1 SPARLON™ (modafinil) Tablets [C-IV] Psychopharmacologic Drugs Advisory Committee 23 March 2006.
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Transcript of 1 SPARLON™ (modafinil) Tablets [C-IV] Psychopharmacologic Drugs Advisory Committee 23 March 2006.
1
SPARLON™ (modafinil) Tablets [C-IV]
Psychopharmacologic Drugs Advisory Committee
23 March 2006
2
Introduction
Victor Raczkowski, M.D., M.S.
VP, Worldwide Regulatory Affairs
Cephalon, Inc.
3
SPARLON Tablets
Proposed Indication Treatment of Attention Deficit Hyperactivity Disorder
(ADHD) in children and adolescents
Regulatory Status– Filing: 20 Dec 2004 – Approvable Letter: 20 Oct 2005– Complete response: 21 Nov 2005
4
SPARLON Formulation
Modafinil is the active ingredient in SPARLON, the same as in PROVIGIL® Tablets
Smaller than PROVIGIL Tablets and film-coated
Dosage strengths of 85, 170, 255, 340, & 425 mg
5
PROVIGIL® (modafinil) Tablets [C-IV]
Marketed in the US since 1999 and in 28 countries worldwide
US approval in adults with excessive sleepiness:– narcolepsy– obstructive sleep apnea / hypopnea syndrome– shift work sleep disorder
Exposure: 780,000 patient-treatment years– Adults: 750,000 patient-treatment years– Pediatrics: 30,000 patient-treatment years
Modafinil: Schedule IV of the Controlled Substances Act
6
Overview
SPARLON has been shown to be effective for the treatment of ADHD in pediatric patients
SPARLON has been shown to be acceptably safe in the treatment of ADHD in pediatric patients
The Benefit-Risk profile of SPARLON in the treatment of ADHD in pediatric patients is favorable
7
Modafinil and Pediatric Stevens Johnson Syndrome (SJS)
Pediatric Clinical Trials– 1 case of probable SJS– Uncertain etiology– 1622 patients
Pediatric Postmarketing Experience– No cases– 30,000 pediatric patient-treatment years
8
Agenda
Introduction Victor Raczkowski, M.D.
Overview of ADHD Joseph Biederman, M.D.
Clinical Pharmacology and Efficacy
Lesley Russell, M.R.C.P.
Safety Review Srdjan Stankovic, M.D.
Benefit-Risk & Conclusions Lesley Russell, M.R.C.P.
9
Consultants
Psychiatry/ADHD– Joseph Biederman, M.D.*– Samuel Boellner, M.D.*– Thomas Spencer, M.D.*– Sharon Wigal, Ph.D.*
Dermatology– Amy Paller, M.D.– Neil Shear, M.D.
Addiction Medicine– Charles Dackis, M.D.
Cardiology– Craig Pratt, M.D.– Jonathan Sackner-Bernstein, M.D.
Child Development– Thomas Rugino, M.D.*– James Swanson, Ph.D.*
Epidemiology– Greg Burkhart, M.D.– John Clark, M.D.– Joel Gelfand, M.D.
*Investigator in ADHD Clinical Studies
10
ADHD as a Lifelong Brain Disorder of Genetic Etiology and Poor Prognosis
Joseph Biederman, M.D.
Professor of Psychiatry, Massachusetts General Hospital and Harvard
Medical School
11
ADHD:Etiology
ADHD is a heterogeneous behavioral disorder with multiple possible etiologies
ADHD
NeuroanatomicNeurochemical
CNS insults
Genetic origins
Environmental factors
12
ADHD:Worldwide Prevalence in School Age Children
0% 5% 10%
Netherlands, 2000
Brazil, 1999
USA, 1996
Spain, 1995
Switzerland, 1998
United Kingdom, 1991
Ontario, 1989
New Zealand, 1987
Puerto Rico, 1988
Ireland, 1991
Germany, 1990
DSM-IV
DSM-III-R
DSM-III
ICD-9
Site, Year
Criteria
Prevalence
Faraone et al (2003). World Psychiatry, 2, 104-113
13
Developmental Trajectories of Brain Volume Abnormalities in Youth w/ADHD
Design: MRI case control study
N=152 youth w/ ADHD and 139 controls of both genders
Objective: assess volumetric changes overtime in medicated vs unmedicated youth w/ADHD and controls
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8
14
Developmental Trajectories of Brain Volume Abnormalities in Youth w/ADHD
Main Findings: – Smaller brain volumes in all regions independently of
medication status– Smaller total cerebral (-3.2%) and cerebellar (-3.5%)
volumes – Volumetric abnormalities (except caudate) persisted
with age – No gender differences– Volumetric findings correlated with severity of ADHD
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8
15
Developmental Trajectories of Brain Volumes
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8From: http://www.nimh.nih.gov/events/pradhdmri.cfm
105 2015850
950
1050
1150
Age (y)
mL
NV MalesADHD MalesNV FemalesADHD Females
16
Developmental Trajectories of Brain Volume Abnormalities in Youth w/ADHD
Conclusions: – Genetic and or early environmental influences on brain
development in ADHD are fixed, nonprogressive and unrelated to stimulant treatment
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8
17
ADHD:Neurobiologic Basis
Alerting
Executive Control
Orienting (Selective Attention)
Posner and Raichle. Images of Mind. Scientific American Books; 1996.
Attention Networks
18
Smaller Dorsal and Rostral ACC in ADHD
Seidman et al.Seidman et al.
