1. A1 29 November 2006 FDA Advisory Committee Meeting Celecoxib in the Treatment of the Signs and Symptoms of Juvenile Rheumatoid Arthritis (JRA)

2. A2 Delegation Dr Edward GianniniEpidemiology Cincinnati Children’s Hospital Medical Center Dr Benjamin GoldPediatric gastroenterology Emory University School of Medicine Dr Gary KochStatistician University of North Carolina at Chapel Hill Dr Daniel LovellPediatric rheumatology Cincinnati Children’s Hospital Medical Center Dr Robert SternDermatology Harvard Medical School

3. 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

4. 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

5. 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

6. A6 Emerging Data in 2004: CV Safety  September 30, 2004: Rofecoxib withdrawn due to increased CV risk vs placebo in the APPROVe trial 1,2  December 2004: Preliminary data from 1 out of 3 long-term trials with celecoxib showed increased CV risk vs placebo 3,4 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.

7. 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 http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html 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.html http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html Jenkins and Seligman. Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk. US Food and Drug Administration Memorandum 6 April 2005

8. 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.

9. 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

10. A10 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 stroke ADAPT Research Group. PLoS Clin Trials; 2006: 1:e33. doi:10.1371/journal.pctr.0010033

11. A11 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.

12. A12 Events in 2006 PRECISION 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

13. 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

15. 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

16. 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)

17. 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

18. 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

19. A19 Timeframe 2002  FDA issues final PWR  Celecoxib JRA Study initiated Recent Regulatory History of NSAIDs in JRA

20. A20 Timeframe 2002  FDA issues final PWR  Celecoxib JRA Study initiated 2004  Rofecoxib approved for use in JRA  APPROVe, APC, PreSAP, ADAPT preliminary data  Rofecoxib withdrawn Recent Regulatory History of NSAIDs in JRA

21. A21 Timeframe 2002  FDA issues final PWR  Celecoxib JRA Study initiated 2004  Rofecoxib approved for use in JRA  APPROVe, APC, PreSAP, ADAPT preliminary data  Rofecoxib withdrawn 2005  Celecoxib JRA Study completed  Class CV warnings for all NSAIDs  Meloxicam approved for use in JRA Recent Regulatory History of NSAIDs in JRA

22. A22 Timeframe 2002  FDA issues final PWR  Celecoxib JRA Study initiated 2004  Rofecoxib approved for use in JRA  APPROVe, APC, PreSAP, ADAPT preliminary data  Rofecoxib withdrawn 2005  Celecoxib JRA Study completed  Class CV warnings for all NSAIDs  Meloxicam approved for use in JRA 2006  Pfizer meets with FDA to agree on proposal for sNDA in JRA  sNDA filed  Advisory Committee convened Recent Regulatory History of NSAIDs in JRA

23. A23 Study 195 Celecoxib vs Naproxen in JRA

24. 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

25. 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

26. A26 Study 195: Exclusion Criteria  Presence of active systemic manifestations of JRA  Initiation of or changing the dose of medications: DrugStabilization Period Allowable Dose Range Methotrexate8 weeks  1 mg/kg/week or 40 mg maximum weekly dosage Other DMARDs12 weeks Sulfasalazine  3 grams/day Biologics12 weeks Gold Salts16 weeks Corticosteroids4 weeks Oral  0.2 mg/kg/day or 10 mg prednisone/day

27. A27 Study 195: Study Design Celecoxib 3 mg/kg BID (N= 77) Celecoxib 6 mg/kg BID (N= 82) 0 4128 Visits (Week) Screening 2 Naproxen 7.5 mg/kg BID (N= 83) 1624 Celecoxib 6 mg/kg BID (N= 202) Double-blindOpen-label NSAIDs were to be discontinued >5 half-lives prior to baseline visit.

