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A1
29 November 2006
FDA Advisory Committee Meeting
Celecoxib in the Treatment of the Signs and Symptoms
of Juvenile Rheumatoid Arthritis (JRA)
A2
Delegation
Dr Edward Giannini EpidemiologyCincinnati Children’s Hospital Medical Center
Dr Benjamin Gold Pediatric gastroenterologyEmory University School of Medicine
Dr Gary Koch StatisticianUniversity of North Carolina at Chapel Hill
Dr Daniel Lovell Pediatric rheumatologyCincinnati Children’s Hospital Medical Center
Dr Robert Stern DermatologyHarvard Medical School
A3
Objectives
To present for Committee discussion the available data regarding celecoxib in the treatment of children with JRA
To demonstrate that, based on current data, celecoxib is efficacious without evidence for unique safety concerns
compared to other NSAIDs in JRA
To highlight the concern of rare events and uncertain long-term risks of NSAID therapies
To highlight the medical need for NSAIDs in the treatment of children with JRA
A4
Objectives and Agenda
Overview of celecoxib
Clinical characteristics and current treatments for children with JRA
Regulatory history, rationale for study of celecoxib in children, and clinical data for celecoxib in JRA
Overall conclusions
Dr S Lowry
Dr D Lovell
Dr S Lowry
A5
Celecoxib Overview
Selective inhibitor of COX-2 – Spares COX-1 at therapeutic doses
Approved indications:– 1998: OA and RA in adults– 1999: FAP– 2001: Acute pain and primary dysmenorrhea– 2005: Ankylosing spondylitis
Studied in over 25,000 adult patients
Epidemiologic data from ~200,000 patients
Experience in over 70 million patients worldwide since approval
A6
Emerging Data in 2004: CV Safety
September 30, 2004: Rofecoxib withdrawn due to increased CV risk vs placebo in the APPROVe trial1,2
December 2004: Preliminary data from 1 out of 3 long-term trials with celecoxib showed increased CV risk vs placebo3,4
1. Merck press release. September 30, 2004; 2. Freudenheim. The New York Times. October 1, 2004; 3. NCI Press Release. December 17, 2004; 4. NIH News Press Release. December 20, 2004.
A7
FDA Actions Taken in 2005
Convened a joint meeting of the AAC and the DSaRM – Outcome: Advisory Committee voted 31-1 that the
overall risk:benefit profile of Celebrex supports continued marketing in the US
FDA memorandum – Questions still remain regarding the CV risks associated
with all NSAIDs– Manufacturers of all prescription NSAIDs were requested
to implement label changes
Class-labeling template on CV / GI risk issued
Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.htmlJenkins and Seligman. Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk. US Food and Drug Administration Memorandum 6 April 2005
A8
US FDA Decision Memorandum
Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk
“It is not possible to conclude at this point that the COX-2 selective drugs confer an increased risk over non-selective NSAIDs in chronic use.”
“We believe that it is reasonable to conclude that there is a “class effect” for increased CV risk for all NSAIDs pending the availability of data from long-term controlled clinical trials that more clearly delineate the true relationships.”
Jenkins and Seligman. Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk. US Food and Drug Administration Memorandum 6 April 2005.
A9
Boxed Warning for All Prescription NSAIDs
Cardiovascular Risk “xxxx” may cause an increased risk of serious cardiovascular
thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk
“xxxx” is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery
Gastrointestinal Risk NSAIDs, including “xxxx”, cause an increased risk of serious
gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events
A10
0.1 0.4 0.7 1.0 1.3 1.6 1.9 2.2 2.5 2.8 3.1 3.4
Favors NSAID Favors placebo
Hazard Ratio (95% CI)
ADAPT: Composite CV Events
APTC
APTC/CHF
APTC/CHF/TIA
1.14 (0.61, 2.15)
1.57 (0.87, 2.81)
1.06 (0.60, 1.88)
1.66 (1.00, 2.77)
1.10 (0.67, 1.79)
1.63 (1.04, 2.55)
Celecoxib
Naproxen
Celecoxib
Naproxen
Celecoxib
Naproxen
APTC events = CV death, nonfatal MI, nonfatal strokeADAPT Research Group. PLoS Clin Trials; 2006: 1:e33. doi:10.1371/journal.pctr.0010033
A11
0.1 0.4 0.7 1.0 1.3 1.6 1.9
Better than Non-use/Remote Exposure
Worse than Non-use/Remote Exposure
Relative CV Risk (95% CI)
CV Risk of NSAIDs
Naproxen
Ibuprofen
Celecoxib
Piroxicam
Meloxicam
Indomethacin
Rofecoxib
Diclofenac
0.97 (0.87, 1.07)
1.07 (0.97, 1.18)
1.06 (0.91, 1.23)
1.06 (0.70, 1.59)
1.25 (1.00, 1.55)
1.30 (1.07, 1.60)
1.35 (1.15, 1.59)
1.40 (1.16, 1.70)
McGettigan and Henry. JAMA 2006; 296(13):1633-1644.