19
Cortical Volume
Cortical Thickness
Cerebral Cortex
Vogt, 2005Vogt, 2005
20
•Dorsolateral Frontal Cortex (BA 8, 9)
•Supramarginal Gyrus
(BA 40)
•Superior Temporal Gyrus
(BA 22)
•Anterior Cingulate Gyrus (BA 24) •Angular Gyrus
(BA 39)
•Middle Temporal Gyrus
(BA 21)
21
Anterior Cingulate (ACG) gyrus white matter fractional anisotropy (FA) decrease in adults with ADHD. Alteration of anatomic connections is suggested on the perigenual and dorsal (dACG) anterior cingulate white matter region in adults with ADHD
dACG white matter
Perigenual ACG white matter
Corpus callosum(body)
Corpus callosum(genu)
Diffusion Tensor MRIDiffusion Tensor MRI Fractional Anisotropy (FA) differences between normal controls and adults Fractional Anisotropy (FA) differences between normal controls and adults with ADHD overlayed onto a parasagittal T2 anatomical templatewith ADHD overlayed onto a parasagittal T2 anatomical template
22MGH-NMR Center & Harvard- MIT CITPMGH-NMR Center & Harvard- MIT CITP Bush et al, Bush et al, Biological PsychiatryBiological Psychiatry 1999 1999
1 x 10-3
1 x 10-2
y = +21 mm
Normal ControlsNormal Controls
1 x 10-2
1 x 10-3
y = +21 mm
ADHDADHD
Dorsal Anterior Cingulate Cortex (Cognitive Division) Fails to Activate in ADHD
23
Directed AttentionDirected Attention FascinationFascination
Executive circuitExecutive circuit
Inhibitory deficitsInhibitory deficits Executive dysfunctionExecutive dysfunction
Executive circuitExecutive circuit
Inhibitory deficitsInhibitory deficits Executive dysfunctionExecutive dysfunction
Reward circuitReward circuit
Reduce time to rewardReduce time to reward Delay aversionDelay aversion
Reward circuitReward circuit
Reduce time to rewardReduce time to reward Delay aversionDelay aversion
ADHD
Toward a Dual Pathway Model
Sonuga-Barke. Neurosci Biobehav Rev. 2003;27:593.
24
GeneticBasis
of ADHD
ADHD: Genetics
Twin Studies Family Studies
Adoption Studies Molecular Genetics
Schizophrenia HeightPanic Disorder
Mean Heritability=.77
26
ADHD:Molecular Genetics
Specific genes associated with ADHD– rare mutations in the human thyroid
receptor- gene on chromosome 3– dopamine transporter gene (DAT1) on
chromosome 5– dopamine receptor D4 gene (DRD4) on
chromosome 11
Hauser et al. N Engl J Med 1993;328:997.Gill et al. Mol Psychiatry 1997;2:311.Swanson et al. Mol Psychiatry 1998;3:38.
27nida.gov
28
Pooled Odds Ratios from Positive Meta Analyses
(Faraone et al., Biological Psychiatry, in press)
29
ADHD: MTA Results
• Behavioral treatment alone • Community based treatment
All treatment arms found to be effective on an absolute basis
Nearly equally effective and superior to both:
Medication management alone
Medication management + behavioral treatment
MTA Study Group, Arch Gen Psych, 1999 Dec;56(12):1073-86
30
Long-Term Outcomes of Therapies for ADHD in the MTA Study
Hyperactive Impulsive Symptoms (Teacher Reports)
0
10
20
30
40
50
60
70
Medicationmanagement
Combinationtherapy
(medication +behavior therapy)
Behavioraltreatment
Community-basedtreatment
Impr
ovem
ent a
t 14
mon
ths
(%)
56%60%
45%
36%
31
Why Non-Stimulant Treatments For ADHD?
Problems with the stimulants
Scheduled II drugs (abuse liability, diversion, medico-legal concerns)
30% - 40% do not adequately respond or cannot tolerate stimulant treatment
Side effect profile adversely impacting sleep, appetite, mood and anxiety
Concerns about growth suppression and tic development
32
ADHDMotor Vehicle Driving
Study of 16 to 22 year olds – 35 with ADHD (not on medication)– 36 controls
Significantly more drivers with ADHD– drove without a license– had licenses revoked or suspended– had multiple crashes (2+)– had multiple traffic citations (3+), especially for
speeding
Barkley et al. Pediatrics 1993;92:212.
Subgroups of ADHD with comorbid oppositional defiant or conduct disorder were at highest risk
33
Parent stress
Family conflict
Accidents and injuries
Smoking and substance abuse
Legal difficulties
Poor peer relationships
School failure
Psychiatric comorbidity
ADHD:Impairment in ADHD
34
ADHD Etiology and Impact Summary
ADHD is a neurobehavioral disorder with a– complex etiology– neurobiologic basis– strong genetic component
ADHD – affects millions of people of both genders– persists through adolescence and adulthood in a high
percentage of cases– can have negative impact on multiple areas of
functioning– Although stimulants are highly effective in the
treatment of ADHD, 30%-40% of patients do not improve of or cannot tolerate them
35
Clinical Pharmacology and Efficacy
Lesley Russell, MRCP
Senior VP, Clinical Research
Cephalon, Inc.
