. We
know quite a bit about heterogeneous neuroanatomy
and neurochemistry. We know that CNS insults, if
affecting key regions of the brain like the
prefrontal cortex, can produce very similar
problems as those produced by genes. Even
environmental factors can be important in ADHD. We
need to consider that environmental factors are not
bad mothers or bad teachers, like frequently
thought, but include things like poverty, exposure
to parental psychopathology, etc., etc., things
that in themselves can be driven by genes. So,
heterogeneous illness requires different treatment.
Different patients require different alternative
therapeutic options.
[Slide]
Another thing that has been highlighted
today but I would like to stress again is that ADHD
is a worldwide condition, not only an American
invention. It affects children in the 5-10 percent
range worldwide. Data are coming from Asia now,
from China and Japan and data from South American,
Western and Eastern Europe and, of course, North
and South American point to the fact that no matter
what criteria you want to use, it is an
extraordinarily common disease. You have to
remember that at least 50 percent--at least 50
percent of the children of today are going to be
adults tomorrow and we now know that ADHD affects
at least 4 percent or 5 percent of adults in this
country, not only that it affects them but it is
very morbid and dysfunctional.
I would like to stress that the yardstick
of considering the severity of an illness just by
mortality may not be an adequate yardstick. Many
conditions are devastating to our patients, even
though they are not necessarily lethal in the
traditional sense, like malignancies. This is a
condition that profoundly affects the lives of
those affected and everybody around them.
[Slide]
Many of the MRI studies that have been
conducted have been small and many of the children
participating in them have been medicated, creating
the suspicion that perhaps what we see in MRI
studies may reflect the toxic effects of
medications. Therefore, this study that I briefly
want to review for you is extraordinarily
important. This study is large. It was published
in a very prestigious medical journal, JAMA. It
was done by colleagues at the National Institute of
Mental Health. The lead author is Dr. Castellanos.
And, 152 children and adolescents of both genders
and a similar number of controls of both genders
were assessed longitudinally. The specific
objective of the study was to assess the issue of
medication status, whether medication is important
in brain abnormalities.
[Slide]
What this study found is that the brain of
children and adolescents with ADHD was
significantly smaller, in the 3 percent range,
independently of medication status. These
volumetric abnormalities were persistent over time
so this is not a neurodegenerative disease. It is
early disease that persists into adult life. There
were no gender differences and there was some
evidence of an association between severity of ADHD
and brain findings.
[Slide]
The visual of this study shows the
brains--these are males up to the age of 20;
females out to age 15. You can see that both
genders have significantly smaller brains and the
lines are flat over time.
[Slide]
The conclusion of this study is that
either genetic or early environmental influences on
brain development are operant in ADHD. These are
fixed, nonprogressive and unrelated to stimulant
treatment.
[Slide]
If you look at key regions of the brain
that are involved in attention and executive
function, anyone of us in this room irrespective of
having or not having ADHD, we have this area of the
brain--this is the cingulate gyrus; this is the
dorsal anterior cingulate associated with executive
control; dorsolateral prefrontal cortex associated
with selective attention; and the right frontal
lobe associated with alerting. These are
interconnected areas, key regions for cognition and
attention. Their disruption will cause symptoms of
ADHD.
[Slide]
This is a recent study that we just
submitted for publication from our program at the
Mass. General. This is a three-dimensional
reconstruction of the anterior cingulate. What you
see here is a study of adults with ADHD. The
anterior cingulate area is 13 percent smaller in
individuals with ADHD compared with controls.
[Slide]
With imaging studies you can do not only
volume, as I just showed you with the
three-dimensional reconstruction so you can measure
volume of this region--this is the cingulate gyrus
again--but you can also measure the thickness of
the cortex, how thick or thin is the cortex in
critical brain regions.
[Slide]
So, this is another study that we have
done in our program of cortical thickness. This
has not yet been published but I promise you it
will be published. What you see, first of all, in
red here is a statistical comparison between the
brains of ADHD individuals compared with controls.
What this depicts, in orange and yellow, is
significant differences in cortical thinness.
These areas are selectively thinner in these
regions. So, you don't see thinness across the
entire brain; you see thinness in critical cortical
regions involved with executive control and
attention. This is the dorsal anterior cingulate.
This region hovers between the cognitive and
emotional division of the anterior cingulate--very
important issues for clinical understanding of the
symptoms of this condition. This is, of course,
the dorsolateral prefrontal cortex that is clearly
involved in cognition and in the symptoms that
subserve this illness.
[Slide]
We have also done this analysis. It is
very exciting. This is diffusion tensor imaging
that measures white tracts. What you see here is
that we are documenting disruptions in the
perigenual area of the anterior cingulate and
dorsal anterior cingulate selectively. So, this
area of the brain that is involved in cognition,
executive functions and regulatory controls is
smaller in volume, is thinner in cortical thickness
and has other abnormalities as well. I am not
aware of many other psychiatric illnesses can claim
such conversion of information, focusing on the
same brain regions that could certainly account for
the clinical picture.
[Slide]
If you look at functional MRI in the same
region, if you look at the coronal view of the
brain, if you put people without ADHD on the
scanner you can very nicely activate anterior
cingulate doing a very mild cognitive task. If you
put adults with ADHD, they fail to activate the
same region and, instead, they activate insular so
these adults can do the task but they are not using
the part of the brain that is specifically wired to
do the task at hand. We have very exciting new
data that you can correct this malfunction with
medications.
[Slide]
These findings on neuroimaging are
extraordinarily congruent with conceptualization
from neuropsychology. As you know, ADHD is
considered a neuropsychological disease. What is
called directed attention, the circuit that allows
people to pay attention to things that they are not
interested in is disrupted. Inhibitory deficits,
the person fails to inhibit when destructions
occur; and executive dysfunction issues of planning
and organization, working memory, etc., etc. are
disturbed. These are the regions that are in this
part of the brain where we are documenting
abnormalities.
Another circuit that is involved in ADHD
is called fascination reward circuit. People with
ADHD have difficulties with delayed gratification;
difficulties with regulating mood. This kind of
hot temper that characterizes people with ADHD and
some of the road rages that lead to accidents, and
so on and so forth, may be accounted for by these
neuropsychological deficits.
[Slide]
Another key aspect to document that ADHD
is a neurobiological disorder is genetic research.
ADHD clearly runs in families. There is a 5-7-fold
increased risk of ADHD in first-degree relatives of
children with ADHD. Of course, that is not
evidence for genetics so we need to have additional
information to make a genetic hypothesis or genetic
claim. Twin studies are very important because
twins come from two varieties, monozygotic and
dizygotic twins. For genetic illnesses, you expect
that monozygotic twins will have a higher level of
concordance than dizygotic or fraternal twins.
Twin studies are also very important
because they can allow us to compute coefficients
of heritability that I will tell you about in a
moment. Adoption studies are important because
with genetic illness you expect to have a higher
rate of the disease in biological rather than
adopting relatives. Finally, molecular genetic
studies will look at specific genes that may be
associated with this condition.
[Slide]
Coefficients of heritability are based on
twin studies. I would like to point out to you
that there are a lot of twin studies in ADHD.
Coefficients of heritability range from zero/zero
percent of the variance accounted for by genes to
100/100 percent of the variance accounted for by
genes. The congruence of the genetic studies for
the coefficient of heritability in ADHD is
remarkable. Even though the studies use different
methods, parent support, teacher support,
structured interviews questionnaires, look how
consistent this is. On average, coefficients of
heritability are close to 80 percent, in other
words, 80 percent of the variance of ADHD can be
accounted for by genes. For example, height, a
very genetic trait, is about 90 percent genetic;
schizophrenia and bipolar illness, very genetic.
Recognized genetic illnesses are equally genetic as
ADHD, 80 percent. Panic disorder and major
depression are genetic as well, about 50 percent,
0.5 for coefficient of variability; other medical
conditions like asthma or breast cancer at 0.3, 0.4
coefficients of heritability. So, we are dealing
with a very genetic brain disorder here.
[Slide]
Specific genes have been associated with
ADHD. The first genes that were looked at in ADHD
are genes that are associated with the dopamine
system, candidate genes because the drugs that we
usually use to treat this condition are
dopaminergic drugs. Mutation in a dopamine
transporter gene, what is called DAT1 or DAT10;
mutation in the dopamine receptor of D4 and D5
genes--these are cortically distributed receptors.
There is also an association between a very rare
thyroid disease on chromosome 3. People that have
this mutation also have ADHD, but this probably
accounts for very little of ADHD out there.
[Slide]
So, the genes that have bee associated
with ADHD in a consistent fashion are the dopamine
transporter genes that bring back dopamine to the
presynaptic neuron. This gene over-expresses the
dopamine transporter, make more it active or more
transported, too much dopamine to the presynaptic
neuron. Cortically distributed genes are the D4
and D5. There is also a gene, SNAP25, that is
involved in the presynaptic encapsulation of
dopamine.
[Slide]
Well, I see this slide is totally
degenerated. I am very sorry. But what I would
like to say is that Dr. Faraone published in
Biological Psychiatry a review of a meta-analysis.
There are certain genes, about seven genes that
consistently have been associated with ADHD,
several genes in the serotonergic system, DBH,
dopamine transporter gene and also dopamine
receptor DR D4 and DR D5. These genes have been
found in multiple studies in meta-analyses of these
specific genes to be associated with ADHD. You
probably have these details in the handout, as well
as the reference for the paper that support these
claims.
[Slide]
The treatments that we have available are
clearly effective. This study was not done by
industry. It was funded by the NIMH on the
multi-modal treatment of ADHD. This study studied
close to 600 children 7-9 years of age in this
country, in 5 sites. This was a study in which
children were randomized to very aggressive
medication management, very aggressive,
comprehensive behavioral treatment, a behavioral
treatment that was so comprehensive that you could
not possibly improve on it, and it is so expensive
that it is not doable. But that was the purpose of
the study. Children received both medication and
behavioral management and community-based
treatment.
[Slide]
What this study found, and I would like to
point this out to you, is that these two arms, the
very aggressive medication arm and combination
treatment were superior to just behavioral
treatment and community based treatment that
consisted largely of communication too. This
group, here, is a group that received the best
treatment that we can offer, very aggressive
pharmacotherapy and very aggressive behavioral
treatment. And, even using the best we can, the
response is 60 percent, leaving 40 percent of our
patients inadequately treated with intolerable side
effects or with difficulty tolerating this
treatment.
