29 November 2006

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September 30, 2004: Rofecoxib withdrawn due to increased CV risk vs placebo in the APPROVe trial1,2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

http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html

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





Overall conclusions

Dr S Lowry

Dr D Lovell

Dr S Lowry

A15





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


2004

Rofecoxib approved for use in JRAAPPROVe, APC, PreSAP, ADAPT preliminary dataRofecoxib withdrawn


A21

Timeframe


2004


2005

Celecoxib JRA Study completedClass CV warnings for all NSAIDsMeloxicam approved for use in JRA


A22

Timeframe


2004


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


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)


0 4 128Visits (Week)

Screening

2

Naproxen 7.5 mg/kg BID (N= 83)

16 24


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


N = 77


N = 82


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


N = 77


N = 82


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


N = 77


N = 82


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%)






Patients Completedn = 67 (87.0%)



Patients Withdrawn

n = 9 (10.8%)






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%.




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


Week 12 Responder Analysis: Celecoxib - Naproxen (95% CI)


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




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




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




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

**** **




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




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




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



A52


N=77


N=82


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


N=77


N=82


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)



A54



N=77


N=82


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)


A55

Study 195: Serious Adverse EventsDouble-Blind Phase


N=77


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


N=77


N=82


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


Adverse events

Body weight

Cardiorenal


A58

Study 195: Body WeightDouble-Blind Phase


N=77


N=82


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


Adverse events

Body weight

Cardiorenal


A60

Study 195: Systolic Blood PressureDouble-Blind Phase—Changes at Week 12/Final Visit


N=77


N=82


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


N=73


N=80


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


Adverse events

Body weight

Cardiorenal


A63

Study 195: HemoglobinDouble-Blind Phase


N=71


N=75


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


N=73


N=80


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%)



Patients Withdrawn

n = 7 (3.5%)



Protocol specific withdrawal criteria

1 (0.5%)


Celecoxib 6 mg/kg BIDN= 202


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

**




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




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


N=77


N=82


N=83


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


All Patients


N=77


N=82


N=83


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)


A72



All Patients


N=77


N=82


N=83


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


N = 202

Any Event 3 (1.5)

Allergic dermatitis

Gastritis

Gastroenteritis

n (%) of patients

A74

Study 195: Serious Adverse Events Open-Label Phase


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




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)



problems

A79




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



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



rat / dog

Development

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


A84



rat / dog

Development

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


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

29 November 2006

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