36
Pediatric ADHD Development Program
Study 113 (BA)n=24
Study 113 (BA)n=24
Study 213(POP)n=248
Study 213(POP)n=248
Study 207(DR)n=47
Study 207(DR)n=47
Study 206 (PK/DR)
n=20
Study 206 (PK/DR)
n=20
Study 312 (OL, EXT)
n=533
Study 312 (OL, EXT)
n=533
Study 310 (DB,PC) n=189
Study 310 (DB,PC) n=189
Study 309 (DB,PC) n=198
Study 309 (DB,PC) n=198
Phase 1 Phase 2 Phase 3 Phase 3BsNDAsNDA
Study 311 (DB,PC)n=246
Study 311 (DB,PC)n=246
Study 3044 (OL)
n=303
Study 3044 (OL)
n=303
37
Clinical Pharmacology
38
Modafinil Pharmacokinetics:Children/AdolescentsDose proportional over the studied dose rangeAbsorption
– Tmax 2-3 hours – 1 hr delay with foodDistribution
– V/F increases linearly with weightMetabolism
– Primarily by liver (<10% excreted unchanged in urine) Two primary metabolites; modafinil acid and modafinil sulfone
– Higher levels of modafinil sulfone in younger childrenElimination
– Time and age dependent Clearance changes over time
– steady-state reached by week 6 Decrease in clearance gradual with pronounced shift between 9 to 11
years t½ 7 hours in younger children; t½ 15 hours in adults
39
Dose Selection
40
Phase 2 ADHD (Study 207) ADHD Rating Scale (Home Version)
Double-blind, randomized, four period, crossover study (N=48)
Totalmean (SD)
Baseline 37.8 (9.54)
Placebo 32.5 (13.67)
100 mg 32.2 (13.69)
200 mg 29 (15.50)300/400 26.5
(13.89)
41
Phase 2 ADHD (Study 213) QD vs. BID Dosing of 300 mg/day
-8.6
-6.2
-11.3
-12
-10
-8
-6
-4
-2
0
All <30 ≥30
300/0 mg
-8.6
-12
-10
-8
-6
-4
-2
0
Ch
an
ge
fro
m b
as
elin
e t
o e
nd
po
int
AD
HD
-RS
(To
tal S
co
re)
300/0200/100100/200placebo
42
Identification of Target Systemic Exposure
Weight and Dose Groups
AU
C μ
g •
hr/
mL
>30 kg, 300 mg <30 kg, 300 mg >30 kg, 200+200 mg
200
150
100
118
146
130
43
PK/PD Modeling
Estimated systemic exposure associated with PD response– 150 μg•hr/mL
Estimated doses – 340 mg <30 kg– 425 mg ≥ 30 kg
44Includes patients receiving 340 mg (< 30 kg) and patients receiving 425 mg (≥ 30 kg)
Systemic Exposure Following Administration of modafinil up to 21 Weeks (Phase 3 Studies)
N=42
149.9
N=177
153.5
Dose
AU
C μ
g •
hr/
mL
340 mg 425 mg
350
150
100
300
250
200
50
45
Pivotal Efficacy Studies
Study # Study 309 Study 311 Study 310
Duration 9 weeks 9 weeks 7 weeks + 2 weeks withdrawal period
Design DB, PC, PG, flex-dose
DB, PC, PG, flex-dose
DB, PC, PG, fixed-dose
Patients 198131 (Modafinil)
246164 (Modafinil)
189125 (Modafinil)
Dose 170-425 mg 170-425 mg 340 mg (<30kg)425 mg (≥30kg)
Titration Wk1 (170-mg) 85 mg inc q7day
titrate according to efficacy and tolerability
Wk1 (170-mg) 85 mg inc q7day
titrate according to efficacy and tolerability
85 mg inc q2day
340 mg (<30kg) - D7425 mg (≥30kg) - D9
46
Patient Population
KeyInclusions
• 6–17 years• Diagnostic and Statistical Manual of Mental Disorders,
4th ed. (DSM-IV) criteria for ADHD • At least moderately ill (CGI-S ≥4)• ADHD RS-IV (School Version) total and/or subscale
scores ≥1.5 SD above age/gender norm• Normal intelligence; no learning disability• Attending school full-time
KeyExclusions
• Failure to respond to 2 or more adequate courses (dose and duration) of stimulant therapy (1 stimulant failure permitted)
• Psychiatric comorbidities requiring pharmacotherapy• Well controlled with current ADHD therapy
47
Efficacy AssessmentsPrimary
Evaluator
Primary School ADHD Rating Scale-IV (ADHD RS-IV) Total Score
Teacher
Secondary School ADHD RS-IV Hyperactivity/impulsivity, Inattention Subscales
Teacher
Home ADHD RS-IV Total Score, Hyperactivity/impulsivity, Inattention Subscales
Parent
Clinical Global Impression of Change (CGI-C) Physician
Conners’ Parent Rating Scale: Revised Short Form (CPRS:R-S)
Parent
Test of Variables of Attention (TOVA) CPT
Social Skills Rating Scale (SSRS) Parent
Child Health Questionnaire (CHQ) Parent
48
Baseline Demographics
309 N=198
311N=246
310N=189
Total N=633
Age<12 yrs, n (%)
9.9136 (69)
10.3156 (63)
10.0129 (68)
10.1 421 (67)
Sex, male, n (%)
144 (73) 174 (71) 135 (71) 453 (72)
Race,white, n (%) 142 (72) 190 (77) 151 (80) 483 (76)
Weight,≥30 kg, n (%)
40.1 134 (68)
42.9 175 (71)
40.3121 (64)
41.1430 (68)
Height, (cm) 141.8 144.2 141.7 142.6
49
Baseline Disease Characteristics
309 (N=198)
311 (N=246)
310 (N=189)
Total (N=633)
Clinical Global Impression – Severity, n (%)
Moderate 76 (38) 115 (47) 117 (62) 308 (48)
Marked 87 (44) 93 (38) 55 (29) 235 (37)
Severe 34 (17) 38 (15) 17 (9) 89 (14)
Current ADHD Subtype, n (%)
Combined 139 (70) 145 (59) 126 (67) 410 (64)
Inattentive 47 (24) 94 (38) 51 (27) 192 (30)
Hyperactive 10 (5) 7 (3) 10 (5) 27 (4)
Baseline ADHD-RS-IV Total Score
School 38.5 35.7 37.4 37.2
Home 40.8 37.4 38.8 39.0
50
Patient Disposition
Number (%) of Patients
Modafinil Placebo Total
Randomized 423 (100) 215 (100) 638 (100)
Treated 420 (99) 213 (99) 633 (99)
Completed double-blind 277 (65) 114 (53) 391 (61)
Lack of efficacy 67 (16) 73 (34) 140 (22)
Adverse event 21 (5) 7 (3) 28 (4)
Consent withdrawn 17 (4) 11 (5) 28 (4)
Lost to follow-up 12 (3) 1 (<1) 13 (2)
Other 29 (7) 9 (4) 38 (6)* Based on study termination CRF. Two additional patients experienced adverse events for which drug was discontinued.