[Slide]
Stimulants are Schedule II drugs. About
40 percent or perhaps more do not tolerate or to
not respond to these treatments. The side effect
profile of sleep, appetite, difficulties with mood
and anxiety can seriously hinder our ability to
treat all the patients that otherwise could
benefit, and concerns about growth suppression and
tic development continue to plague stimulant
treatment in ADHD, Although the data is generally
reassuring, people continue to be concerned about
these issues.
[Slide]
ADHD not only affects school and school
performance, it is clearly a life disease. For
example, ADHD has been shown to be associated with
a significantly increased risk for automobile
accidents, and automobile accidents, as you know,
are the leading cause of death in our young. So,
patients not only have poor grades in school or may
not reach college but may not reach adult life
altogether or may kill somebody in the process of
driving and not paying attention to the road.
[Slide]
So, if you look at the morbidity of ADHD
as a serious--perhaps not a lethal illness but a
very devastating illness to the individual, the
family and society secondary to under-achievement,
under-employment, marital difficulties, drugs and
substance abuse, legal difficulties, or morbidity,
we are dealing with an extraordinarily morbid
disease that can profoundly affect those afflicted
with this condition.
[Slide]
So, in summary, ADHD is a neurobehavioral
disorder with complex etiology. It is a disorder
that affects the brain; has a strong genetic
component, as I alluded to; affects millions of
people worldwide, both sexes. It is highly
persistent in the majority of those affected. It
has a negative impact on the life of the individual
affected and everybody around. Although the
stimulants are clearly an effective treatment for
ADHD, a sizeable number, in the order of magnitude
of 40 percent, are non-responsive or not tolerating
this treatment, calling for alternative treatment
for this condition. Thank you very much for your
attention.
[Slide]
The next presentation will be by Dr.
Lesley Russell who will be talking about clinical
pharmacology and efficacy.
Clinical Pharmacology
DR. RUSSELL: Thank you, Dr. Biederman.
Today I would like to briefly overview the
clinical pharmacokinetics of modafinil in children,
and then summarize for you the efficacy findings of
our program in ADHD.
[Slide]
Just to begin with, here is an outline of
the development program that Cephalon undertook in
children and adolescents with ADHD. The three
Phase 3 studies, studies 309, 310 and 311, formed
the basis of the efficacy and safety that will be
discussed today. In addition, we had two
pharmacokinetic studies, studies 113 and study 206,
that outline the pharmacokinetic parameters of
modafinil in children. In addition, we conducted
two studies, 207 and 213, to help us define the
dose required for the Phase 3 studies. All
patients in the Phase 3 studies and some from the
Phase 2 studies were allowed to enroll into study
312 which is an ongoing open-label extension
program. Following submission of the sNDA, we
initiated a further study, study 3044, in which 303
patients were enrolled. This study is still
ongoing.
[Slide]
I would now like to briefly summarize the
pharmacokinetics of modafinil in children.
[Slide]
As shown on this slide, the
pharmacokinetics and exposure are dose-proportional
over the dose range studied. The absorption is
rapid, with a maximum concentration observed 2-3
hours after administration. When administered with
food, there is an approximate 1 hour delay in the
time to Cmax although the overall absorption is not
affected. The volume of distribution increases in
children linearly with their weight. The
metabolism of modafinil is primarily hepatic, with
less than 10 percent excreted unchanged in the
urine. There are 2 primary metabolites, modafinil
acid and modafinil sulfone. As you heard earlier,
we did observe higher levels of modafinil sulfone
in the younger children. The elimination of
modafinil is time- and age-dependent. We observe a
decrease in clearance over time with steady state
being reached by about week 6 of treatment. There
is a gradual decrease in clearance with age, with a
pronounced shift between 9-11 years of age. So, we
see that there is a half-life in the younger
children of approximately 7 hours which is compared
to a half-life of 15 hours in the adults.
[Slide]
I would now like to outline for you the
basis of the dose selection that we used in the
Phase 3 studies. Study 207 was a relatively small,
double-blind, randomized, 4-period crossover study,
and this was the first program undertaken to assess
the efficacy of modafinil in the treatment of ADHD.
The results shown for you are the total
scores on the ADHD rating scale as assessed by the
parent. With the caveats of this being a small
study, you can see that those patients who received
100 mg barely discriminated from placebo. A
slightly larger treatment effect was seen with the
200 mg dose group and a larger treatment effect was
seen with the 300 mg or 400 mg dose group. And, I
should reiterate here that the 300/400 mg doses
were administered based on weight, with the 300
given to children less than 30 kg and the 400 to
those children weighing at least 30 kg or more.
[Slide]
The next study we undertook was study 213,
and this was designed to see the best way of
administering a single dose of 300 mg either as a
single dose administered first thing in the
morning, which is depicted in blue, or as a split
dose of 200 mg in the morning and 100 mg at lunch,
depicted in orange, 100 mg in the morning and 200
mg at lunch time, depicted in pink and compared to
placebo.
As you can see from the slide, there
appeared to be little benefit to splitting the dose
and the largest response we saw was in the 300 mg
dose group administered as a single dose. As you
can see on the right-hand side of the slide, this
is for all patients, but when we looked at it
stratified by weight you can see that it is clearly
the younger and lighter children that had the
larger response. So, from this study we concluded
that older and heavier children may require a
higher dose.
[Slide]
This slide identifies the systemic
exposure that we saw following these dosing
regimens. In the middle, here, are those children
weighing less than 30 kg who received 300 mg. Here
are those children weighing more than 30 kg who
received. You can see that the systemic exposure
associated with the lighter children is clearly
higher than the systemic exposure with the heavier
children.
[Slide]
Using these data and the clinical efficacy
results from the Phase 2 studies, we developed a
pharmacokinetic/ pharmacodynamic model and
estimated that the systemic exposure which would be
associated with a consistent pharmacodynamic effect
would be in the order of 150 mcg/hour/ml, and that
the doses that would be required to achieve this
exposure at steady state would be 340 mg for those
children weighing less than 30 kg and 425 mg for
those children weighing 30 kg or more.
[Slide]
Following the Phase 3 program which
included sampling from population pharmacokinetics,
we went back to test this hypothesis. As you can
see from this slide, we pretty much got it right in
that here are the children weighing less than 30 kg
who received 340 mg and here are those heavier
children who received 425 mg, and the systemic
exposure in those groups is pretty similar, around
150 mcg/hour/ml. As you will see from the next
slides, these doses were associated with
substantial efficacy.
[Slide]
Here are the designs of the 3 pivotal
studies that were undertaken. All studies were
double-blind, randomized, placebo-controlled and
had a 2:1 randomization. Study 309 and 311 were
identical in design. Both were 9 weeks in duration
and employed a flexible dose titration regimen
whereby children could be titrated from a minimum
dose of 170 mg to a maximum dose of 425 mg based on
perceived efficacy and their tolerability to
treatment. The dosing increments occurred on a
weekly basis at 85 mg.
Study 310 was slightly different. This
study had a 7-week efficacy period and a 2-week
period that assessed abrupt discontinuation of the
drug, the results of which I will not show you
today. This study was also a fixed dose study and
patients were titrated at 85 mg increments every 2
days to their target dose based on weight, so 340
mg for the children weighing less than 30 kg and
425 mg for those children weighing 30 kg or more.
[Slide]
The patients enrolled in the study were
very similar. All patients were 6-17 years of age
with a diagnosis or ADHD according to the
Diagnostic and Statistical Manual of Mental
Disorders. The children were required to be at
least moderately ill on the Clinical Global
Impression of severity and have an ADHD rating
scale which was at least 1.5 standard deviations
above the norm for age and gender. Patients were
required to be of normal intelligence with no
learning disability and attend school full time.
Patients were excluded from study if they
failed to respond to 2 or more adequate courses of
stimulant therapy, although it should be noted that
patients who had failed one stimulant therapy were
allowed to be enrolled. Patients were also
excluded if they had psychiatric comorbidities
requiring current pharmacotherapy and were well
controlled with their current ADHD therapy and had
no good reason to change treatments.
[Slide]
The efficacy assessments were identical
for each of the 3 studies. The primary outcome
measure was the change from baseline in the Total
Score ADHD Rating Scale as assessed by the teacher.
Secondary outcome measures included a
change from baseline in the Home ADHD Rating Scale
as assessed by the parents in the evening between
6:00 and 8:00 at night; the Clinical Global
Impression of change as assessed by the treating
physician; the Conners' Parent Rating Scale as
assessed by the parent; the test of Variables of
Attention, which is a continuous performance test;
the Social Skill Rating Scale and the Child Health
Questionnaire.
[Slide]
As you can see, the average age of
patients entering into the program was around 10,
with the majority of patients being less than 12
years of age. The majority were boys and white,
and about two-thirds of the patients actually
weighed 30 kg or more.
[Slide]
As per inclusion criteria, patients were
required to be at least moderately ill on the
Clinical Global Impression of severity and, as you
can see from the slide, about 50 percent of the
patients were considered to be moderately ill and
the other 50 percent were considered to be markedly
or severely ill. Around two-thirds of the patients
had the combined inattentive and hyperactive
subtype of ADHD. About a third were predominantly
inattentive and very few were purely hyperactive.
The baseline ADHD rating scale at entry was on
average 37, which is well above the norm for a
10-year boy which is roughly 18.
[Slide]
A total of 638 patients were randomized
into the study and 630 received treatment, 420 in
the modafinil treatment group and 213 in the
placebo treatment group. Around two-thirds of the
patients completed the double-blind treatment
period, with the reasons for discontinuation
outlined here. As you can see, some of the main
reasons for discontinuation were lack of efficacy
with a much higher proportion in the placebo
treatment group, and adverse events with the higher
proportion in the modafinil treatment group. The
other reasons are listed for you here.
[Slide]
The following three slides will show the
outcomes of the primary efficacy variables for each
individual study. Here are the results for study
309, the first of the flexible dose studies. Just
to orient you, on the Y axis is the Total ADHD
Rating Scale with the lowest score showing benefit,
and across the X axis is the duration of the
treatment period in weeks.
Just as a reminder, the primary outcome
variable was the change from baseline to endpoint
using the last observation carried forward
analysis. As you can see from this slide, there
was a statistically significant difference in favor
of those patients being treated with modafinil.