A12
Events in 2006PRECISION Trial Initiated
Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen
~ 20,000 OA and RA patients with CV disease or at high-risk for developing CV disease
– Primary endpoint: APTC composite endpoint (762)– Secondary endpoints: GI events, renal events, efficacy
Treatments– Celecoxib (100-200 mg BID)– Naproxen (375-500 mg BID)– Ibuprofen (600-800 mg TID)
Study will continue to allow all patients the opportunity for 18 months of follow-up
Upper bound of 95% CI ≤ 1.33 and the point estimate of the hazard ratio is not >1.12
A13
Objectives and Agenda
Overview of celecoxib
Clinical characteristics and current treatments for children with JRA
Regulatory history, rationale for study of celecoxib in children, and clinical data for celecoxib in JRA
Overall conclusions
Dr S Lowry
Dr D Lovell
Dr S Lowry
A15
Objectives and Agenda
Overview of celecoxib
Clinical characteristics and current treatments for children with JRA
Regulatory history, rationale for study of celecoxib in children, and clinical data for celecoxib in JRA
Overall conclusions
Dr S Lowry
Dr D Lovell
Dr S Lowry
A16
Context for Studying NSAIDs in JRA
JRA is a relatively rare condition in a pediatric population
Studies for approval range from 59 patients to 432 patients
– 8 weeks to 64 weeks in duration
Similar size / duration to DMARD / biologic trials for approval
– Etanercept (69 patients)
– Sulfasalazine (69 patients)
– Methotrexate (127 patients)
A17
Celecoxib Pediatric Written Request Key Elements
FDA issued PWR in January 2002
Study Type/Objective:– Efficacy & safety of two doses celecoxib vs. standard
active control– PK of celecoxib in children with JRA
Design:– Single study: 12-week double-blind, 3-arm study with
12-week open-label, single-arm phase– PK – multi-dose assessment
Age Group/Population:– JRA patients aged 2-16; 10% < 5 years old– Polyarticular & pauciarticular allowed– Approximately 10% with systemic onset encouraged
A18
Drug-Specific Safety Issues: – General safety and laboratory testing– Development to be assessed and developmental
adverse events targeted– Close monitoring of systemic JRA patients
Drug Information:– Oral; appropriate formulation for pediatric population
Labeling:– Information collected should provide for appropriate
labeling
Celecoxib Pediatric Written Request Key Elements
A19
Timeframe
2002FDA issues final PWRCelecoxib JRA Study initiated
Recent Regulatory History of NSAIDs in JRA
A20
Timeframe
2002FDA issues final PWRCelecoxib JRA Study initiated
2004
Rofecoxib approved for use in JRAAPPROVe, APC, PreSAP, ADAPT preliminary dataRofecoxib withdrawn
Recent Regulatory History of NSAIDs in JRA
A21
Timeframe
2002FDA issues final PWRCelecoxib JRA Study initiated
2004
Rofecoxib approved for use in JRAAPPROVe, APC, PreSAP, ADAPT preliminary dataRofecoxib withdrawn
2005
Celecoxib JRA Study completedClass CV warnings for all NSAIDsMeloxicam approved for use in JRA
Recent Regulatory History of NSAIDs in JRA
A22
Timeframe
2002FDA issues final PWRCelecoxib JRA Study initiated
2004
Rofecoxib approved for use in JRAAPPROVe, APC, PreSAP, ADAPT preliminary dataRofecoxib withdrawn
2005
Celecoxib JRA Study completedClass CV warnings for all NSAIDsMeloxicam approved for use in JRA
2006
Pfizer meets with FDA to agree on proposal for sNDA in JRAsNDA filedAdvisory Committee convened
Recent Regulatory History of NSAIDs in JRA
A23
Study 195Celecoxib vs Naproxen in JRA
A24
Study 195: Study Objectives
Primary To evaluate the efficacy and safety of celecoxib
suspension for the treatment of the signs and symptoms of JRA compared with naproxen suspension
Secondary
• Obtain pharmacokinetic information to guide the dosing of celecoxib in pediatric patients
A25
Study 195: Inclusion Criteria
Age 2 - 16 years of age and ≥9 kg
Pauciarticular or polyarticular course
≥1 swollen joint and ≥ 1 joint with limitation of motion
Systemic-onset eligible
Candidates for NSAID therapy
Score of ≥10 mm at Screening visit– Physician’s Global Assessment of Disease
Activity– Parent’s Global Assessment of Overall Well-Being
A26
Study 195: Exclusion Criteria
Presence of active systemic manifestations of JRA
Initiation of or changing the dose of medications:
Drug Stabilization Period
Allowable Dose Range
Methotrexate 8 weeks 1 mg/kg/week or 40 mg maximum weekly dosage
Other DMARDs 12 weeks Sulfasalazine 3 grams/day
Biologics 12 weeks
Gold Salts 16 weeks
Corticosteroids 4 weeksOral 0.2 mg/kg/day or 10 mg prednisone/day
A27
Study 195: Study Design
Celecoxib 3 mg/kg BID (N= 77)
Celecoxib 6 mg/kg BID (N= 82)
0 4 128Visits (Week)
Screening
2
Naproxen 7.5 mg/kg BID (N= 83)
16 24
Celecoxib 6 mg/kg BID (N= 202)
Double-blind Open-label
NSAIDs were to be discontinued >5 half-lives prior to baseline visit.