28. A28 Study 195: Primary Endpoint  Percent of patients improved as defined by the ACR Pediatric 30 Response Criterion at Week 12 – ≥30% improvement in any 3 of 6 core set measures with no 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)

29. 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

30. 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

31. 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

32. A32 Study 195: Demographic Characteristics Celecoxib 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 years13 (16.9)16 (19.5)10 (12.0) 5 – 7 years9 (11.7)9 (11.0)11 (13.3) 8 – 12 years31 (40.3)35 (42.7)35 (42.2) 13 – 16 years24 (31.2)22 (26.8)27 (32.5) Gender, n (%) Female59 (76.6)53 (64.6)59 (71.1) Race, n (%) White41 (53.2)47 (57.3)52 (62.7) Black9 (11.7)7 (8.5)4 (4.8) Asian1 (1.3)3 (3.7)1 (1.2) Not listed26 (33.8)25 (30.5)26 (31.3)

33. 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 ± 2.83.8 ± 3.43.4 ± 3.2 JRA disease subtype, n (%) Pauciarticular course37 (48.1)45 (54.9)46 (55.4) Polyarticular course40 (51.9)37 (45.1)37 (44.6) Systemic onset, n (%)4 (5.2)10 (12.2)8 (9.6)

34. 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 ± 2.83.8 ± 3.43.4 ± 3.2 JRA disease subtype, n (%) Pauciarticular course37 (48.1)45 (54.9)46 (55.4) Polyarticular course40 (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 use35 (45.5)33 (40.2)34 (40.9) Any biologic use2 (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

35. 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 ± 2.341.1 ± 1.941.2 ± 1.8 Parent’s Global Assessment of Overall Well Being (0-100 mm) 38.4 ± 2.542.7 ± 2.245.0 ± 2.5 Parent’s Assessment of Physical Function (0-3 scale) 0.9 ± 0.1 Parent’s Assessment of Child’s Arthritis Pain (0-100 mm) 41.3 ± 2.841.5 ± 2.442.7 ± 2.3 Mean ± SE

36. A36 Study 195 Patient Disposition Double-Blind Phase Patients Randomized N = 242 Celecoxib 3 mg/kg BID N = 77 Celecoxib 6 mg/kg BID N = 82 Naproxen 7.5 mg/kg BID N = 83 Patients Withdrawn n = 10 (13.0%) Adverse event3 (3.9%) Lack of efficacy2 (2.6%) Consent withdrawn4 (5.2%) Lost to follow-up1 (1.3%) Protocol violation0 (0.0%) Patients Withdrawn n = 11 (13.4%) Adverse event7 (8.5%) Lack of efficacy1 (1.2%) Consent withdrawn2 (2.4%) Lost to follow-up0 (0.0%) Protocol violation1 (1.2%) Patients Completed n = 67 (87.0%) Patients Completed n = 71 (86.6%) Patients Completed n = 74 (89.2%) Patients Withdrawn n = 9 (10.8%) Adverse event3 (3.6%) Lack of efficacy4 (4.8%) Consent withdrawn1 (1.2%) Lost to follow-up0 (0.0%) Protocol violation1 (1.2%)

37. A37 Study 195 Efficacy

38. A38 Study 195 ACR Pediatric 30 Response Percentage of Responders 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 Percentage of Patients (95% CI)

39. A39 Study 195: ACR Pediatric 30 Response Difference 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%. Favors naproxen Favors celecoxib Treatment Difference

40. A40 Study 195: ACR Pediatric 30, 50, and 70 Response Percentage of Responders at Week 12 Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID Percentage of Patients (95% CI)

41. A41 Study 195: Percentage of Responders Core Set Measures at Week 12 (  30% improvement) * 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

42. A42 Study 195: Global Assessments Parent’s Global Assessment of Overall Well Being Physician’s Global Assessment of Disease Activity *p < 0.05, celecoxib 3 mg/kg BID vs naproxen Scales range from 0-100 mm * Week Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID

43. A43 Study 195: Joint Counts Active 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 BID Total joints = 73 Total joints = 67 Week * * * Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID

44. A44 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

45. A45 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

46. A46 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 Percentage of Patients (95% CI) Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID

47. A47 Study 195: ACR Pediatric 30 Response DMARD/Biologic Use N = 38 42 40 39 40 43 * p < 0.05 vs. celecoxib 3 mg/kg BID * Percentage of Patients (95% CI) Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID Week 12