More specifically, the treatment effect on the
modafinil treatment group was 17.5 points with the
treatment effect on the placebo group of 9.7 points
for an effect estimate, which is the difference
between the 2 treatment groups using the Lee
squared means of 7.4. In addition, statistically
significant results were seen using the observed
cases analysis.
[Slide]
A similar result was seen in study 311
which is the second flexible dose study. At
endpoint the treatment effect on the modafinil
treatment group was 15 points and a treatment
effect on the placebo group was 7.3 points for an
effect estimate of 8. Again, this is statistically
significant both at endpoint and using the observed
case analysis.
[Slide]
The last study is study 310 and, again, a
very consistent treatment effect was seen in this
study, with a treatment effect of minus 17.2 points
on the modafinil group versus 8.2 points on the
placebo treatment group for an effect estimate of
9.
[Slide]
Outlined for you on this slide is just
another way of viewing the data. On the left-hand
side of the screen is the modafinil treatment group
at baseline and at endpoint. On the right-hand
screen is the placebo group at baseline and at
endpoint. This slide illustrates the remarkably
consistent effect seen not only in the modafinil
treatment group but in the placebo treatment group.
The red line depicts what would be considered to be
a normative value on the ADHD rating scale for a 10
year-old boy. As you can see, those patients
treated with modafinil are beginning to approach
this normative value.
[Slide]
We also assessed the effect of treatment
using a responder analysis on the School ADHD
Rating Scale with those patients who had at least a
30 percent reduction in their scores from baseline
to endpoint or a 50 percent reduction from baseline
to endpoint. As you can see, in all 3 studies a
significantly higher proportion of patients treated
with modafinil had either a 30 percent or a 50
percent reduction in their ADHD symptoms.
[Slide]
This slide shows for you in all 3 studies
the home version of the ADHD Rating Scale. As a
reminder, this was assessed by the parents in the
early evening. The results seen here very much
mirror the results we saw using the school version
of the ADHD Rating Scale, with significant
differences seen both at endpoint and in the
observed case analyses in all 3 studies in favor of
the modafinil treatment group.
[Slide]
Depicted here is the responder analysis on
the Clinical Global Impression of improvement.
Outlined for you are those patients who were either
considered to be much or very much improved by the
treating physician. Again, in all 3 studies we see
a very consistent treatment effect, with a
significantly higher proportion of patients
considered to be much or very much improved on this
scale by the treating physician.
[Slide]
Another commonly used scale for assessing
ADHD and their response to medication is the
Conners' Parent Rating Scale. Again, you can see
in each of the 3 studies, using this scale, a very
similar effect to the observation seen using the
ADHD rating scale, with improvements on the
modafinil treatment group in cognitive problems and
in attention, hyperactivity and their total ADHD
index.
This scale also allows the assessment of
treatment on the oppositional behavior. As you can
see, in all 3 studies there appears to be a
treatment effect in favor of modafinil, although
this is only statistically significant in study
311.
[Slide]
The one inconsistent effect that we saw
was using the Test of Variable Attention. Outlined
for you in this study is the pooled analysis using
data from all 3 studies. Although you can see that
those patients treated with modafinil tend to do
better than those patients treated with placebo, it
should be noted that this is actually a decline in
performance rather than an improvement in
performance over time.
[Slide]
Children with ADHD often have poor peer to
peer relationships and difficulties with
socialization. We wanted to assess the effects of
treatment on these parameters and we used the
Social Skills Rating Scale. Again, this is the
data from all 3 studies pooled. The individual
studies did show a consistent treatment effect. As
you can see, there appears to be an improvement in
many of these parameters when treated with
modafinil, including the Social Skills Total Scale.
[Slide]
A similar improvement was seen in other
problem behaviors as measured by this scale. It
should be noted that these results were only seen
in the children in grades kindergarten to 6th grade
and we observed no major differences between
treatment groups in the older age groups.
[Slide]
Lastly, here are the results of the Child
Health Questionnaire, a global sort of quality of
life instrument that assesses many behaviors that
can be impaired with ADHD. Again, this is the
pooled analysis of all 3 studies. As you can see
from this slide, there appears to be an improvement
in many of the behavioral aspects seen for those
patients treated with modafinil--
[Slide]
--including an improvement in the total
psychosocial summary. We did not see significant
improvements in the physical functioning domain,
although it should be noted that these values were
normal at baseline.
[Slide]
We have undertaken many subgroup analyses,
many of which are outlined in your briefing
document. Here I just want to show for you the
subgroup analysis for those patients who were
either stimulant naive at study entry, and that was
for about 50 percent of the patients, and those
patients who had received a prior stimulant before
enrolling into the study, which was again about 50
percent of the patients.
Here you can see that treatment with
modafinil was effective even in those patients who
had had prior stimulant therapy, although it should
be noted that the treatment effect appears to be
larger in those who were stimulant naive.
[Slide]
In conclusion, we saw consistent efficacy
results across 3 pivotal studies. The improvement
in ADHD symptoms was seen by the teachers, the
parents and the treating physicians. Improvements
were seen at school, at home and across the day.
As well as improvement in the core ADHD symptoms,
we did observe improvement in other psychosocial
domains. Finally, we saw efficacy in stimulant
naive patients and in patients who had had prior
stimulant experience.
[Slide]
I would now like to hand over to Dr.
Srdjan Stankovic who will outline safety for you.
General Safety
DR. STANKOVIC: Thank you. My name is
Serge Stankovic and I am with the Cephalon clinical
research group.
[Slide]
My presentation this morning on modafinil
safety is organized as follows: I will review
overall modafinil exposure in clinical trials.
Following that, I will review the safety data for
the modafinil ADHD program in children and
adolescents, and this will include review of
general safety and events of special interest such
as skin reactions and psychiatric events. In the
balance of my presentation I will briefly summarize
high level safety information from our development
program in excessive sleepiness in pediatric
patients. Finally, I will review modafinil
information coming from our postmarketing safety
surveillance.
[Slide]
Overall, safety data for 933 patients with
ADHD were included in the supplemental NDA,
submitted in December of 2004. Of these, in the 3
Phase 3 placebo-controlled trials, 420 patients
were treated with modafinil and 213 patients were
treated with placebo. Please note these numbers as
I will often refer back to them when I am
presenting data from our controlled trials.
Following the sNDA submission, one
additional open-label study in children with ADHD
was initiated. With that, as of February, 2006, a
total number of pediatric ADHD patients exposed to
modafinil was 1236. Additional pediatric exposure
comes from our development program in excessive
sleepiness, 270 pediatric patients, and from
pediatric patients exposed to a variety of foreign
studies for various indications, 116 patients.
Finally, just a reminder that 4000 adult
patients were exposed to modafinil in the
development program for excessive sleepiness and in
other clinical trials.
[Slide]
Looking at patient exposure in the
pediatric ADHD program, this slide presents
exposure by modal dose and duration for 933
patients as of February 1, 2006. A total of 246
patients were treated with modafinil for a minimum
of 12 months, and as many as 164 were on drug for
18 months or longer. About half of the patients
received modafinil at the modal dose of 425 mg a
day, while about one-third at the modal dose of 340
mg a day. The total exposure to modafinil in the
pediatric ADHD program is 575 patient-years.
[Slide]
Next I will discuss adverse events
observed in ADHD studies of children and
adolescents.
[Slide]
A general overview of adverse events
reported in 3 Phase 3 placebo-controlled studies is
presented on this table. While the majority of
patients in both groups experienced at least one
adverse event, a higher incidence was observed in
the modafinil treatment group. Relatively few of
these events were reported to be severe, were
reported to be a reason for study discontinuation
or were reported to be a serious regulatory
definition of that word.
[Slide]
The most commonly observed adverse events
in the Phase 3 placebo-controlled studies were
insomnia, headache and anorexia. The COSTART term
of anorexia used here includes both loss of
appetite and decreased appetite. In fact, about 70
percent of patients reporting anorexia experienced
decreased appetite. Insomnia and anorexia were
reported at a substantively higher rate in the
modafinil group compared to placebo. Review of
these two events indicated that very few were
reported as severe, specifically 9 out of 115
events for insomnia and 1 event for anorexia.
Likewise, only 5 events in insomnia led to
discontinuation, while 2 patients reporting
anorexia discontinued study due to that adverse
event. In most instances, these 2 events first
occurred in the initial 2 weeks of treatment and
the median duration reported was about 2 weeks.
[Slide]
Out of 933 patients included in the sNDA,
18 patients experienced at least one serious
adverse event by the time of the 10-month safety
update submitted in November of 2005. Four of
these patients were enrolled in the 3
placebo-controlled Phase 3 studies and all of them
were in the modafinil treatment group. From the 2
ongoing pediatric studies in ADHD, 3 patients
experienced a serious adverse event during the
period up to February, 2006. Discussion of serious
skin adverse events as well as psychiatric events
in more detail with be part of the discussion of
special safety.
[Slide]
In the next four slides I will review
relevant information related to laboratory
evaluations from the pediatric ADHD studies. Data
for selective hematology and blood chemistry
parameters will be reviewed in more detail.
Although included in your background package, data
for other laboratory parameters did not raise
questions or concerns and, therefore, will not be
presented here today.
[Slide]
Based on some early observations from the
Phase 2 studies, concern was raised regarding
modafinil treatment effects on absolute neutrophil
count and white blood cell count in children. Our
Phase 3 controlled data did not show a meaningful
difference in mean change from baseline or
incidence in clinically significant values between
modafinil and placebo. Furthermore, as presented
on this slide, when the lowest on treatment values
are grouped by range there was no meaningful
difference between modafinil and placebo treatment
groups.
[Slide]
With respect to serum chemistry, as in
adults, we did observe a difference in mean change
from baseline between modafinil and placebo for
alkaline phosphatase and GGT. In the Phase 3
placebo-controlled studies there were few patients
experiencing a clinically significant change on any
of the parameters, with no apparent imbalance
between treatment groups. On the next slide we
will discuss LFT elevations highlighted in the
background document as cases of possible concern.
These cases are included in this table in the
column for all modafinil studies.
[Slide]
In the FDA approvable letter it was stated
that although controlled trials data did not reveal
a signal for drug-related mean increase in
transaminase values or in drug-related outliers,
there were 3 modafinil-treated patients who had
transaminase increases of concern, but insufficient
other information to further assess the
significance of these changes. Details related to
these 3 patients are presented on the slide.