A28
Study 195: Primary Endpoint
Percent of patients improved as defined by the ACR Pediatric Percent of patients improved as defined by the ACR Pediatric 30 Response Criterion at Week 1230 Response Criterion at Week 12
– ≥≥30% improvement in any 3 of 6 core set measures with no 30% improvement in any 3 of 6 core set measures with no more than 1 of the remaining measures worsening by >30%more than 1 of the remaining measures worsening by >30%
Core Set Measures
Physician’s Global Assessment of Disease Activity
Parent’s Global Assessment of Overall Well Being (CHAQ subsection)
Parent’s Assessment of Physical Function (CHAQ Disability Index)
Number of joints with active arthritis
Number of joints with limited range of motion
Laboratory measure of inflammation (CRP)
A29
Study 195: Secondary Measures
Change from baseline to each post-baseline assessment for:– Each ACR Pediatric 30 core set measure– Parent’s Assessment of Child’s Arthritis Pain
(VAS) [CHAQ Subsection]
• Celecoxib pharmacokinetics in pediatric patients
• Safety• Adverse events• Clinical laboratory values• Vital signs
A30
Study 195: Statistical Methods
Non-inferiority margin of 25% for ACR Pediatric 30 Response – Hypothesis testing was one-sided at the 2.5%
level of significance– Non-inferiority claimed if lower limit of 2-sided
95% confidence interval for percent responders (celecoxib – naproxen) was above -25%
Sample size = 75 patients / treatment group– At least 80% power to conclude non-inferiority
Last observation carried forward, intent-to-treat population
A31
Study 195: Rationale for Non-inferiority Margin
Prospectively specified in discussions with FDA
Surveyed practicing pediatric rheumatologists to assess clinically meaningful difference
Assumption that response rate for naproxen would be 60-80%
Meta-analysis of placebo-controlled studies in JRA– Range for placebo response = 9%-36%
Ruperto et al. Arthritis Rheum 2003;48 Suppl:S90
A32
Study 195: Demographic CharacteristicsCelecoxib
3 mg/kg BID
N = 77
Celecoxib 6 mg/kg BID
N = 82
Naproxen 7.5 mg/kg BID
N = 83
Age, n (%)
2 – 4 years 13 (16.9) 16 (19.5) 10 (12.0)
5 – 7 years 9 (11.7) 9 (11.0) 11 (13.3)
8 – 12 years 31 (40.3) 35 (42.7) 35 (42.2)
13 – 16 years 24 (31.2) 22 (26.8) 27 (32.5)
Gender, n (%)
Female 59 (76.6) 53 (64.6) 59 (71.1)
Race, n (%)
White 41 (53.2) 47 (57.3) 52 (62.7)
Black 9 (11.7) 7 (8.5) 4 (4.8)
Asian 1 (1.3) 3 (3.7) 1 (1.2)
Not listed 26 (33.8) 25 (30.5) 26 (31.3)
A33
Study 195: Baseline Characteristics
Celecoxib 3 mg/kg BID
N = 77
Celecoxib 6 mg/kg BID
N = 82
Naproxen 7.5 mg/kg BID
N = 83
Duration of JRA (yr ± SD) 2.7 ± 2.8 3.8 ± 3.4 3.4 ± 3.2
JRA disease subtype, n (%)
Pauciarticular course 37 (48.1) 45 (54.9) 46 (55.4)
Polyarticular course 40 (51.9) 37 (45.1) 37 (44.6)
Systemic onset, n (%) 4 (5.2) 10 (12.2) 8 (9.6)
A34
Study 195: Baseline Characteristics
Celecoxib 3 mg/kg BID
N = 77
Celecoxib 6 mg/kg BID
N = 82
Naproxen 7.5 mg/kg BID
N = 83
Duration of JRA (yr ± SD) 2.7 ± 2.8 3.8 ± 3.4 3.4 ± 3.2
JRA disease subtype, n (%)
Pauciarticular course 37 (48.1) 45 (54.9) 46 (55.4)
Polyarticular course 40 (51.9) 37 (45.1) 37 (44.6)
Systemic onset, n (%) 4 (5.2) 10 (12.2) 8 (9.6)
DMARD/biologic use, n (%) 39 (50.6) 40 (48.8) 43 (51.8)
Any methotrexate use 35 (45.5) 33 (40.2) 34 (40.9)
Any biologic use 2 (2.6) 3 (3.7) 3 (3.6)
Corticosteroid use, n (%) 13 (16.9) 16 (19.5) 22 (26.5)
DMARDs/biologics used: azathioprine, hydroxychloroquine sulfate, methotrexate, sulfasalazine, etanercept infliximab
A35
Study 195: Baseline Disease Characteristics
Celecoxib 3 mg/kg BID
N = 77
Celecoxib 6 mg/kg BID
N = 82
Naproxen 7.5 mg/kg BID
N = 83
Physician’s Global Assessment of Disease Activity (0-100 mm)