48. A48 Study 195: Summary of Efficacy Double-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

49. A49 Study 195 Safety

50. A50 Study 195: Safety Results  Adverse events  Body weight  Cardiorenal  Hematology and biochemistry

51. A51 Safety Analyses – Double-Blind Phase

52. A52 Celecoxib 3 mg/kg BID N=77 Celecoxib 6 mg/kg BID N=82 Naproxen 7.5 mg/kg BID N=83 Any event49 (63.6)57 (69.5)60 (72.3) Eye disorders4 (5.2)4 (4.9)4 (4.8) Gastrointestinal disorders20 (26.0)20 (24.4)30 (36.1) Abdominal pain3 (3.9)6 (7.3)6 (7.2) Abdominal pain upper6 (7.8)5 (6.1)8 (9.6) Vomiting2 (2.6)5 (6.1)9 (10.8) Diarrhea4 (5.2)3 (3.7)7 (8.4) Nausea5 (6.5)3 (3.7)9 (10.8) General disorders10 (13.0)9 (11.0)15 (18.1) Pyrexia6 (7.8)7 (8.5)9 (10.8) Incidence ≥ 5% in any treatment group n (% of patients) Study 195: Adverse Events By System Organ Class—Double-Blind Phase

53. A53 Celecoxib 3 mg/kg BID N=77 Celecoxib 6 mg/kg BID N=82 Naproxen 7.5 mg/kg BID N=83 Infections19 (24.7)16 (19.5)22 (26.5) Nasopharyngitis4 (5.2)5 (6.1)4 (4.8) Injury and poisoning3 (3.9)5 (6.1)4 (4.8) Investigations2 (2.6)9 (11.0)6 (7.2) Musculoskeletal disorders6 (7.8)8 (9.8)14 (16.9) Arthralgia2 (2.6)6 (7.3)3 (3.6) Nervous system disorders13 (16.9)9 (11.0)17 (20.5) Headache10 (13.0)8 (9.8)13 (15.7) Dizziness1 (1.3)1 (1.2)6 (7.2) Study 195: Adverse Events By System Organ Class—Double-Blind Phase Incidence ≥ 5% in any treatment group n (% of patients)

54. 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 disorders6 (7.8)12 (14.6)12 (14.5) Cough5 (6.5)6 (7.3)7 (8.4) Skin disorders8 (10.4)6 (7.3)15 (18.1) Incidence ≥ 5% in any treatment group n (% of patients)

55. A55 Study 195: Serious 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 Event3 (3.9)2 (2.4)0 (0.0) Abdominal Pain*JRA aggravated* Cytomegalovirus hepatitis* Asthma* Viral Infection * Led to withdrawal from study n (%of patients)

56. 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 Event3 (3.9)7 (8.5)3 (3.6) DysphagiaHypersensitivityUpper abdominal pain Cytomegalovirus hepatitis Hematuria presentAbdominal pain, nausea, vomiting Abdominal pain and esophageal pain LFTs abnormalJRA, aggravated Transaminase increased Rash generalized JRA, aggravated Asthma n (% of patients)

57. A57 Study 195: Safety Results  Adverse events  Body weight  Cardiorenal  Hematology and biochemistry

58. A58 Study 195: Body Weight 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 LS mean change from baseline to Week 12/Final Visit ± SE (kg) 1.01 ± 0.171.01 ± 0.160.87 ± 0.16 ≥5% decrease from baseline, n (%) Week 12/Final visit0 / 69 (0)1 / 77 (1.3)1 / 79 (1.3) Any visit0 / 69 (0)1 / 77 (1.3)1 / 79 (1.3)

59. A59 Study 195: Safety Results  Adverse events  Body weight  Cardiorenal  Hematology and biochemistry

60. A60 Study 195: Systolic Blood Pressure Double-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)99.3101.3101.9 LS mean change from baseline ± SE 0.91 ± 1.090.76 ± 1.061.60 ± 1.05 ≥15% increase from baseline7 / 73 (9.6)5 / 80 (6.3)11 / 83 (13.3) ≥15% decrease from baseline5 / 73 (6.8)2 / 80 (2.5)1 / 83 (1.2)