In all 3 cases, total bilirubin values
both at the time of observation of abnormal LFT
values and throughout the study were normal. In
one case laboratory abnormalities returned to
normal while patients continued treatment with
modafinil. In the second case treatment was
continued for an additional 6 months prior to study
discontinuation. At that time, all abnormal LFT
values returned to normal except for a mild
elevation in ALT. In the third patient abnormal
values returned to normal after withdrawal of
modafinil. This case will be discussed later in
relation to possible hypersensitivity reactions.
[Slide]
The next segment of the safety
presentation is focused on cardiovascular safety.
I will review blood pressure and pulse data, ECG
information including QTc interval and
cardiovascular adverse events from the Phase 3
placebo-controlled trials. It should be noted that
the vital signs measurements in ECGs were recorded
in these studies at variable time points during the
day and in relation to the intake of study
medication.
[Slide]
With respect to blood pressure, no notable
effects in sitting blood pressure were observed in
the Phase 3 controlled studies. Presented on this
slide are box plots for systolic blood pressure on
the left side of the screen and diastolic blood
pressure on the right side of the screen in
modafinil and placebo treatment arms respectively.
Changes from baseline for both systolic
and diastolic blood pressure were similar in the 2
treatment groups with respect to both mean values,
overall distribution and extreme outliers.
[Slide]
This graph presents the distribution of
observed change from baseline in sitting pulse for
the 2 treatment groups. As presented, we observed
similar distribution between the 2 treatment arms
and the occurrence of outliers.
[Slide]
Review of the ECG tracings from the ADHD
pediatric studies did not reveal specific concerns
both with respect to morphology or interval
measures. This slide presents an overview of QTc
interval data from the 3 placebo-controlled trials
expressed as maximum change from baseline or as
maximum duration observed. The slide presents data
for QTc using the Fridericia correction, but the
findings are similar when other corrections are
used. Either way, there is no apparent effect on
QTc interval or imbalance between treatment arms.
[Slide]
Finally, when reported adverse events are
reviewed, we observe relatively few cardiovascular
events. Only a small fraction of these, 2 patients
on modafinil and 1 on placebo, reported events
leading to treatment discontinuation. In all 3
cases the stated reason for discontinuation was
tachycardia. None of the reported cardiovascular
events were reported to be serious.
[Slide]
Important consideration in the safety
evaluation of any ADHD compound is assessment of
its effects on growth. [Slide]
In the placebo-controlled Phase 3 studies
modafinil treatment of up to 9 weeks duration led
to relative weight loss compared to weight gain
observed in the placebo group. Similarly, a
significantly higher proportion of
modafinil-treated patients experienced clinically
significant weight loss, defined as at least 7
percent in weight reduction. To be precise, 9
percent of modafinil-treated patients versus 1
percent of placebo-treated patients experienced
significant weight loss during the study.
[Slide]
Naturally, we did look at the longer term
treatment data related to weight and growth in
general. As you know, for accurate evaluation of
growth effect in children, we need to evaluate them
relative to norms. To achieve this, we expressed
changes in weight and height using Z-scores. Just
a quick reminder, Z-score is a statistical measure
that quantifies the distance measured in standard
deviations of a patient data point, in this case
individual weight or height, from the population
mean, in this case CDC growth norm for
corresponding age and gender.
This graph presents mean weight and height
Z-scores over 12 months of treatment with
modafinil. A decline in Z-score is observed
initially in the first 3 months of treatment
consistent with the reported weight loss in our
short-term trials. In the following months the
line remains horizontal, meaning that the normative
pattern of growth is regained. Using the same
presentation, it is apparent that there was no
indication of adverse effects on height over the 12
months of treatment with modafinil.
[Slide]
In the course of the modafinil ADHD
pediatric development cases of serious skin
reactions were reported. Some of these were
indicative of a possible Stevens-Johnson syndrome
or hypersensitivity reaction, generally a rare but
very serious complication of treatment. Cephalon
shares the important concerns raised by our
colleagues at FDA in regard to these events.
Therefore, I will review skin events in greater
detail.
[Slide]
To bring everybody on the same page with
respect to cases of interest, I will start with the
list of events, included in the FDA briefing
document, in the second dermatology consult report
dated February 27, 2006. In this report the events
were grouped in 3 categories based on the level of
diagnostic confidence. The 3 groups are events
representing EM, SJS or TEN; events somewhat
suggestive but lacking confirmation; and events
resembling prodromal presentation but without
sufficient information for diagnosis. Cephalon has
performed a similar review and in the next two
slides I will review cases from the first two
groups. With respect to the third group, our
review did not support the conclusion that any of
these cases should be classified as SJS or
prodrome. We based this on the low specificity and
low predictive value of reported symptoms.
Additionally, many of the symptoms are quite common
and many were not reported concomitantly or
concurrently.
[Slide]
First, we will review the clinical trial
cases. Patient number 1 is a 7 year-old boy who,
on day 16 of treatment with a 340 mg dose,
presented with symptoms described by the
investigator as erythema multiforme,
Stevens-Johnson syndrome and both FDA and Cephalon
reviewers agreed that the diagnosis of
Stevens-Johnson syndrome is likely accurate, with
less consensus on the possible etiology. I am sure
that this case will be discussed in more details
later and, as Dr. Raczkowski said, we have the
investigator here who was treating the patient, as
well as members of our panel of dermatologists who
can talk more about the case.
Patient number 2 is an 11 year-old girl
reported with morbilliform rash on day 15 with
treatment of a 200 mg dose of modafinil. This
patient was hospitalized and the SJS diagnosis was
excluded. FDA review indicated that this was a
case representative of EM/SJS. Cephalon's panel of
independent reviewers, on the other hand, was
unanimous that the reported diagnosis of
morbilliform rash is probably correct and the event
did not represent Stevens-Johnson syndrome.
Patient number 3 is a 6 year-old boy who
reported rash, fever and vomiting 2 weeks after
initiation of treatment. Review of the source
documentation received from the investigator
indicated that this event was diagnosed as fifth
disease.
Patient number 4 is an event in an 8
year-old boy described as rash on the cheeks and
blisters on the lips, and was reported as erythema
multiforme. The event occurred on day 23 of
treatment with a 300 mg dose of modafinil. This
case is considered by the FDA reviewer as somewhat
suggestive but not representative of EM/SJS or TEN.
Cephalon's reviewers, on the other hand, agreed
that this is unlikely erythema multiforme, but did
not agree on the alternative diagnosis. One
considers this event to be possible SJS. A second
reviewer considered it to be probable herpetic
gingivostomatis and a third independent reviewer
attributed to the event as either viral etiology or
SJS.
Patient number 5 is a 9 year-old boy with
reported symptoms of urticaria, fever and facial
edema. This patient also had elevated
transaminases. Cephalon's review indicates that
this is a possible case of hypersensitivity
reaction and it is not consistent with SJS.
[Slide]
In the review of postmarketing reports
both FDA and Cephalon concluded that there were 4
reports of serious skin reactions, 1 SJS/EM and 3
SJS reports. Of the 12 suggestive but not
confirmed cases on the FDA list, Cephalon has
identified 8 reports considered suggestive of
possible hypersensitivity but not indicative of EM,
SJS or TEN spectrum. The other 4 cases were also
not considered suggestive of SJS.
[Slide]
In the Phase 3 placebo-controlled trials
the incidence of rashes coded by the COSTART coding
system was 4 percent in the modafinil treatment
group and 2 percent in placebo. As we all know,
the preferred term "rash" in the COSTART coding
system does not include many terms that could be
considered non-urticarial rash. Therefore,
Cephalon undertook an additional analysis to
ascertain the incidence of non-urticarial rash. In
collaboration with 2 external dermatology experts,
we defined a category of non-urticarial rash which
included all adverse events indicative of rash,
excluding urticaria and related reactions.
Using this definition, cases of
non-urticarial rash in the pediatric ADHD studies,
as well as in the pediatric studies for excessive
sleepiness and in all adult studies with modafinil
were identified and frequency tables were
constructed. Additionally, all reported adverse
events of urticaria, hypersensitivity reactions and
all allergic reasons in the pediatric ADHD studies
were reviewed for possible underlying causality and
prior medical history.
[Slide]
Based on the described methodology, we
calculated the incidence of non-urticarial rash
across treatment groups in controlled pediatric
ADHD trials and in all pediatric patients. This
table presents the incidence in the
placebo-controlled trials. We also present the
incidence of those described as severe and those
leading to treatment withdrawal. The overall
incidence of rash was higher in the modafinil
treatment groups, with few being described as
severe or leading to treatment discontinuation.
[Slide]
In the ongoing open-label study in ADHD
initiated after the supplemental NDA submission a
total of 303 additional newly exposed patients
entered the study, with 188 receiving modafinil for
at least 4 weeks. Presented on this slide is the
observed incidence of non-urticarial rash in that
study. As in the previous slide, we also present
the incidence of events described as severe or
those leading to discontinuation.
As seen on this slide, the reported
incidence is somewhat lower compared to the
modafinil group in the controlled studies. One
patient reported a severe rash on day 10 and
discontinued the study on day 13 due to this rash
which was described by the investigator as rash.
[Slide]
The overall incidence of non-urticarial
rash reported in the controlled pediatric studies
for excessive sleepiness was similar between
modafinil treatment groups and placebo. These are
much smaller studies Additionally, the observed
incidence was lower compared to ADHD pediatric
studies. Only one event was reported as severe for
events described by the investigator as fifth
disease. No events led to discontinuation or were
serious by regulatory definition.
[Slide]
The observed imbalance in incidence of
non-urticarial rash in the controlled ADHD
pediatric studies prompted further evaluation for
possible association with treatment. We approached
this in 3 ways. We evaluated the relationship
between rash and dose; relationship between rash
and modafinil plasma exposure; and, finally, we
evaluated the relationship between rash and
modafinil sulfone exposure, one of the metabolites
known to be present in higher concentrations in
children. With respect to relationship of
non-urticarial rash and dose, we conducted a
case-control analysis where patients with rash were
matched with controls based on the study protocol,
time in the study to event and weight. Based on
this analysis, we did not find statistical evidence
for association between rash and modafinil dose.