42.4 ± 2.3 41.1 ± 1.9 41.2 ± 1.8
Parent’s Global Assessment of Overall Well Being (0-100 mm)
38.4 ± 2.5 42.7 ± 2.2 45.0 ± 2.5
Parent’s Assessment of Physical Function (0-3 scale) 0.9 ± 0.1 0.9 ± 0.1 0.9 ± 0.1
Parent’s Assessment of Child’s Arthritis Pain (0-100 mm)
41.3 ± 2.8 41.5 ± 2.4 42.7 ± 2.3
Mean ± SE
A36
Study 195 Patient DispositionDouble-Blind Phase
Patients Randomized N = 242
Celecoxib 3 mg/kg BIDN = 77
Celecoxib 6 mg/kg BIDN = 82
Naproxen 7.5 mg/kg BID N = 83
Patients Withdrawn
n = 10 (13.0%)
Adverse event 3 (3.9%)
Lack of efficacy 2 (2.6%)
Consent withdrawn 4 (5.2%)
Lost to follow-up 1 (1.3%)
Protocol violation 0 (0.0%)
Patients Withdrawn
n = 11 (13.4%)
Adverse event 7 (8.5%)
Lack of efficacy 1 (1.2%)
Consent withdrawn 2 (2.4%)
Lost to follow-up 0 (0.0%)
Protocol violation 1 (1.2%)
Patients Completedn = 67 (87.0%)
Patients Completedn = 71 (86.6%)
Patients Completedn = 74 (89.2%)
Patients Withdrawn
n = 9 (10.8%)
Adverse event 3 (3.6%)
Lack of efficacy 4 (4.8%)
Consent withdrawn 1 (1.2%)
Lost to follow-up 0 (0.0%)
Protocol violation 1 (1.2%)
A37
Study 195 Efficacy
A38
Study 195 ACR Pediatric 30 ResponsePercentage of Responders
0
20
40
60
80
100
2 4 8 12
Responder: 30% improvement in 3 core set variables and no more than 1 variable worsening by >30%.
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
Week
Per
cen
tag
e o
f P
atie
nts
(95
% C
I)
A39
Study 195: ACR Pediatric 30 ResponseDifference in Percent Responders at Week 12
Celecoxib 3 mg/kg BID
Week 12 Responder Analysis: Celecoxib - Naproxen (95% CI)
Celecoxib 6 mg/kg BID
1.36%, (-13. 1%, 15.8%)
13.0%, (-0.2%, 26.3%)
Non-inferiority margin = 25%; non-inferiority claimed if the LL of the 95% CI for the difference in percent improved (celecoxib – naproxen) was above -25%.
-30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30
Favors naproxen Favors celecoxib
Treatment Difference
A40
0
20
40
60
80
100
ACR Ped 30 ACR Ped 50 ACR Ped 70
Study 195: ACR Pediatric 30, 50, and 70 ResponsePercentage of Responders at Week 12
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
Per
cen
tag
e o
f P
atie
nts
(95
% C
I)
A41
Study 195: Percentage of Responders Core Set Measures at Week 12 (30% improvement)
0
10
20
30
40
50
60
70
80
90
100
Physician'sGlobal
Parent'sGlobal
Joints withActive
Arthritis
Joints withLimited
Range ofMotion
FunctionalAbility
CRP
Pe
rce
nta
ge
of
Pa
tie
nts
(9
5%
CI)
**
p < 0.05 vs celecoxib 3 mg/kg BID
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
A42
10
20
30
40
50
0 2 4 6 8 10 12
Mea
n m
m V
AS
(S
E)
Study 195: Global Assessments
Parent’s Global Assessmentof Overall Well Being
Physician’s Global Assessmentof Disease Activity
10
20
30
40
50
0 2 4 6 8 10 12
*p < 0.05, celecoxib 3 mg/kg BID vs naproxenScales range from 0-100 mm
**
Week
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
A43
0
2
4
6
8
10
0 2 4 6 8 10 12
Mea
n N
um
ber
of
Join
ts (
SE
)
0
2
4
6
8
10
0 2 4 6 8 10 12
Study 195: Joint CountsActive Arthritis and Limited Range of Motion
Number of Joints with Limited Range of Motion
Number of Joints with Active Arthritis
*p < 0.05, celecoxib 3 mg/kg BID vs celecoxib 6 mg/kg BIDTotal joints = 73 Total joints = 67
Week
**** **
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
A44
0
5
10
15
20
25
0 2 4 6 8 10 12
Mea
n m
g/L
(S
E)
0.0
0.5
1.0
1.5
0 2 4 6 8 10 12
Mea
n U
nit
s (S
E)
Study 195: Functional Ability and CRP
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
Scale ranges from 0-3
CRPFunctional Ability
Week
A45
15
25
35
45
0 2 4 6 8 10 12
mm
VA
S (
SE
)
Study 195: Parent’s Assessment of Child’s Arthritis Pain (VAS)
Scale ranges from 0-100 mm
Week