51
Primary Outcome: School ADHD-RS – Study 309
*p<0.05 (change from baseline vs placebo) EP = Endpoint (LOCF)
15
20
25
30
35
40
45
BL 1 2 3 5 7 9 EP
***
*
AD
HD
-RS
(Tota
l S
core
)
ModafinilPlacebo
Weeks
52
15
20
25
30
35
40
45
BL 1 2 3 5 7 9 EP
Primary Outcome: School ADHD-RS – Study 311
ModafinilPlacebo
*p<0.05 (change from baseline vs placebo) EP = Endpoint (LOCF)
AD
HD
-RS
(Tota
l S
core
)
***
*
*
*
Weeks
53
Primary Outcome: School ADHD-RS – Study 310
15
20
25
30
35
40
45
BL 1 2 3 5 7 EP
*
* *
*
**
ModafinilPlacebo
Weeks
*p<0.05 (change from baseline vs placebo) EP = Endpoint (LOCF)
AD
HD
-RS
(Tota
l S
core
)
54
Phase 3 ADHD Primary EndpointADHD-RS-IV (School Version)
0
10
20
30
40
50
Modafinil Placebo
AD
HD
-RS
(T
ota
l Sco
re)
309
309
309
309
310
310
310
311
311
311
310
311
Normative data for 10 y/o male (school version)
Baseline Endpoint
55
School ADHD-RS-IV Responders≥30% Reduction from BL to EP
0
10
20
30
40
50
60
70
80
Resp
on
ders
(%
)
309 310
0
10
20
30
40
50
60
70
80
311 309 310311
88/127
26/65
105/162
28/81
78/119
24/62
61/127
13/65
58/162
12/81
71/119
15/62
≥50% Reduction from BL to EP
**
* **
*p<0.05 vs placebo
*
Study StudyModafinilPlacebo
56
15
20
25
30
35
40
45
BL 1 2 3 5 7 9 EP
Study 309
AD
HD
-RS (
Tota
l Sco
re)
*
* ** *
*
Weeks:
Home ADHD-RS
15
20
25
30
35
40
45
BL 1 2 3 5 7 9 EPWeeks:
Study 311
AD
HD
-RS (
Tota
l Sco
re)
*
**
* *
*
15
20
25
30
35
40
45
BL 1 2 3 5 7 EP
Study 310
AD
HD
-RS (
Tota
l Sco
re)
**
**
**
Weeks:*p<0.05 for change from baseline vs placebo
ModafinilPlacebo
57
CGI Improvement: Responders (Patients Much Improved or Very Much Improved)
0
10
20
30
40
50
60
70
80
1 2 3 5 7 9 EP
0
10
20
30
40
50
60
70
80
1 2 3 5 7 9 EP
Study 311Study 309
Weeks
Re
sp
on
de
rs (
%)
* *
* **
*
*
Weeks
Re
sp
on
de
rs (
%)
**
** *
*
*
Weeks
0
10
20
30
40
50
60
70
80
1 2 3 5 7 EP
Study 310
Re
sp
on
de
rs (
%)
**
* *
*
*
*p<0.05 vs placebo
ModafinilPlacebo
58
Conners’ Parent Rating Scale
*p<0.05 vs placebo
-18-16-14-12-10-8-6-4-20
OppositionalBehavior
CognitiveProblems/Inattention
Hyperactivity ADHDIndex
Study 309
-18-16-14-12-10-8-6-4-20
OppositionalBehavior
CognitiveProblems/Inattention
Hyperactivity ADHDIndex
** * -18
-16-14-12-10-8-6-4-20
OppositionalBehavior
CognitiveProblems/Inattention
Hyperactivity ADHDIndex
*
Study 311
**
*
Mean s
core
ch
ang
e f
rom
base
line
Mean s
core
ch
ange f
rom
base
line
*
Study 310
**
Mean s
core
ch
ang
e f
rom
base
line
ModafinilPlacebo
59
TOVA Results
* p<0.05 vs placeboNS=not significant
EP: Last observation carried forwardPositive value changes denote improvement
Modafinil (n=411) Placebo (n=210)
*
Mea
n (±
SE
M)
RT
(m
sec)
Cha
nge
Fro
m B
asel
ine
Mea
n (±
SE
M)
Sco
reC
hang
e F
rom
Bas
elin
e
**
NS
-0.2
0.7
-0.3
0.7
-1.2
-0.4
-1.5
-1.0
-0.5
0.0
0.5
1.0
OmissionErrors
CommissionErrors
ADHDScore
-0.7-0.8
-2.0
-1.5
-1.0
-0.5
0.0
ResponseTime
60
Social Skills Rating ScaleSocial Skills Subscale
EP: LOCF
Mea
n (±
SE
M)
Sco
reC
hang
e F
rom
Bas
elin
e
Imp
rove
men
t
Elementary school version: Grades K-6
1.7
0.7
1.42.1
6.0
0.1
1.30.80.8
2.9
0
1
2
3
4
5
6
7
Cooperation Assertion Responsibility Self Control Social SkillsTotal
Modafinil (n=300) Placebo (n=151)
61
Social Skills Rating Scale Problem Behaviors Subscale
Mea
n (
±SE
M)
Sco
reC
han
ge
Fro
m B
asel
ine
Imp
rove
men
t
-4.8
-2.1
-1.4-1.2
-0.5 -0.7
-1.9
-0.7
-6
-5
-4
-3
-2
-1
0
Externalization Internalization Hyperactivity ProblemBehavior Total
Modafinil (n=300) Placebo (n=151)
EP: LOCFElementary school version: Grades K-6
62
Child Health Questionnaire
15.114.0
10.9
8.2 7.47.8
3.7
5.64.9
2.6
02468
101214161820
Role–Emotional/Behavioral
Behavior GlobalBehavior
MentalHealth
SelfEsteem
Mea
n (±
SE
M)
Sco
reC
hang
e F
rom
Bas
elin
e
EP: Last observation carried forward
No significant improvements in physical functioning domain – baseline values normal
Imp
rove
men
t
Modafinil (n=411) Placebo (n=210)
Andrew E Stein:
SPARLON to modafinil
Andrew E Stein:
SPARLON to modafinil
63
Child Health Questionnaire
No significant improvements in physical functioning domain – baseline values normal
Mea
n (±
SE
M)
Sco
reC
hang
e F
rom
Bas
elin