[Slide]
A second analysis looked at the modafinil
plasma exposure by comparing area under the curve
between patients reporting non-urticarial rash, in
the far left box on the slide, controls, in the
middle box, and overall patient population in Phase
3 studies, in the far right box. Areas under the
curve were calculated based on sparse sampling data
from the Phase 3 trials and PK modeling. As
presented on this slide, no difference was apparent
between the 3 groups.
[Slide]
An assessment of the relationship between
non-urticarial rash and exposure to modafinil
sulfone was also conducted. Here we graphically
depict the distribution of modafinil sulfone
concentrations in patients developing rash--small
red boxes at the bottom, and in patients not
developing rash--blue boxes. On the Y axis the
number of patients is depicted and different
modafinil sulfone concentration ranges are depicted
on the X axis.
We observed that the distribution of
sulfone concentrations in patients with rash
appears to closely mimic the distribution of
sulfone concentrations in the full population of
treated patients in placebo-controlled studies. We
conclude, therefore, that there appears to be no
correlation between non-urticarial rashes and
systemic exposure to modafinil sulfone. One
additional piece of information is that 2 cases in
question had modafinil sulfone concentration of
less than 6 mcg/ml.
[Slide]
We have also examined the adverse events
database from the controlled ADHD pediatric studies
for COSTART preferred terms indicative of
urticaria, hypersensitivity reactions or allergies.
This slide presents a tabular summary of the
reviewed preferred terms and associated medical
history reported prior to treatment initiation.
One can easily see from the table that the vast
majority of these events was reported in patients
with prior history of seasonal allergies or asthma.
[Slide]
Psychiatric adverse events related to ADHD
treatment have enjoyed special interest in the
recent months, culminating in some important
discussions as recently as yesterday. In response
to the request from the Division issued to all ADHD
drug manufacturers, Cephalon has performed a full
analysis of psychiatric events from all pediatric
studies and from our pharmacovigilance database as
per prespecified methodology.
In addition, we have reviewed serious
adverse events occurring after the last safety
update cutoff in October, 2005, covering the period
through February 1, 2006. The results will be
presented in the next several slides.
DR. GOODMAN: Excuse me just a moment, I
want to ask a question of clarification on the
previous metabolite levels that you showed. What
was the relationship between the timing of
obtaining the sulfone metabolite level and the
dosing? Obviously, there can be a lot of noise
contributed by relationship between time of assay
and dose.
DR. STANKOVIC: We obtained the values for
concentrations of modafinil sulfone closest to the
event for those patients that reported a rash.
DR. GOODMAN: But it might not have been
the same relationship to the time the dose was
actually taken. Right?
DR. STANKOVIC: That is right, yes. That
is correct.
[Slide]
A brief introduction on methodology of the
psychiatric evaluation, all adverse events reported
in the ADHD and excessive sleepiness pediatric
programs were subject to a review by a string
search for COSTART preferred terms of investigator
verbatim terms indicative of psychiatric events.
Once identified, all events are classified in the
following groups, psychotic events including mania,
suicidal ideation and behavior, aggressive and
violent behavior and miscellaneous psychiatric
events that were serious by regulatory definition.
A similar string search approach was employed in
the review of our psychovigilance reports. Event
terms and narratives from the ongoing pediatric
studies for serious adverse events were reviewed in
order to identify psychiatric events as well.
[Slide]
We present here psychiatric adverse events
from the ADHD pediatric program. Just a quick
note, this table includes both events that occurred
during treatment as well as those that occurred 48
hours following last dose of modafinil. As I will
be discussing these cases, we put them together.
This is somewhat different than the methodology
applied in the tabulations presented yesterday.
In the controlled studies all psychotic
events, as well as all events of suicidal ideation
or behavior were reported in modafinil treatment
groups. Reports of aggression or violent behavior
were relatively balanced between treatment groups,
with a slight higher proportion of these events
occurring in placebo. Additionally, no serious
miscellaneous events were reported in either group.
When the smaller pediatric program in excessive
sleepiness was examined, no psychotic or suicidal
events were found. Obviously, even few events or a
psychotic or suicidal nature are a great concern so
we will review them in more detail.
[Slide]
A total of 5 patients reported psychotic
symptoms while on modafinil treatment, all within
48 hours post last dose. Three of these events
were relatively short in duration and why patients
continued modafinil in one case or following
withdrawal of the drug in two cases. One
additional case, described as psychotic disorder
aggravated, was also relatively short in duration
but did require hospitalization and led to
withdrawal from study. This case, also in the
narrative, we learned reported as suicidal
verbalization but it is included in this table in
the psychotic disorders. The fifth case was an
interesting case of reported ideas of reference
that apparently did not require any specific
treatment--yes, sir?
DR. GOODMAN: We have a question.
DR. PINE: I want to understand both of
these cases because the last two cases don't really
make sense to me and I am wondering if you could go
into them in a little detail, really the last case
more than the second to the last one. When it says
psychotic disorder aggravated, that implies to me
that there was either a preexisting psychotic
disorder or some other factor that was contributing
and it sounds concerning that the child was
hospitalized. So, that is one question.
The second question is that this is a case
of ideas of referential control which, again,
sounds somewhat concerning and the event lasted ten
months, which is also somewhat concerning if those
are really ideas of referential control, but the
action taken was to continue with modafinil. So,
that doesn't make any sense to me. I wondered if
you could explain those situations.
DR. STANKOVIC: Yes, I can talk a bit
about those cases additionally. The psychotic
disorder aggravated is an 8 year-old boy with ADHD.
He presented with severe psychosis beginning on day
19 of the open-label study. He was hospitalized
and at the time of hospitalization we learned that
there was a prior history of a psychotic disorder
that was not reported at the time of the entry to
the study.
The second case is a very interesting case
to us as well. Unfortunately, we do not have quite
a clarification of continuing modafinil treatment
in ten months of continued ideas of reference. We
don't have any additional details. It is
interesting and somewhat confusing but that is what
happened. The investigator continued treatment for
an additional ten months.
DR. PINE: Just to make a comment about
that, I mean, not only does that raise questions
about this case but it raises questions about the
nature of the data in general because it just
wouldn't make sense that somebody would see
something like this, and idea of reference, that
would be ongoing for ten months but not feel the
need to take any treatment. Anyway, I guess it
speaks for itself.
[Slide]
DR. STANKOVIC: We have here a similar
presentation for the 5 patients reporting adverse
events classified as suicidal ideation or behavior.
The first 3 patients experienced brief episodes of
suicidal ideation, described as suicidal statement.
In 1 patient this happened on 2 occasions. None of
these events required either treatment for the
event or study drug discontinuation. One patient
verbalized a suicidal threat which was resolved
after study drug was discontinued.
One case, however, is a case of aggressive
behavior reported initially as normal behavior.
The case narrative described suicidal behavior in a
6 year-old girl with a psychiatric history and
possible family history. The event occurred 2 days
following the last dose of study medication and
required hospitalization and prolonged treatment.
[Slide]
Between the last safety update in
November, 2005 and February, 2006 4 serious adverse
events indicative of suicidality of psychotic
symptoms were reported in the ongoing pediatric
studies. These include both ADHD studies and
ongoing pediatric studies in excessive sleepiness.
Three patients reported events that were classified
as suicidal events, ideation or gesture. In 2 of
these cases no treatment intervention was required
and the patients continued in the study. Treatment
was withdrawn for 1 patient. One additional
patient reported paranoid reaction following 16
days of treatment. The event lasted 5 days and the
study drug was withdrawn.
[Slide]
In the request from the Division for
analysis of psychiatric adverse events, we have
been asked to review postmarketing reports received
during the period January, 2000 to June, 2005. We
estimate that for this particular period the total
pediatric exposure approximates 24,700
patient-treatment years. A total of 7 psychiatric
reports were received during this period.
[Slide]
These are the events reported. The events
were reported in a wide ranges of ages, as you can
see, from 6 to 17 years, and across both genders.
Four events involved psychotic symptoms. One event
was reported as a suicide attempt. However, in
this case modafinil was not taken prior to the
event but was only taken as a part of the cocktail
of drugs used in the multi-drug overdose. The 2
remaining cases are events of aggressive symptoms
and violent behavior.
[Slide]
You may wonder at this time how does the
safety profile of modafinil observed in pediatric
ADHD studies compare to other programs in children.
We have one additional program, smaller, completed
as a part of the pediatric retail request in
narcolepsy and obstructive sleep apnea for
excessive sleepiness. I will review here the
general safety profile observed during the
pediatric development program in this indication.
[Slide]
Overall, a similar safety profile was
observed in the small patient population; a similar
AE profile, effects in vital signs or laboratory
parameters were observed. Notably, no adverse
effects on weight were observed during the
short-term trials in this patient population.
Lower incidence of non-urticarial rash was observed
compared to ADHD studies, and no events led to
discontinuation or were serious in nature.
[Slide]
One serious adverse event from the
pediatric studies in excessive sleepiness requires
discussion as it was mentioned as a point of
concern in the FDA clinical review as a possible
case of Reye's syndrome.
The clinical picture in a 6 year-old boy
was that of a non-specific viral syndrome--nausea,
vomiting, pharyngitis, followed 3-4 days later by a
change in mental status characterized by
somnolence, delirium, hallucinations and seizures.
The patient had elevated serum ammonia but not
transaminases.
The case was reviewed at Cephalon's
request by two external consultants, one pediatric
neurologist and one pediatrician. The consensus
opinion was that the most likely diagnosis was
viral encephalitis or inborn error of metabolism.
Urea cycle disorder was mentioned. Reye's syndrome
was considered unlikely because of normal LFTs.
According to the FDA briefing package, the FDA
consultant also concluded that this case is not
drug related.
[Slide]
Some of the postmarketing information has
been reviewed earlier as part of the discussion on
skin and psychiatric reactions. Here we will
review the profile of the reported events through
our pharmacovigilance system from the perspective
of different system organ classes.
[Slide]
First, review of estimated postmarketing
exposure, we estimate that as of February, 2006
total postmarketing exposure to modafinil was
780,000 patient-treatment years. This includes
worldwide exposure for the period since drug
approval in the first country in 1999. As it
appears, based on the prescription data market
research that we have, 4 percent of these exposures
included individuals less than 18 years of age so
we estimate that the overall pediatric exposure is
about 30,000 patient-years. Based on some
information that we have available, the estimated
median duration of treatment with Provigil in the
market is approximately 3 months. So, using those
numbers, one can estimate exposure to modafinil to
be higher than a million, up to 3 million adults
and in excess of 100,000 children.