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
A46
0
20
40
60
80
100
Pauciarticular Course Polyarticular Course
Study 195: ACR Pediatric 30 Response JRA Course
**
p < 0.05 vs. celecoxib 3 mg/kg BID and naproxen
N = 37 45 46 40 37 37
Week 12
Per
cen
tag
e o
f P
atie
nts
(95
% C
I)
Celecoxib 3 mg/kg BIDCelecoxib 6 mg/kg BIDNaproxen 7.5 mg/kg BID
A47
0
20
40
60
80
100
No DMARD/Biologic Use DMARD/Biologic Use
Study 195: ACR Pediatric 30 ResponseDMARD/Biologic Use
N = 38 42 40 39 40 43
* p < 0.05 vs. celecoxib 3 mg/kg BID
**
Per
cen
tag
e o
f P
atie
nts
(95
% C
I)
Celecoxib 3 mg/kg BIDCelecoxib 6 mg/kg BIDNaproxen 7.5 mg/kg BID
Week 12
A48
Study 195: Summary of EfficacyDouble-Blind Phase
Both doses of celecoxib demonstrated non-inferiority to naproxen for the ACR Pediatric 30 Response at Week 12
Secondary efficacy endpoints supportive of the primary analysis
Subgroup analyses by disease type and baseline DMARD/biologic use consistent with results for overall population
A49
Study 195 Safety
A50
Study 195: Safety Results
Adverse events
Body weight
Cardiorenal
Hematology and biochemistry
A51
Safety Analyses – Double-Blind Phase
63.6
3.9 3.9
69.5
8.52.4
72.3
3.60.0
0
10
20
30
40
50
60
70
80
At least 1 AdverseEvent
Withdrawal Due toAdverse Event
Serious AdverseEvent
Pe
rce
nta
ge
of
Pa
tie
nts Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
A52
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Any event 49 (63.6) 57 (69.5) 60 (72.3)
Eye disorders 4 (5.2) 4 (4.9) 4 (4.8)
Gastrointestinal disorders 20 (26.0) 20 (24.4) 30 (36.1)
Abdominal pain 3 (3.9) 6 (7.3) 6 (7.2)
Abdominal pain upper 6 (7.8) 5 (6.1) 8 (9.6)
Vomiting 2 (2.6) 5 (6.1) 9 (10.8)
Diarrhea 4 (5.2) 3 (3.7) 7 (8.4)
Nausea 5 (6.5) 3 (3.7) 9 (10.8)
General disorders 10 (13.0) 9 (11.0) 15 (18.1)
Pyrexia 6 (7.8) 7 (8.5) 9 (10.8)
Incidence ≥ 5% in any treatment groupn (% of patients)
Study 195: Adverse Events By System Organ Class—Double-Blind Phase
A53
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Infections 19 (24.7) 16 (19.5) 22 (26.5)
Nasopharyngitis 4 (5.2) 5 (6.1) 4 (4.8)
Injury and poisoning 3 (3.9) 5 (6.1) 4 (4.8)
Investigations 2 (2.6) 9 (11.0) 6 (7.2)
Musculoskeletal disorders 6 (7.8) 8 (9.8) 14 (16.9)
Arthralgia 2 (2.6) 6 (7.3) 3 (3.6)
Nervous system disorders 13 (16.9) 9 (11.0) 17 (20.5)
Headache 10 (13.0) 8 (9.8) 13 (15.7)
Dizziness 1 (1.3) 1 (1.2) 6 (7.2)
Study 195: Adverse Events By System Organ Class—Double-Blind Phase
Incidence ≥ 5% in any treatment groupn (% of patients)
A54
Study 195: Adverse Events By System Organ Class—Double-Blind Phase
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Respiratory disorders 6 (7.8) 12 (14.6) 12 (14.5)
Cough 5 (6.5) 6 (7.3) 7 (8.4)
Skin disorders 8 (10.4) 6 (7.3) 15 (18.1)
Incidence ≥ 5% in any treatment groupn (% of patients)
A55
Study 195: Serious Adverse EventsDouble-Blind Phase
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen
7.5 mg/kg BID
N=83
Any Event 3 (3.9) 2 (2.4) 0 (0.0)
Abdominal Pain* JRA aggravated*
Cytomegalovirus hepatitis*
Asthma*
Viral Infection
* Led to withdrawal from studyn (%of patients)
A56
Study 195: Withdrawals due to Adverse Events
Double-Blind Phase
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Any Event 3 (3.9) 7 (8.5) 3 (3.6)
Dysphagia Hypersensitivity Upper abdominal pain
Cytomegalovirus hepatitis
Hematuria present Abdominal pain, nausea, vomiting
Abdominal pain and esophageal pain
LFTs abnormal JRA, aggravated
Transaminase increased
Rash generalized
JRA, aggravated
Asthma
n (% of patients)
A57
Study 195: Safety Results
Adverse events
Body weight
Cardiorenal
Hematology and biochemistry
A58
Study 195: Body WeightDouble-Blind Phase
