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


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


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


Conclusions: – Genetic and or early environmental influences on brain

development in ADHD are fixed, nonprogressive and unrelated to stimulant treatment


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




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


ModafinilPlacebo


AD

HD

-RS

(Tota

l S

core

)

***

*

*

*

Weeks

53


15

20

25

30

35

40

45

BL 1 2 3 5 7 EP

*

* *

*

**

ModafinilPlacebo

Weeks


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




** * -18

-16-14-12-10-8-6-4-20




*

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


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


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


Andrew E Stein:

SPARLON to modafinil

Andrew E Stein:


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


Andrew E Stein:


Andrew E Stein:


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*


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)*


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


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


Adverse Event(verbatim)


ModafinilDose

(mg/day)


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


Adverse Event

(verbatim)


Modafinil Dose

(mg/day)


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

1 sparlon™ (modafinil) tablets [c-iv] psychopharmacologic drugs advisory committee 23 march 2006

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