e
Imp
rove
men
t
EP: Last observation carried forward
6.68.0
12.1
2.8
7.9
1.32.7
3.5
1.9 3.1
0
2
4
6
8
10
12
14
16
ParentImpact–
Emotional
ParentImpact–
Time
FamilyActivities
FamilyCohesion
PsychosocialSummary
Modafinil (n=411) Placebo (n=210)
Andrew E Stein:
SPARLON to modafinil
Andrew E Stein:
SPARLON to modafinil
64
Previously Stimulant Treated Patients vs Stimulant Naïve Patients
* p<0.05 vs placebo
Me
an
sco
re
cha
nge
from
ba
selin
e
School ADHD total score
With Stimulants
Without Stimulants
Home ADHD total score
With Stimulants
Without Stimulants
-22
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
-22
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
* **
188 107 220 101189 108 221 102
ModafinilPlacebo
*
65
Efficacy Conclusions
Consistent efficacy results across three pivotal studies
Improvement of ADHD symptoms as evaluated by teachers, parents and physicians
Improvement seen at school, home, and across the day
Improvement in core ADHD symptoms/behaviors as well as other psychosocial domains
Efficacy in treatment naïve patients and in patients with prior stimulant experience
66
Safety
Srdjan Stankovic, M.D.
VP Neuroscience, Clinical Research
Cephalon, Inc.
67
Review of Safety
Modafinil exposure in clinical studies
ADHD studies in children and adolescents– General safety– Skin reactions– Psychiatric events
Pediatric studies in excessive sleepiness
Postmarketing experience
68
Modafinil Exposure in Clinical TrialsPlacebo-controlled Trials All Trials
Modafinil Placebo Modafinil
ADHD pediatric trials
Phase 1 24
Phase 2 244 95 311
Phase 3 420 213 598
Total patients included in sNDA 664 308 933
Phase 3B 303
Total ADHD pediatric patients 1236
Pediatric patients from studies for excessive sleepiness in narcolepsy and OSA
142 49 270
Pediatric patients from foreign trials 116
Total pediatric patients 1622
69
Exposure by Dose and DurationPediatric ADHD Clinical Trials (Phase 1-3)
Duration of Exposure*
All ModafinilN=933n (%)
Modal Dose Group
≤255 mgN=167n (%)
340 mgN=316n (%)
425 mgN=450n (%)
<1 month 122 (13) 43 (26) 46 (15) 33 (7)
≥1 month 798 (86) 116 (69) 268 (85) 414 (92)
≥3 months 468 (50) 48 (29) 133 (42) 287 (64)
≥6 months 344 (37) 34 (20) 88 (28) 222 (49)
≥12 months 246 (26) 22 (13) 63 (20) 161 (36)
≥18 months 164 (18) 14 (8) 48 (16) 102 (22)
≥24 months 24 (3) 4 (2) 5 (2) 15 (3)
* As of February 1, 2006 Dosing information for thirteen patients incomplete
70
Adverse Events
71
Adverse Events: Pediatric ADHD Studies
Phase 3 Placebo-controlled Trials
Modafinil(N=420)
n (%)
Placebo (N=213)
n (%)Adverse event 328 (78) 135 (63)Severe adverse event 24 (6) 4 (2)Adverse events leading to withdrawal 23 (5) 7 (3)
Serious adverse events 4 (<1) 0
72
Adverse Events*
Phase 3 Placebo-controlled Trials
Adverse Event(COSTART preferred term)
Modafinil (N=420) n (%)
Placebo (N=213)
n (%)
Insomnia 115 (27) 8 (4)
Headache 82 (20) 27 (13)
Anorexia 67 (16) 6 (3)
Abdominal pain 40 (10) 17 (8)
Fever 21 (5) 7 (3)
Nervousness 19 (5) 9 (4)* ≥5% and > placebo
73
Serious Adverse EventsPediatric ADHD Studies
18 patients experienced an SAE (Phase 1-3)– 4 patients reported SAEs in Phase 3 Placebo-
controlled Trials
3 additional patients experienced an SAE in the ongoing trials (as of February 1, 2006)
74
Clinical Laboratory Evaluations
75
White Blood Cell Count (WBC) andAbsolute Neutrophil Count (ANC)*
Phase 3 Placebo-controlled Trials
Modafinil(N = 420)
n (%)
Placebo(N = 213)
n (%)
ANC (10E9/L)
≤1 7(2) 5 (2)
>1 - <1.5 25(6) 9(4)
≥1.5 382(92) 196(93)
WBC (10E9/L)
≤3 8(2) 3(1)
>3 - <4 44(11) 18(9)
≥4 362(87) 189(90)
*Lowest on-treatment value
76
Mean Changes from Baseline and Clinically Significant Serum Chemistry Values
Phase 3 Placebo-Controlled Trials
All Trials Combined
Serum Chemistry Variable Criteria
Modafinil (N=420)
n (%)
Placebo (N=213)
n (%)
Modafinil (N=933)
n (%)
AST ≥3 x ULN 0 0 3 (<1)
ALT ≥3 x ULN 3 (<1) 1 (<1) 8 (<1)
Alkaline phosphatase ≥2 x ULN 0 0 5 (<1)
GGT ≥3 x ULN 1 (<1) 0 5 (<1)
Total bilirubin ≥34.2mol/L 0 0 1 (<1)
ULN=upper limit of normal range; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma-glutamyl transpeptidase.