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
LS mean change from baseline to Week 12/Final Visit ± SE (kg)
1.01 ± 0.17 1.01 ± 0.16 0.87 ± 0.16
≥5% decrease from baseline, n (%)
Week 12/Final visit 0 / 69 (0) 1 / 77 (1.3) 1 / 79 (1.3)
Any visit 0 / 69 (0) 1 / 77 (1.3) 1 / 79 (1.3)
A59
Study 195: Safety Results
Adverse events
Body weight
Cardiorenal
Hematology and biochemistry
A60
Study 195: Systolic Blood PressureDouble-Blind Phase—Changes at Week 12/Final Visit
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Baseline mean (mmHg) 99.3 101.3 101.9
LS mean change from baseline ± SE
0.91 ± 1.09 0.76 ± 1.06 1.60 ± 1.05
≥15% increase from baseline 7 / 73 (9.6) 5 / 80 (6.3) 11 / 83 (13.3)
≥15% decrease from baseline 5 / 73 (6.8) 2 / 80 (2.5) 1 / 83 (1.2)
A61
Study 195: Creatinine Double-Blind Phase
Celecoxib 3 mg/kg BID
N=73
Celecoxib 6 mg/kg BID
N=80
Naproxen 7.5 mg/kg BID
N=81
Baseline mean (µmol/L) 39.9 39.3 40.5
Mean change from baseline to Week 12/Final Visit ± SE
-0.03 ± 0.97 0.74 ± 0.86 -0.60 ± 0.80
Shift from normal value at baseline above normal, n (%)
Week 12/Final visit 0 / 73 (0) 0 / 80 (0) 0 / 81 (0)
Any visit 0 / 73 (0) 0 / 80 (0) 0 / 81 (0)
2 – 12 years: normal = ≤92 µmol/L≥13 years: normal = ≤110 µmol/L
A62
Study 195: Safety Results
Adverse events
Body weight
Cardiorenal
Hematology and biochemistry
A63
Study 195: HemoglobinDouble-Blind Phase
Celecoxib 3 mg/kg BID
N=71
Celecoxib 6 mg/kg BID
N=75
Naproxen 7.5 mg/kg BID
N=77
Baseline mean (g/L) 123.2 123.5 123.6
Mean change from baseline to Week 12/Final Visit ± SE
-2.1 ± 0.96 -1.2 ± 0.95 -4.4 ± 1.01*
>10 g/L decrease from baseline and below lower limit of normal,
n (%)
Any visit 1 / 71 (1.4) 2 / 75 (2.7) 2 / 77 (2.6)
* p < 0.05 vs. celecoxib 6 mg/kg BID2 years: normal = 110-140 g/L3-5 years: normal = 118-147 g/L (F), 110-145 g/L (M)6-11 years: normal = 112-155 g/L≥12 years: normal = 116-164 g/L (F), 127-181 g/L (M)
A64
Study 195: ALTDouble-Blind Phase
Celecoxib 3 mg/kg BID
N=73
Celecoxib 6 mg/kg BID
N=80
Naproxen 7.5 mg/kg BID
N=80
Baseline mean (U/L) 16.5 16.2 17.2
Mean change from baseline to Week 12/Final Visit ± SE 3.3 ± 2.84 2.0 ± 2.19 -0.9 ± 1.00
Shift from normal value at baseline above normal, n (%)
Week 12/Final visit 1 / 73 (1.4) 1 / 80 (1.3) 0 / 80 (0.0)
Any visit 1 / 73 (1.4) 3 / 80 (3.8) 0 / 80 (0.0)
All patients: normal = ≤75 U/L
A65
Study 195: Safety SummaryDouble-Blind Phase
GI disorders, infections and nervous system disorders most commonly reported
Similar safety profile for both celecoxib doses relative to naproxen
No apparent effect on growth and no developmental adverse events reported
Mean effects and changes in SBP similar between celecoxib and naproxen
Few serious adverse events and withdrawals from the study
A66
Study 195 Open-Label Phase
A67
Study 195: Patient Disposition12-Week Open-Label Phase
Celecoxib 6 mg/kg BIDCompleted Double Blind
N = 71
Entered Open LabelN = 62 (92.5%)
Entered Open LabelN = 70 (98.6%)
Entered Open LabelN = 70 (94.6%)
Patients Withdrawn
n = 7 (3.5%)
Adverse event 3 (1.5%)
Consent withdrawn 2 (1.0%)
Protocol specific withdrawal criteria
1 (0.5%)
Protocol violation 1 (0.5%)
Celecoxib 6 mg/kg BIDN= 202
Patients Completedn = 195 (96.5%)
Naproxen 7.5 mg/kg BIDCompleted Double Blind
N = 74
Celecoxib 3 mg/kg BIDCompleted Double Blind
N = 67
A68
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
mm
VA
S (
SE
)
Study 195: Physician’s Global Assessment of Disease Activity—Double Blind and Open Label
**
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
Open-label Celecoxib 6 mg/kg BID
Week
Open-Label Phase
*p < 0.05, celecoxib 3 mg/kg BID vs naproxenScale ranges from 0-100 mm.