[Slide]
Presented on this graph are comparative
profiles of postmarketing adverse drug reactions
reported for adult patients, in blue rectangles,
and pediatric patients, in orange. The total
number of reported adverse drug reactions in a
particular system organ class is presented on the Y
axis while different system organ classes are
presented on the X axis. We had a total of 105
adverse drug reaction reports for all pediatric
patients.
As you can see, although it is a little
hard on this slide, the two profiles appear largely
similar across different organ systems. It should
be noted, however, that the we do not have reliable
information on how the two populations relate with
respect to underlying indications for which the
drug is prescribed or doses used.
[Slide]
Based on the postmarketing reports, the
Provigil label is continuously reviewed and updated
as deemed necessary. This slide is a reminder of 3
label changes initiated by Cephalon within the past
3 years. As you can see, some of the safety events
observed in the pediatric ADHD program are fairly
consistent with the postmarketing experience that
resulted in label changes.
[Slide]
I have reviewed a considerable amount of
safety information and will try in the next two
slides to briefly summarize the main points. We
believe that it is fair to say that modafinil is
generally well tolerated at doses studied. Not
unusual for ADHD medication, the most frequently
reported adverse events were insomnia, headache and
anorexia. These events were seldom severe and few
led to treatment discontinuation. Likewise, few
significant laboratory abnormalities were observed.
No effects on mean systolic blood pressure,
diastolic blood pressure, pulse or QTc interval
were observed in the controlled trials.
[Slide]
Beyond initial weight loss, there were no
consistent adverse effects on growth observed over
12-month treatment with modafinil. We did observe
events of suicidal ideation and psychotic events in
the ADHD pediatric patients treated with modafinil.
These events were short in duration in general and
did not require additional treatment in many cases.
We believe that there is one case of probable
Stevens-Johnson syndrome reported in the pediatric
clinical program so far at this point, at an
exposure of 1622 patients. This case resolved
without any adverse sequelae. As I mentioned, I am
sure that there will be more discussion of this
case and we will hear from the investigator and
consultants on this.
[Slide]
In the next presentation Dr. Lesley
Russell will review--
DR. GOODMAN: Before you go to that
presentation, Dr. Rappley?
DR. RAPPLEY: I have two questions; the
first, in the 30,000 children that you expect were
exposed in the postmarketing period, do you expect
that most of them received the 200 mg dose?
DR. STANKOVIC: As I said, it is very
difficult to know exactly what dose was prescribed
and for what indication it was prescribed so I
cannot comment on that. I don't really know. As
Dr. Temple mentioned earlier, one can assume a
variety of things. Whether it was 200 mg or
higher, we don't know.
DR. RAPPLEY: And, in your study 310 it
was cited for not obtaining hematologic values, and
one of the sites was with 21 patients. In looking
at your table on slide 76 which describes
neutrophilia, to what extent did those missed
samples affect your data? How many samples were
missed?
DR. STANKOVIC: I can't give you the exact
number; I don't know it off the top of my head, but
I think that the number of analytes may be 390 or
maybe 20 or 30 patients that don't have all of the
analytes, but I am not positive about that. I can
find you that number.
DR. RAPPLEY: Thank you.
DR. GOODMAN: Dr. Leon?
DR. LEON: I would like clarification on
the case control analysis you did. In the sponsor
book it is on page 64-65. You very briefly made
reference to your analyses--
DR. STANKOVIC: Yes.
DR. LEON: --in your slides, that you
found no risk of a variety of dosing factors for
the rash. It was a dependent variable. It was a
case control where you had 39 cases and 3 times
that number, 117, controls apparently matched on 3
variables. I have some questions.
First of all, it looks like you entered
about 14 variables that were very highly correlated
simultaneously. I mean, that is what it says here.
The effects were measures of dose entered at one
time.
DR. RAPPLEY: Will you show us the
document you are referring to? Is it this one?
DR. LEON: Yes. Sponsor's book page
64-65. I mean, this is being used as evidence of
no association when the analyses were not conducted
in the way that I believe an association would be
detected. So, my first question has to do with
entering all those variables simultaneously, very
highly correlated measures of dosing.
My second question has to do with what is
the statistical power you would have with this
sample size? You would have statistical power to
detect what effect? The sample size is only 39
versus 117. Would that be an odds ratio of maybe 2
or 2.5? You could miss some pretty substantial
associations.
Third, did the analyses account for the
clustering of these sets of 4 who were matched? In
what way did it account for it?
DR. KINGSBURY: Let me address these one
at a time. First of all, let me inform you that we
did not use all 14 variables at a time. This was
just different approaches to explore those and they
were done one at a time. Okay?
First of all, let me describe the matched
control analysis that we did. There were 39 cases.
We found 3 matched controls, as described in the
briefing document. As already indicated they were
matched by the study they came from; by the weight
stratum they were in; and also by having been in
the study at least as long as the time taken for
the event to take place. So, in that set, using
each of those 14 variables one at a time, we looked
at the distribution of whatever the dose was in
quartiles and tried to ascertain whether there was
a relationship, but understanding the limited
power. This is more of an exploratory analysis--
DR. LEON: What was the way that you
accounted for the clustering of these quartets of
case controls there? What was the analysis?
DR. KINGSBURY: I am sorry?
DR. LEON: Well, you have groups of
people, as you would in a paired T-test if you had
diads, and you have sets of 4 people who are
matched on these criteria that you just described,
and I want to know what is the statistical analysis
that was used to account for this clustering, the
correlation among these sets, these quartets.
DR. KINGSBURY: We did essentially a
conditional logistic regression in which we defined
this stratum as the case. We identified each case
and the corresponding matched controls. Then we
looked at the odds ratios of each of the various
increasing quartiles relative to the fist quartile
just to get a sense--I mean, this was very much a
descriptive statistical approach to see if there
was any evidence of a consistent dose response. We
did not find that.
DR. LEON: So, you acknowledge limited
power. You have power here with 150 subjects total
to detect what size odds ratio? Just so you can
let us know the magnitude that might have been
missed there.
DR. KINGSBURY: Because it was not an a
priori designed analysis, we did not focus on that
issue. We actually did not test anything; we were
just obtaining confidence intervals because that is
all we felt would be appropriate. As I mentioned
before, although the confidence intervals
overlapped 1, the odds ratios extended from 0.09 to
a little over 2.
DR. LEON: But when you are looking to see
if confidence intervals are overlapping 1, then you
are doing tests, exactly the same as looking at p
values. You are getting more information as well
about the magnitude of the change and about the
variability of that change, that association.
DR. KINGSBURY: We don't claim to have
shown no association. All the conclusion we are
making is that--by the way, consistent with the
limitation in the numbers that we have no
compelling evidence of an association, we did an
additional analysis based on the randomized
clinical trial data, and from that analysis we
found an odds ratio of 1.4 with a confidence
interval extending from 0.678 to 3.094. Going back
to the case control analysis--
DR. GOODMAN: Thank you very much. Let's
go on to our next speaker. Thank you.
[Slide]
DR. STANKOVIC: The next speaker is Dr.
Lesley Russell.
Benefit-Risk Conclusions
DR. RUSSELL: Thank you, Dr. Stankovic.
We have presented a lot of information this morning
regarding the efficacy and safety profile of
modafinil in the treatment of ADHD.
[Slide]
Following your deliberations, you will be
asked to answer two questions, the first being has
modafinil been shown to be effective for the
treatment of ADHD in children and adolescents?
We believe that the answer to this first
question is yes. In the 3 pivotal studies
consistent benefit of treatment with modafinil was
seen in all 3 studies, with these effects observed
by the teacher, the parent and the treating
physician across different rating scales and
instruments, and with effects being observed both
at home and at school.
[Slide]
You are also going to be asked today
whether modafinil has been shown to be acceptably
safe for the treatment of ADHD in children and
adolescents.
In the Phase 3 clinical program modafinil
was generally well tolerated. The most common
adverse events reported, insomnia and anorexia,
were generally mild to moderate in severity and
rarely a cause for treatment discontinuation. No
adverse signals were observed in the Phase 3
program with respect to pulse, blood pressure or
growth.
We were asked in the approvable letter to
provide more information on 3 cases of liver
transaminase elevations. As outlined in our
response to the approvable letter and presented
here today, in 2 of these cases the transaminase
elevations were resolving on continued treatment
with modafinil with, in 1 case, ALT values
returning to normal whilst continuing treatment.
In the third case the transaminase levels were
returning to normal on discontinuation of
treatment. We do not believe that an adverse
signal with respect to liver function has been
observed.
Concerns have been raised over the
reporting of psychiatric adverse events. As you
are aware, these events were fully discussed
yesterday at the Pediatric Advisory Committee for
all ADHD products. Although no consensus was
reached on how to label aggression, psychosis,
mania and suicidality, Cephalon has proposed
language in the warning section of the label which
we believe provides appropriate information
regarding these events seen in our clinical
program.
[Slide]
Concerns have also been raised over the
reporting of serious skin reactions, and in the
approvable letter we were asked to provide you with
more information on 3 cases of interest seen in the
clinical trials and 4 cases reported in adults in
the postmarketing setting.
As suggested by FDA, these cases were
reviewed by experts in the field and there appeared
to be general concurrence reached by these reviews
and Dr. Porres, from the FDA, with respect to the
first case, the 7 year-old boy with possible SJS.
But there does appear to be some diversity of
opinion regarding the other 2 clinical trial cases.
This seems to be in keeping with the diagnostic and
etiologic uncertainty surrounding the diagnosis of
these types of skin reactions. However, we
acknowledge that an association with modafinil
cannot fully be excluded. In all 3 of these cases,
however, the events did abate following
discontinuation of drug and no adverse sequelae
occurred.
In assessing the risk for SJS and
reviewing the totality of the data in the clinical
trials and postmarketing database for both adults
and children as reviewed, we believe that the risk
for SJS is low. However, we have proposed language
to be included in the warning section of the label.
Based on your deliberations today, we will be happy
to modify this as appropriate in order to provide
patients and healthcare providers with adequate
information concerning these events.
Lastly, modafinil is not a new chemical
entity and to date there have been 780,000
patient-years of exposure which, when looking at
actual patients exposed, may equate to
approximately 3 million exposures since
introduction of the drug in France, in 1994.