77
FDA Approvable Letter: LFT Cases of Interest
Study/ Number
Age Sex
Modafinil Dose
(mg/day)LFT
Abnormalities AEs Comment312/063009
17 yM
425 ALT,AST
Myalgia No other laboratory or physical abnormalities
Total bilirubin normalLaboratory abnormalities and adverse
event resolved with continued modafinil treatment
312/006007
9 yM
425 GGT,ALT,AST
Abnormal LFTs
No other laboratory or physical abnormalities
Total bilirubin normalPatient withdrawn – ALT elevated but
not clinically significant, other laboratory parameters normal
312/056003
9 yM
340 ALT,AST,GGT
Urticaria,Face
edema,Fever,
Vomiting
Total bilirubin normalAbnormal values returned to normal
after withdrawalPossible hypersensitivity reaction (?)
78
Cardiovascular Safety
79
Sitting BP – Change From Baseline Phase 3 Placebo-Controlled Trials
Systolic
Ch
an
ge (
mm
Hg
)
Modafinil Placebo
50
-25
25
0
-50Modafinil Placeb
o Diastolic
Modafinil N=420Placebo N=213
80
Sitting Pulse – Change From Baseline Phase 3 Placebo-Controlled Trials
81
Phase 3 Placebo-Controlled TrialsModafinil (N=420)
n (%)
Placebo(N=213)
n (%)Maximum change from baseline (msec)
<30 367 (87) 188 (88)30 – 60 33 (8) 14 (7)
>60 0 0Maximum value on treatment (msec)
<450 400 (95) 201 (94)450 – 500 0 1 (<1)
>500 0 0
Missing 20 11
ECG Data: QTc Interval (Fridericia Correction)
82
Cardiovascular Adverse Events
Phase 3 Placebo-controlled Trials
Modafinil (N=420)
n (%)
Placebo(N=213)
n (%)
Adverse events 10 (2) 3 (1)
Adverse events leading to withdrawal
2 (0.5) 1 (0.5)
Serious adverse events 0 0
83
Growth
84
Body Weight Change Phase 3 Placebo-Controlled Trials
Mea
n C
han
ge
Fro
m B
asel
ine
to E
nd
po
int
(kg
)
-0.7
1.0
-5
-4
-3
-2
-1
0
1
2
3
4
5Modafinil (N=420)Placebo (N=213)
85
Height and Weight (Z-Scores Over 12 Months)
Completers (n=237)
-1.0
-0.5
0.0
0.5
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Weight
Height
Z-S
core
Months
86
Dermatological Safety
87
Review of Skin Adverse Events of Interest(FDA Dermatology Consultant Grouping)
Case DefinitionCases from
Clinical Trials*
Cases from Postmarketing
Reports**
Represent EM/SJS/TEN 2 4
Features somewhat suggestive, confirmation lacking 3 12
Features resembling prodrome, incomplete information 7 9
*ADHD Clinical Studies (N=933)
**No cases reported in children
88
Clinical Trial Cases of Interest
FDA Dermatology Review Cephalon Review
Representative cases
Patient 1) 062338 (EM/SJS) Probable SJS case
Patient 2) 315 (Morbilliform rash) SJS diagnosis excluded
Somewhat suggestive cases
Patient 3) 18001 (Rash, fever, vomiting) Event reported in source document as fifth disease
Patient 4) 18004 (EM Case) Possible Herpetic Gingivostomatis/Possible SJS
Patient 5) 056003 (Fever, urticaria, swollen eyes, vomiting, incr. ALT/AST)
Possibly suggestive of hypersensitivity reaction
89
Review and Grouping of Postmarketing Cases
FDA Dermatological Review Cephalon Review
4 ADR Reports: - SJS/TEN – one report- SJS – three reports
4 ADR Reports: - SJS/TEN – one report- SJS – three reports
Cases described as “suggestive” but no confirmation available
1. Face, hands and legs swelling2. Angioedema, urticaria, anaphylactic shock* 3. Urticaria, swollen tongue, anaphylactoid reaction*4. Angioedema*5. Face hot and tender*6. Urticaria, generalized edema*7. Anaphylactic reaction*8. Rash, hypersensitivity, abnormal LFTs, HIV*9. Urticaria, fever, swelling, incr. WBC*10. Pruritic rash, throat pain11. Lupus chilblain12. Flu like symptoms, sweating, arthralgia
*Hypersensitivity (Urticaria, Angioedema)
90
Additional Analyses
Non-Urticarial Rash
Case definition in collaboration with a panel of dermatologists
All COSTART “preferred” terms and investigator “verbatim” terms for rash included
Urticaria (and related reactions) as well as terms indicating clear alternative etiology excluded
Hypersensitivity Reactions
Review of all adverse events coded as urticaria, hypersensitivity reaction, asthma and/or allergic reactions
91
Non-Urticarial Rash In Pediatric Studies
Pediatric ADHDControlled Studies
Modafinil (N=664)
n (%)
Placebo (N=308)
n (%)
All Events 32 (4.8) 10 (3.2)
Severe Events 4 (0.6) 0
Withdrawals Due to Event 7 (1.1) 0
92
Non-Urticarial Rash in Phase 3b Study
All EnrolledPatients(N=303)
n (%)
All Events 6 (2)
Severe Events 1 (<1)
Withdrawals Due to Event 1 (<1)
93
Non-Urticarial Rash in Pediatric Excessive Sleepiness Studies
Placebo-controlled Studies
All Modafinil(N=142)
n (%)
Placebo (N=49)n (%)
All Events 3 (2) 1 (2)
Severe Events 1 (<1) 0
Withdrawals Due to Event 0 0
94
Non-Urticarial Rash Analyses
No association with modafinil dose– Cumulative dose– Average dose, absolute and mg/kg– Maximum dose
No association with modafinil plasma exposure
No association with modafinil sulfone concentration
95
Non-Urticarial Rash Distribution of Estimated Modafinil AUC
Andrew E Stein:
Data?