A69
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
mm
VA
S (
SE
)
Study 195: Parent’s Assessment of Child’s Arthritis Pain—Double Blind and Open Label
Scale ranges from 0-100 mm
Week
Celecoxib 3 mg/kg BID
Celecoxib 6 mg/kg BID
Naproxen 7.5 mg/kg BID
Open-label Celecoxib 6 mg/kg BID
Open-Label Phase
A70
Study 195: Adverse Events by System Organ Class Double-Blind and Open-Label Phases
Double-Blind Phase Open-Label Phase
All Patients
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Celecoxib 6 mg/kg BID
N = 202
Any event 49 (63.6) 57 (69.5) 60 (72.3) 96 (47.5)
Eye disorders 4 (5.2) 4 (4.9) 4 (4.8) 3 (1.5)
GI disorders 20 (26.0) 20 (24.4) 30 (36.1) 35 (17.3)
Abdominal pain 3 (3.9) 6 (7.3) 6 (7.2) 2 (1.0)
Abdominal pain upper 6 (7.8) 5 (6.1) 8 (9.6) 9 (4.5)
Vomiting 2 (2.6) 5 (6.1) 9 (10.8) 6 (3.0)
Diarrhea 4 (5.2) 3 (3.7) 7 (8.4) 11 (5.4)
Nausea 5 (6.5) 3 (3.7) 9 (10.8) 4 (2.0)
General disorders 10 (13.0) 9 (11.0) 15 (18.1) 14 (6.9)
Pyrexia 6 (7.8) 7 (8.5) 9 (10.8) 9 (4.5)
n (% of patients)
A71
Double-Blind Phase Open-Label Phase
All Patients
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Celecoxib 6 mg/kg BID
N = 202
Any event 49 (63.6) 57 (69.5) 60 (72.3) 96 (47.5)
Infections 19 (24.7) 16 (19.5) 22 (26.5) 38 (18.8)
Nasopharyngitis 4 (5.2) 5 (6.1) 4 (4.8) 8 (4.0)
Injury and poisoning 3 (3.9) 5 (6.1) 4 (4.8) 3 (1.5)
Investigations 2 (2.6) 9 (11.0) 6 (7.2) 6 (3.0)
Musculoskeletal disorders
6 (7.8) 8 (9.8) 14 (16.9) 18 (8.9)
Arthralgia 2 (2.6) 6 (7.3) 3 (3.6) 7 (3.5)
Nervous system disorders
13 (16.9) 9 (11.0) 17 (20.5) 17 (8.4)
Headache 10 (13.0) 8 (9.8) 13 (15.7) 13 (6.4)
Dizziness 1 (1.3) 1 (1.2) 6 (7.2) 0 (0.0)n (% of
patients)
Study 195: Adverse Events by System Organ Class Double-Blind and Open-Label Phases
A72
Study 195: Adverse Events by System Organ Class Double-Blind and Open-Label Phases
Double-Blind Phase Open-Label Phase
All Patients
Celecoxib 3 mg/kg BID
N=77
Celecoxib 6 mg/kg BID
N=82
Naproxen 7.5 mg/kg BID
N=83
Celecoxib 6 mg/kg BID
N = 202
Any event 49 (63.6) 57 (69.5) 60 (72.3) 96 (47.5)
Respiratory disorders 6 (7.8) 12 (14.6) 12 (14.5) 8 (4.0)
Cough 5 (6.5) 6 (7.3) 7 (8.4) 4 (2.0)
Skin disorders 8 (10.4) 6 (7.3) 15 (18.1) 10 (5.0)
n (% of patients)
A73
Study 195: Withdrawals due to Adverse Events
Open-Label Phase
Celecoxib 6 mg/kg BID
N = 202
Any Event 3 (1.5)
Allergic dermatitis
Gastritis
Gastroenteritis
n (%) of patients
A74
Study 195: Serious Adverse Events Open-Label Phase
Celecoxib 6 mg/kg BID
N = 202
Any Event 4 (2.0)
Myopericarditis
Non-accidental overdose, upper abdominal pain, vomiting
Lower respiratory tract infection
Sore throat, lymphadenopathy, pyrexia, torticollis
n (%) of patients
A75
Study 195: Summary of Open-Label Phase
Efficacy response to celecoxib was sustained for 24 weeks of treatment
The general safety profile during the open-label phase was similar to the double-blind phase
No new safety findings emerged
A76
Pharmacokinetics
Steady state PK evaluated in 152 JRA patients
Compared to adults, JRA patients require higher mg/kg doses to achieve similar plasma levels
A77
Parallel Pediatric Formulation Development Suspension Sprinkle Capsule
Multi-year development effort for traditional pediatric dosage forms
– Suspension used in Study 195 – Orally disintegrating tablet– Chewable tablet
Non-viable due to production, scaling,
stability or bioavailability
problems
A78
Parallel Pediatric Formulation Development Suspension Sprinkle Capsule
Multi-year development effort for traditional pediatric dosage forms
– Suspension used in Study 195 – Orally disintegrating tablet– Chewable tablet
Bridging strategy based on PK data to support use of sprinkle capsule (in applesauce) developed by sponsor
Proposal accepted by FDA (pre sNDA meeting, Jan 2006)
Non-viable due to production, scaling,
stability or bioavailability
problems
A79
Parallel Pediatric Formulation Development Suspension Sprinkle Capsule
Multi-year development effort for traditional pediatric dosage forms
– Suspension used in Study 195 – Orally disintegrating tablet– Chewable tablet
Bridging strategy based on PK data to support use of sprinkle capsule (in applesauce) developed by sponsor
Proposal accepted by FDA (pre sNDA meeting, Jan 2006)
Capsule dosing in JRA– JRA patients 10-25 kg: 50 mg BID– JRA patients >25 kg: 100 mg BID– Administration: As sprinkles or swallowed intact
Non-viable due to production, scaling,
stability or bioavailability
problems
A80
Study 195: Conclusions
Both doses of celecoxib were as effective as naproxen in treating the signs and symptoms of JRA