Pharmacovigilance is undertaken to assess
risks associated with modafinil usage and, as you
have heard today, this has led to 3 labeling
changes, one regarding the incidence of severe skin
reactions. Cephalon is committed to improving
these risk assessments further by undertaking a
more structured case ascertainment with respect to
skin adverse events.
[Slide]
So, in conclusion, we believe we have
shown you today that modafinil is an effective
treatment for ADHD with an acceptable safety
profile, with the benefits of treatment outweighing
its risks. Thank you for your attention.
Questions from the Committee to FDA and Sponsor
DR. GOODMAN: Thank you. May I suggest
that your team stay at the podium to address some
questions? I am going to assume that most of the
committee members are going to have questions for
you. If we start to run out of time, we are going
to have more opportunity to ask those questions
later this afternoon.
Let me start off with what may be the
easier of the two questions we are asked to vote on
today, the one regarding efficacy. From the FDA
standpoint and what I read, they were satisfied
with the efficacy data. I certainly feel satisfied
from what I have seen. Yet, before we move on to
the harder question of evaluating issues of safety,
it is very important to have the context in mind of
the benefit.
So, I want to give you an opportunity to
answer, from your perspective, where you see this
medication fitting in; where is it going to add
value or options in the marketplace? Is it going
to be advantages in the area of efficacy,
tolerability? I wonder if you could just expand on
those issues to give a little bit of a framework to
think about the benefits of this medication.
DR. RUSSELL: Well, as you heard from Dr.
Biederman with the MTS study, despite treatment
with drugs that are considered to be very
effective--and we certainly don't doubt that--there
does remain a group of patients that still either
cannot tolerate drugs or don't respond to them. We
saw in our program that, although maybe not
considered refractory, patients who had failed on a
prior stimulant therapy did appear to benefit from
the drug. We also saw that if you are stimulant
naive you respond slightly better to the drug.
So, we see this as a viable treatment
alternative to other drugs that are obviously
commonly used and considered to be effective
agents. However, I would like to have a treating
physician in the field come up and maybe give you
that from his perspective. So, if I could ask Dr.
Biederman?
DR. GOODMAN: Sure, go ahead.
DR. BIEDERMAN: I think that in clinical
practice we need alternative treatments to treat
our patients. The idea that the most efficacious
treatment treats all our patients is not true to
life. So, clinicians in practice need to have
options to allow us to better serve the people that
consult with us.
The issue of adverse effects is a
statistical issue. That means that even if side
effects are similar within a class of drugs, some
patients clearly tolerate one versus another even
if on average they have a similar spectrum of
adverse effects. So, patients that have poor
tolerability may benefit from a drug that may have
on average similar issues but may be better
tolerated for them.
Finally, the issue of scheduling--I think
that even though many of the new generation
stimulants that are available today are clearly
less of an issue for diversion and abuse, many
clinicians and many families do not want their
children to be on a Schedule II drug. So, I think
that this gives an option for clinicians to use a
lesser scheduled drug in cases where they choose
not to use a scheduled compound.
DR. GOODMAN: Joe, before you step down,
has it been your impression so far that there is
less abuse potential, less potential for diversion
as, say, compared to stimulants?
DR. BIEDERMAN: Yes. I am not an expert
on abuse and we have here a colleague that
specializes in that. The abuse and
diversion--first of all, let me comment on abuse
and diversion. There are different publics that
use these drugs recreationally and therapeutically.
Our battles in clinical practice are to encourage
our patients to remain in treatment. There is a
very severe problem of non-adherence to these
treatments. So, it is not something that our
patients look forward to taking.
The attraction of the stimulants is when
the tablet can be crushed and snorted for an
IV-like experience. It is the parenteral intake
that produces the euphoria, not the oral intake.
So, this drug is not snortable, injectable, and so
on and so forth, so it is not a drug that the
addict community on the street would pay a high
price for to get it. But maybe we can get some of
our colleagues that are here with better expertise
than mine on diversion and abuse to give a
perspective.
DR. RUSSELL: Does that answer your
question?
DR. GOODMAN: I would like to hear a
little more on that issue.
DR. RUSSELL: Dr. Dackis?
DR. DACKIS: With regard to the abuse
potential of modafinil, I think it is important to
note that it is chemically unrelated to central
stimulants and has a very weak effect on the
dopamine transporter so that it is extremely
unlikely to increase dopamine levels, except in
very high dosages.
There have also been a number of studies
in humans to assess what the subjective effects of
this agent are and these studies, which have been
conducted by Jasinski demonstrate that in males
there is no effect of modafinil. There was a
smaller study in females that did show some
stimulant effects using these various rating
scales. Two other studies, again, showed that
there was not a significant high; that the subjects
were not willing to pay money for modafinil, etc.
In addition, animal studies, looking at
things like self-administration and condition-place
preference showed very weak stimulant-like effect
of this agent. So, there is some reinforcing
quality but it is very, very weak. DR. GOODMAN: I
thought monkey studies showed preference.
DR. DACKIS: Yes, that is correct. Gold
and Balster's study did show that monkeys, trained
to self-administer cocaine, if given modafinil
would continue to self-administer large doses of
this agent, as they would with other compounds like
ephedrine. So, large doses are required to
continue to self-administer.
DR. GOODMAN: Thank you. Dr. Temple?
DR. TEMPLE: I am sympathetic to the idea
that drugs with different pharmacology may have
different usefulness, but I want to address the
question of whether they have documented the
ability of this drug to work in people who are
resistant to stimulant drugs, and the answer is
that they have not.
There is a perfectly simple, never done
kind of study design to do that. You take people
who fail on whatever it is you want to test and
then you randomize back to that drug and to the new
drug. It is a perfectly simple study. That is how
clozapine came to the market because we wouldn't
have approved clozapine unless it worked in
failures because of the 1.5 percent
agranulocytosis. That study could be done. You
might even think about whether it is something that
ought to be done, but it has not been done. The
mere fact that people given a second drug after
failing the first respond to it tells you nothing
at all. We have many examples where drugs don't
particularly work in non-responders to other
therapy but the second time around the people do
better. So, I just want to make it clear they have
not shown that. It might be true. It is plausible
even but it hasn't been shown.
DR. PINE: Can I ask a question about
that? Of course, there have been other medications
that have been discussed over the last couple of
years for new indications for ADHD and I am sure
that that issue came up. I think that those
studies have not been done and what was the
thinking and discussion around that?
DR. TEMPLE: Well, they are almost never
done. We don't usually have a reason to say, for
example, only use this drug in people who have
failed on other therapy, if one thought that was an
appropriate thing because I am not saying you
should or not--you are going to get to that. I am
just making the point that they have not documented
in a rigorous way that the drug would actually work
in those people. You might think that there is a
little evidence that it does, and you might think
the pharmacology difference suggests that it might,
all of which I agree with but that hasn't been
studied and it can be studied, and it never is
studied.
DR. PINE: For what it is worth, my take
on it would be that that would only be one of the
potential uses of the medicine clinically, and it
seems like some of the other issues are, you know,
kind of bigger in terms of thinking about the
medicine as opposed to, you know, is it primarily
for people who don't respond to stimulants.
DR. REESE: We are going to get to
everyone's questions. First we are going to have
Dr. Bronstein and then we will have Dr. Wang.
Thank you.
MS. BRONSTEIN: My question is a fairly
straightforward, easy one. On slide 93, in the
Phase 3 study you have one person who had a severe
event and withdrew from the study. What kind of
rash was this?
DR. RUSSELL: Unfortunately, the only
description on the case report form, which reflects
the source documents, is just a verbatim of rash so
I am unable to describe it further for you.
MS. BRONSTEIN: We can assume though that
it was severe.
DR. RUSSELL: It certainly led to
discontinuation of the drug. That is all the
information I can give you.
MS. BRONSTEIN: Thank you.
DR. REESE: Ms. Dokken?
MS. DOKKEN: Yes, I apologize, I thought
we were supposed to hold our questions until the
end so my question really goes back to slides 30
and 31 and this issue of the 40 percent who are
non-responders or had intolerable side effects. I
am wondering whether anyone can sort of unpack, you
know, how many people are in which category because
it seems to me that what we have been hearing is
that one of the marketing messages for modafinil
will be that it is an alternative. If it is an
alternative and we are talking about whatever
percentage of that 40 percent are ones who suffered
"intolerable" side effects, certainly this
particular drug--and those of us who were fortunate
or unfortunate enough to be present yesterday, you
know, the side effects are present in almost all.
Then that leads me to the worry about the next step
which is, you know, if it were approved how is it
marketed and what are the messages because probably
it was the Pediatric Advisory Committee that has
seen, you know, other situations where something is
marketed as being free of something else,
suggesting that there are no risks and to say that
because it is a non-stimulant it has no risk would
be a concern for me.
DR. TEMPLE: Drug advertising reports to
me so I have to worry about this. We are fairly
careful about making claims when you don't have a
direct comparison and there aren't any direct
comparisons. However, if one is scheduled at a
different place, or something like that, that is
true and they would be allowed to claim that.
There are some cases in which the
difference in certain side effects is so
obvious--like it never happens with this and it
happens all the time--where we might allow
something like that. But we are very careful about
comparisons in the absence of actual comparative
data across study comparisons and treat it with
suspicion.
DR. REESE: Dr. Pfeffer?
DR. PFEFFER: Thank you. I am not
questioning the efficacy but I have some questions
on slides 52, 53 and 54, please. Maybe you can
help us understand the longitudinal process of the
three studies. For example, it looks as if in
slide 52 I guess efficacy was being demonstrated by
week 5. Then in slide 53 and 54 it seems that it
was earlier, although on slide 53 at week 5 there
was perhaps less of that. I don't know if that is
due to dropouts and then resumption.
So, my question is on the early phase of
these, week 3 and even week 2 on slide 54, what
were the general doses that the children were on at
that point in time? Then, if you can tell us what
happened in week 5, on slide 53? Finally, if you
could tell us a little bit about when were blood
tests taken in the process of the study and when
did the side effects emerge, especially skin
reactions, etc.? I am trying to link the time
course with the doses and the longitudinal course.
DR. RUSSELL: In study 10, which is the
slide up here, this is the fixed dose study so that
by the second week patients would have been
titrated to that target dose. That would have
occurred by day 7 for those randomized to 340 and
day 9 respectively.