Andrew E Stein:
Data?
96
Concentrations of Modafinil Sulfoneand Incidence of Rash
Range of concentration (g/mL)
0-2
2-4
4-6
6-8
8-10
10-1
212
-14
14-1
616
-18
18-2
020
-22
22-2
424
-26
26-2
828
-30
30-3
232
-34
34-3
636
-38
38-4
040
-42
42-4
444
-46
46-4
848
-50
50-5
252
-54
Num
ber
of p
atie
nts
in r
ange
0
20
40
60
80
100
All 213 & Phase 3 ADHD patientsPatients in the studies with rash
97
Hypersensitivity and Allergic ReactionsPlacebo-Controlled Trials
Number of Patients (%) with AEs Reported
Number of Patientswith Prior History*
Modafinil(N=664)
Placebo(N=308)
Modafinil Placebo
Allergies 10 (2) 3 (<1) 7 2
Urticaria 3 (<1) 0 2 0
Face Edema 1 (<1) 0 1 0
Asthma 6 (<1) 1 (<1) 5 1* Described on the medical history as: seasonal allergy; asthma; environmental allergy; drug
allergies; hayfever; seasonal rhinitis; “wheezes with colds, takes albuterol 2-3 x year”; “large reaction to bug bites”
98
Psychiatric Events
99
Analysis of Psychiatric EventsMethodology and Definitions
ADHD and ES Pediatric Studies– Psychosis/mania– Suicidal ideation/behavior– Aggression and violent behavior– Serious miscellaneous events
Pharmacovigilance Data:– “String” search for psychiatric events– Identification of pediatric cases
Ongoing Studies: – Review of SAEs and AEs discontinuations for
psychiatric events
“String” search
100
Psychiatric Adverse EventsADHD Pediatric Studies
Event Category
During Placebo-Controlled Studies
During Open-Label Studies
Modafinil (N=664)
n (%)
Placebo(N=308)
n (%)
All Modafinil (N=799)*
n (%)
Psychosis/Mania 3 (0.5) 0 2 (0.3)
Suicidal Ideation/Behavior 4 (0.6) 0 1 (0.1)
Aggression and Violent Behavior 9 (1.4) 5 (1.6) 14 (1.8)
Miscellaneous Psychiatric Events (SAEs)
0 0 0
*Includes only patients receiving open-label modafinil treatment and cases with onset during open-label treatment.
101
Psychotic EventsADHD Pediatric Studies
Study_Pt#Age (yr)/Sex
Adverse Event(verbatim)
Treatment Days to Onset
ModafinilDose
(mg/day)
Duration of Event (days) Action Taken
213_150106/Boy
Hallucinations 6 300 1 No treatment, cont. modafinil
207_4108/Boy
Formication 18 300 (only received
100)
2 No treatment, modafinil withdrawn
310_406298/Boy
Hallucinations 11 425 5 No treatment, modafinil withdrawn
213_110028/Boy
Psychotic disorder,
aggravated
19 300 7 Hospitalized, modafinilwithdrawn
312_592717/Boy
Ideas of referential
control
59 340 >10 months
No treatment, cont. modafinil
102
Suicidal Ideation/BehaviorADHD Pediatric Studies
Study_Pt#Age (yr)/Sex
Adverse Event(verbatim)
Treatment Days to Onset
ModafinilDose
(mg/day)
Duration of Event (days) Action Taken
207_4057/Boy
Suicidal statement
22 200 1 No treatment, cont. modafinil
207_41110/Boy
Suicidal statement
8 200 1 No treatment, cont. modafinil
311_533178/Boy
Voiced vague suicidal
statement
13 and 21 255 1 No treatment, cont. modafinil
310_401788/Girl
Suicide threat 8 340 2 No treatment, modafinil withdrawn
312_140166/Girl
Abnormal behavior
93 (last taken day 91)
255 97 Hospitalized
103
Psychosis and Suicidality SAEs or Discontinuations Ongoing Modafinil Pediatric Studies
Study_Pt#Age (yr)/Sex
Adverse Event
(verbatim)
Treatment Days to Onset
Modafinil Dose
(mg/day)
Duration of Event (days) Action Taken
312_00310215/girl
Situational depression*
Unknown 425 Ongoing None,Cont. modafinil
312_01600115/girl
Suicidal ideation
219 425 8 Hospitalized, Withdrawn for
depressive disorder NOS
3029_026701 10/girl
Suicidal gesture
75 400 1 None, Cont. modafinil
3044-020088/boy
Paranoid reaction
16 255 5 Modafinil discontinued
*Suicidal ideation was reported as a symptom of depression: suicidal ideation resolved, depression ongoing
104
Psychiatric Pharmacovigilance Reports Pediatric Patients (<18 Years Of Age)
Period January, 2000 to June, 2005
Total estimated pediatric exposure: 24,700 patient-years
Total reports indicative of psychiatric event: 7– 4 psychosis/mania– 1 suicidality– 2 aggression/violence
105
Psychiatric Pharmacovigilance ReportsPediatric Patients (<18 Years of Age)
Age/Sex Event Description (Verbatim Term)
Psychosis / mania
11 y old boy Visual and auditory hallucinations
7 y old boy Visual hallucinations
17 y old boy Mania: flight of ideas, sexual excitation, and increased irritability
6 y old girl Awakening at night crying and screaming about bugs biting her
Suicidal ideation / behavior
14 y old girl
Attempted suicide: multi-drug overdose Intentional
Aggression / violent behavior
13 y old boy Agitation, easily angered, felt terrible
13 y old girl Anger, jittery feeling, achiness, loss of appetite
106
Pediatric Excessive Sleepiness
107
Modafinil Pediatric Studies in Excessive Sleepiness Safety Overview