Adverse event profiles were similar between celecoxib and naproxen
The efficacy response to celecoxib was durable – Similar efficacy results after 24 weeks of
treatment as after 12 weeks
A81
Other Relevant Safety Data
Review of available safety data from various sources:
– Development / Growth
– General safety
– CV safety
A82
Summary of Data Review
Source Study Focus Conclusions
Nonclinical Juvenile toxicology
rat / dog
Development
Growth
No effect on development or growth
A83
Source Study Focus Conclusions
Nonclinical Juvenile toxicology
rat / dog
Development
Growth
No effect on development or growth
COX-2 inhibitor use in JRA
Rofecoxib study
General safety Similar to naproxen
Adult arthritis RCTsGeneral safety
GI safety
Similar to ns-NSAIDs
Favorable GI profile
Pediatric adverse reports
Spontaneous reports
General safety Similar to adult reports
Summary of Data Review
A84
Source Study Focus Conclusions
Nonclinical Juvenile toxicology
rat / dog
Development
Growth
No effect on development or growth
COX-2 inhibitor use in JRA
Rofecoxib study
General safety Similar to naproxen
Adult arthritis RCTsGeneral safety
GI safety
Similar to ns-NSAIDs
Favorable GI profile
Pediatric adverse reports
Spontaneous reports
General safety Similar to adult reports
Long-term placebo studies
Non-arthritis
APC
PreSAP
ADAPT
CV safetyCV risk vs placebo in
APC
CV Meta-analysis RCTs CV safetyNo increase in CV risk
vs ns-NSAIDs
Epidemiology studies
Case control
cohortCV safety
CV risk profile similar to ns-NSAIDs
Summary of Data Review
A85
Hypertension unusual, but increasingly diagnosed in general pediatric population
NSAIDs (selective + nonselective) associated with destabilization of controlled hypertension in adults
Hypertension second only to asthma and obesity as chronic conditions affecting children in the US
– Review of 8 studies from 47,196 school aged children
Systolic hypertension diagnosed in 4.4%
40-50% of JRA patients extend disease into young adult life
Association of hypertension and adverse long term CV outcomes well established in adults
National High Blood Pressure Working Group on High Blood Pressure in Children and Adolescents. Pediatrics 2004:114:555-5765; Cassidy and Petty. Textbook of Pediatric Rheumatology, 2005
A86
24-Hour Mean Systolic Blood Pressure Change OA Type II Diabetes Mellitus and Hypertensive Patients
Rofecoxib25 mg QD
N=138
6 Wks 12 Wks
Naproxen500 mg BID
N=130
6 Wks 12 Wks
Celecoxib200 mg QD
N=136
6 Wks 12 Wks
Sowers et al. Arch Int Med; 2005;165:161-168
Mea
n S
BP
Ch
ang
e (m
m H
g)
-3
-2
-1
0
1
2
3
4
5
6
A87
Safety Conclusions
Celecoxib has a similar safety / tolerability profile vs nonselective NSAIDs
– Use in children has not identified unique safety concerns
Adult data demonstrated significant increase in serious CV events (MI, CVA, CV death) in one of 3 placebo-controlled studies
– No evidence for increased CV risk vs nonselective NSAIDs– Class-labeled CV warnings for all NSAIDs
All NSAIDs associated with hypertension and destabilized blood pressure control
– No evidence that profile in children may be different
A88
Unknown Risks
Size and duration of Study 195 unable to exclude risk for rare events or latent toxicity beyond 6 months of treatment in JRA
Long term sequelae of effects on blood pressure by celecoxib in JRA and serious CV morbidity and mortality in adult life unknown– This effect is equally unknown for NSAIDs
A89
Pharmacovigilance and Postmarketing Activities
Tool Methodology Population Event of Interest
Enhanced Data Capture
Spontaneous reports
Adult and pediatric cases
Attention to indication / co-medications
CV / Cardiorenal events and
SCAR
Expert Dermatology Panel
Spontaneous reports
Adult and pediatrics
cases
SCAR
PRECISION Ongoing RCT Adult OA/RACV / Cardiorenal
events vs. NSAIDs
FAP Trial Ongoing RCT Pediatric FAP population Latent/Delayed events
Expert Pediatric Panel
Spontaneous reports
All pediatric casesUnexpected or rare
events
* RCT = randomized clinical trial; FAP = familial adenomatous polyposis; SCAR = severe cutaneous adverse reactions
A90
Overall Conclusions
Study 195 demonstrated efficacy noninferior to naproxen and met the requirements of the PWR
To inform physicians on appropriate use, labeling could range from minimal information through to approval of the indication
JRA affects many thousands of children – Characterized by pain, inflammation and impact
on function– Medical need for NSAIDs in this population
No evidence of a unique safety concern with celecoxib compared to other NSAIDs
There may be unknown risks of treatment shared by all NSAIDs