DR. PFEFFER: I thought I understood that
but my concern is if, in slide 53 and 54, you see
earlier efficacy is that at the target dose or less
than the target dose?
DR. RUSSELL: In this study, which is the
fixed dose study, they would have been at target
dose.
Could you go back to the previous slide
for 311, please? This is one of the flexible dose
titration studies. So, in the earlier weeks they
would have still been titrating up.
DR. PFEFFER: Do you know approximately
the average doses at the early phase?
DR. RUSSELL: Probably around 255 mg by
the second week and up to the 340 mg by the fourth
| week. | |||
|---|---|---|---|
| DR. PFEFFER: | And on slide 54 it is | ||
| similar. | Is that right? | ||
| DR. RUSSELL: | Slide 54, which I think is | ||
study 310, is where they titrated up more quickly
so they would have been at target dose by day 7 and
9 respectively.
DR. REESE: Dr. Armenteros and then Dr.
Malone?
DR. ARMENTEROS: Just to follow-up a
little bit on the dosing question, I understand the
model that you used to dose the two groups of
children, you know, below 30 kg and above. Now,
most of the children that got into the study were
above 30 kg, like 68 percent that you mention here.
Now, when you presented data on efficacy there
wasn't a differential response between these two
groups by weight.
The reason that I ask that question is
that we already know from your previous studies
that at lower doses you do get response for daytime
sleepiness, and so forth. So, I don't know if we
may be missing perhaps different points in dosing
at which these kids may respond. Because at the
end of the trial I come out with a very fuzzy
impression of what the actual dosing should be and
I hope I can get a better understanding.
DR. RUSSELL: First let me answer the
excessive sleepiness programs first because what we
do find is a very different pharmacodynamic
response when we are treating excessive sleepiness
than when we are treating ADHD. So, in the
excessive sleepiness programs and the pediatric
narcolepsy, although we looked at doses of 100 mg
through 400 mg, doses of 400 mg were clearly
efficacious in that model. Then we did some PK/PD
work and the target exposure needed for an effect
in narcolepsy is substantially lower than the
target plasma exposure associated with effect in
ADHD--so very different pharmacodynamic response
which I don't think I can explain, but it is very
different.
In terms of looking at the doses and how
did they respond to efficacy, what we did was to
look at the different quartiles of dosing and in
the third and fourth dosing quartiles, which are
the higher dose groups, you see numerically a
slightly higher response but it is only a point or
two. So, I would say that the dose response, with
all the caveats because we were titrating to a
target dose, is flat in the doses that we looked at
here.
DR. REESE: Dr. Malone?
DR. MALONE: I have two questions. One is
on efficacy. The stimulants wear off every day by
the end of the day. Is that true for this drug? I
am just wondering if it is like the stimulants,
that you have to dose it every day; you dose it in
the morning and then it wears off by the evening.
DR. RUSSELL: The only data we have with
respect to that is actually in the 2-week
withdrawal period where the patients who had
received modafinil during the double-blind
treatment period were randomized to either stay on
modafinil or were randomized to receive placebo.
What we see is not an immediate return to baseline
in symptoms but a more gradual return towards
baseline and their symptoms. So, based on the
limitations of that data which I acknowledge here,
there doesn't appear to be a sort of complete
rebound effect.
DR. REESE: Dr. Bigby?
DR. BIGBY: I have a question about the
ADHD rating scale. If you gave this test to a
group of normal kids who don't have ADHD, what
would their score be?
DR. RUSSELL: The average for a 10
year-old boy I think is 18.8, and the children
going into our study had an average of around 37.
So, they were clearly much higher than what would
be considered to be normative for a 10 year-old
boy, which was the average population in our study.
It does differ a little bit based on whether you
are a boy or a girl or your age, but that appears
to be the average for a 10 year-old boy.
DR. GOODMAN: Dr. Temple?
DR. TEMPLE: In one of the studies you
actually did a withdrawal phase but I believe the
data weren't shown.
DR. RUSSELL: That is right.
DR. TEMPLE: You must have a slide of it.
That would answer the question of how soon it wears
| off. | ||
|---|---|---|
| DR. RUSSELL: | If I could have the slide, | |
| please? | ||
| [Slide] | ||
This is over the 2-week withdrawal period.
You can see on the right-hand side that the placebo
at the end of the 7-week period and the end of the
9-week period obviously stays the same. In the
modafinil group there is a point difference, but
for those who were on modafinil and then got
changed to placebo you can see that there is a
beginning of deterioration of their symptoms over
that 2-week period. It is not huge but there is a
deterioration and it looks like they are returning
towards baseline. But there doesn't appear to be a
sort of instantaneous effect.
DR. TEMPLE: And you don't have it day by
day or anything like that?
DR. RUSSELL: Unfortunately, we don't.
DR. REESE: Dr. Malone, your second
question and then Dr. Rappley.
DR. MALONE: It was really I guess partly
answered. It had to do with the abuse potential
for modafinil. I think, from the reading, it did
say that it can cause euphoria and that animals
would work for this drug. If that is true, I just
have a question why would a stimulant be a Class II
and this a Class IV? How do they decide that?
DR. GOODMAN: Dr. Temple or Dr. Laughren?
I have a very similar question about the
classification. Currently this drug is classified
Schedule IV compared to the stimulants which are
Schedule II. Could you just explain that
distinction? It would be in the context of a quick
follow-up I was going to do and ask sponsor how
they would best characterize or classify their
compound.
DR. LAUGHREN: Actually, FDA doesn't
decide that classification. The decision is made
by the Drug Enforcement Administration. They do an
8-factor analysis. I haven't looked at that.
Maybe the company could respond to, you know, how
it is that the DEA arrived at a Class IV rather
than a Class II.
DR. TEMPLE: There is a very sharp
distinction between the level of control. I think
we are about to hear about that. II is, you know,
locked cabinets and all the rest; IV is much less.
| DR. GOODMAN: | Yes, please, could we hear |
| about that? | |
| DR. RUSSELL: | The difference between a |
Schedule II and a Schedule IV, is that what you are
asking?
DR. LAUGHREN: How it got a Schedule IV
rather than a Schedule II.
DR. RUSSELL: I wasn't with the
organization at the time of the original
scheduling. Perhaps I could ask Dr. Vaught, who
was here, to explain how that happened.
DR. VAUGHT: Good morning. My name is Dr.
Jeff Vaught, executive vice president for research
and development for Cephalon.
[Slide]
I would like to very briefly just go over
the aspects of scheduling which, certainly the
agency knows as well as I do, has to do not only
with the physical chemical characteristics of the
compound but also testing that is done in human
beings to suggest that there is a reinforcing
property. So, if we look at the overall physical
chemical activity of modafinil, it has very, very
low water solubility which is incompatible with
intravenous injection. It is very unstable at high
temperature, therefore, it is incompatible with
smoking. Importantly, it is structurally unrelated
to other agents that are known to be abused. While
it does have a very, very weak--and it is really
the only neurochemical effect that we have been
able to demonstrate in blood receptor binding
assays, etc.--with dopamine. It doesn't appear to
cause elevations of dopamine of nucleus accumbens,
which is markedly related to drugs of abuse, as
well, it has not releasing properties as do other
Schedule II stimulants. There is also lack of
activation, as I mentioned, of reward centers, and
really the results, as Dr. Dackis described to you,
from preclinical studies suggest that if there is a
signal it is very, very weak.
Now, all this is theoretical because that
is all nonclinical data. Perhaps more importantly
and something that we undertook at Cephalon
spontaneously, is a postmarketing surveillance,
starting in 1999 with the Haight Ashbury group.
The Haight Ashbury group monitors a variety of
areas worldwide where drugs may be diverted to,
including rave scenes, medical professionals, etc.
Now that we have had six years we still have
reporting on this. There have been limited to no
reports of euphoric effects. There are no reports
of reinforcing effects. There has been a very
large increase since the drug has been approved for
wakefulness for mainstream publicity regarding the
use of modafinil, including in The New Yorker
magazine, college newspapers, etc., and across the
Internet every now and then we will see postings of
potential use but nothing that is consistent. In
fact, the Haight Ashbury concludes after evaluating
this for the last six or seven years that if there
is abuse potential for modafinil at all, it is
very, very low.
So, all of this is consistent with what is
seen as an agent with low abuse potential. We now
have considerably more experience with the
substance than we did five or six years ago when we
were getting approval and we thought that was
consistent with the regulatory standards for
Schedule IV.
DR. GOODMAN: Thank you. Apart from how
DEA will classify your drug, how would you
internally classify it? Would you say it is a
stimulant or is it distinct based upon its
mechanism of action, which I understand is unknown.
Although I know at one time it was thought to be
mediated through orexin receptors, I guess that is
not as firmly established at this point.
The reason I ask is not just a semantic
question but whether it gets counted or considered
a stimulant may have labeling implications. As
revealed by discussions yesterday, for example,
Strattera, should that be considered a stimulant
and, if so, should it have certain warnings
attached to it that go with the rest of the class
of stimulants? So, I would just like the sponsor's
perspective on whether you would classify this
medication as a stimulant or not.
DR. VAUGHT: We approach this from a
couple of levels. One is the preclinical data that
we have, as well as the clinical information. In
direct answer to your question, I would not
classify it as a traditional sympathomimetic
stimulant. It is a CNS activating agent and we
have all been taught, prior to the introduction of
modafinil, that, in fact, most of our CNS
activators are psychostimulants. Nonclinically,
modafinil has a profile of wake-promoting activity
that, unlike the classical stimulants--its
wake-promoting activities are not blocked by
haloperidol which has been characteristic of wake,
if you will.
As far as the orexin component that is
involved, we have been able to demonstrate it has
no interaction with the orexin system because in
knock-out animals, as well as human beings and dogs
it is highly effective. When we move to human
beings, we similarly don't see the typical types of
profile that one sees with the stimulant
population. If we include this with
methylphenidate and amphetamines this includes
sympathomimetic-like effects as well as generalized
excitation reinforcing properties, euphoric
effects, etc. So, overall the pharmacology would
suggest that if we want to classify it as CNS
activating agent it is certainly a non-traditional
agent.
DR. GOODMAN: Would you say that it has
less peripheral--if you look at the relationship
between CNS, there is relatively more CNS to
peripheral activation?
DR. VAUGHT: Yes.