Most common AEs: headache, anorexia, infection, abdominal pain and insomnia
No trend in mean changes in vital signs; slightly more modafinil patients experienced clinically significant SBP and DBPs
No adverse effect observed on weight
Increase in mean GGT and AP levels however, few shifts outside the normal range and no transaminase abnormalities
Lower incidence of non-urticarial rash was observed compared to ADHD studies and no events led to discontinuation or were serious
108
Modafinil Pediatric Study in Excessive Sleepiness SAE of Interest: Viral Encephalitis
Event:– 6 year old boy with narcolepsy, receiving modafinil 400mg/day– Vomiting, nausea and fever (day 12), pharyngitis (day 13)– Withdrawn from the study (day 15), hospitalized (day 16)– Severe somnolence and confusion associated with
hypophosphatemia and increased serum ammonia (day 16)– Convulsions and delirium (day 17) – Event resolved with no residual effects
Discussion:– Reye’s syndrome suspected– Case reviewed by two external consultants– Consensus opinion: viral encephalitis or inborn error of
metabolism (urea cycle disorder); Reye’s syndrome considered unlikely due to normal LFTs
– FDA consultant also concluded that this case is not drug-related
109
Postmarketing Safety Data
110
Modafinil Postmarketing Exposure (Cumulative Estimate through 28 Feb 2006)
PopulationExposure
(Patient Treatment Years)*
Adult Exposure 750,000
Pediatric Exposure 30,000
Total Exposure 780,000
*Derived from sales figures and average daily dose estimates.
111
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%B
lood
Car
diac
Con
geni
tal
Ear
End
ocri
ne
Eye G
I
Gen
eral
Hep
atob
ilia
ry
Imm
une
Infe
ctio
ns
Inju
ry
Inve
stig
atio
n
Met
abli
sm
Mus
culo
Neo
plas
ms
Ner
vous
Pre
gnan
cy
Psy
chia
tric
Ren
al
Rep
rodu
ctiv
e
Res
pira
tory
Ski
n
Soc
ial
Sur
gica
l
Vas
cula
r
SOC
% o
f T
otal
Eve
nts
Adults (>=18)
Pediatric (<18)
Modafinil Spontaneous SOC Event Frequency by Age (Serious and non-Serious): Adult vs Pediatric
Pe
rce
nt o
f To
tal E
ven
ts
System Organ Class
112
Provigil Label Updates: Adverse Reactions Postmarketing Reports
October 31, 2002: – Central Nervous System: symptoms of psychosis,
symptoms of mania – Hematologic: agranulocytosis
February 5, 2004: – Hypersensitivity: urticaria (hives), angioedema
December 2, 2004: – Dermatologic: rare reports of serious skin reactions
(including suspected cases of both erythema multiforme and Stevens-Johnson Syndrome)
113
ADHD Safety Conclusions
Modafinil was generally well tolerated
Most common adverse events were insomnia, headache and anorexia
Few adverse events were severe and few were reason for treatment discontinuation
Overall, few laboratory abnormalities observed
No effect on mean SBP, DBP, pulse, or QTc interval
114
ADHD Safety Conclusions
Initial effect on weight observed but no effects on the growth rate seen in studies up to 12 months
Adverse events of suicidal ideation and psychotic symptoms were observed, most were short in duration and did not require additional treatment
Cases of serious skin reactions were reported, all resolved without sequelae
115
Conclusions
Lesley Russell, M.R.C.P.
Senior VP, Worldwide Clinical ResearchCephalon, Inc.
116
Conclusions – Efficacy
Has modafinil been shown to be effective for the treatment of ADHD in children and adolescents?– Consistent efficacy seen in all three studies– Consistent effects observed by multiple assessors– Consistent effects across different rating
scales/instruments– Consistent effects at school and at home
117
Conclusions – Safety
Has modafinil been shown to be acceptably safe for the treatment of ADHD in children and adolescents?– Modafinil is generally well tolerated– No adverse signals observed with respect to pulse,
blood pressure, growth or liver function– Concerns raised over psychiatric adverse events,
including psychosis, mania, aggression and suicidality. Events discussed at PAC on March 22 with no consensus made with respect to labeling for psychosis, mania or aggression. Language proposed in warning section of modafinil label
118
Conclusions – Safety
Concerns raised over skin reactions– General concurrence with expert dermatologists with respect to
Case 1, but some diversity of opinion regarding other cases– Diagnostic and etiologic uncertainty– No adverse sequelae – Association with modafinil cannot be excluded– Language proposed in warning section
Modafinil is not a new chemical entity
780,000 patient-years exposure
PV risk assessment in place– Leading to three labeling changes – Structured case ascertainment now occurring
119
Conclusion
SPARLON is an effective medication for the treatment of ADHD with a favorable risk-benefit ratio