61. 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)39.939.340.5 Mean change from baseline to Week 12/Final Visit ± SE -0.03 ± 0.970.74 ± 0.86-0.60 ± 0.80 Shift from normal value at baseline  above normal, n (%) Week 12/Final visit0 / 73 (0)0 / 80 (0)0 / 81 (0) Any visit0 / 73 (0)0 / 80 (0)0 / 81 (0) 2 – 12 years: normal = ≤92 µmol/L ≥13 years: normal = ≤110 µmol/L

62. A62 Study 195: Safety Results  Adverse events  Body weight  Cardiorenal  Hematology and biochemistry

63. A63 Study 195: Hemoglobin Double-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)123.2123.5123.6 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 visit1 / 71 (1.4)2 / 75 (2.7)2 / 77 (2.6) * p < 0.05 vs. celecoxib 6 mg/kg BID 2 years: normal = 110-140 g/L 3-5 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)

64. A64 Study 195: ALT Double-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)16.516.217.2 Mean change from baseline to Week 12/Final Visit ± SE 3.3 ± 2.842.0 ± 2.19-0.9 ± 1.00 Shift from normal value at baseline  above normal, n (%) Week 12/Final visit1 / 73 (1.4)1 / 80 (1.3)0 / 80 (0.0) Any visit1 / 73 (1.4)3 / 80 (3.8)0 / 80 (0.0) All patients: normal = ≤75 U/L

65. A65 Study 195: Safety Summary Double-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

66. A66 Study 195 Open-Label Phase

67. A67 Study 195: Patient Disposition 12-Week Open-Label Phase Celecoxib 6 mg/kg BID Completed Double Blind N = 71 Entered Open Label N = 62 (92.5%) Entered Open Label N = 70 (98.6%) Entered Open Label N = 70 (94.6%) Patients Withdrawn n = 7 (3.5%) Adverse event3 (1.5%) Consent withdrawn2 (1.0%) Protocol specific withdrawal criteria 1 (0.5%) Protocol violation1 (0.5%) Celecoxib 6 mg/kg BID N= 202 Patients Completed n = 195 (96.5%) Naproxen 7.5 mg/kg BID Completed Double Blind N = 74 Celecoxib 3 mg/kg BID Completed Double Blind N = 67

68. A68 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 naproxen Scale ranges from 0-100 mm.

69. A69 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

70. A70 Study 195: Adverse Events by System Organ Class Double-Blind and Open-Label Phases Double-Blind PhaseOpen-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)

71. A71 Double-Blind PhaseOpen-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

72. A72 Study 195: Adverse Events by System Organ Class Double-Blind and Open-Label Phases Double-Blind PhaseOpen-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)

73. A73 Study 195: Withdrawals due to Adverse Events Open-Label Phase Celecoxib 6 mg/kg BID N = 202 Any Event3 (1.5) Allergic dermatitis Gastritis Gastroenteritis n (%) of patients

74. A74 Study 195: Serious Adverse Events Open-Label Phase Celecoxib 6 mg/kg BID N = 202 Any Event4 (2.0) Myopericarditis Non-accidental overdose, upper abdominal pain, vomiting Lower respiratory tract infection Sore throat, lymphadenopathy, pyrexia, torticollis n (%) of patients

75. 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

76. 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

77. 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

78. 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

79. 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

80. 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

81. A81 Other Relevant Safety Data  Review of available safety data from various sources: – Development / Growth – General safety – CV safety

82. A82 Summary of Data Review SourceStudyFocusConclusions NonclinicalJuvenile toxicology rat / dog Development Growth No effect on development or growth

83. A83 SourceStudyFocusConclusions NonclinicalJuvenile toxicology rat / dog Development Growth No effect on development or growth COX-2 inhibitor use in JRA Rofecoxib study General safetySimilar to naproxen Adult arthritisRCTs General safety GI safety Similar to ns-NSAIDs Favorable GI profile Pediatric adverse reports Spontaneous reports General safetySimilar to adult reports Summary of Data Review

84. A84 SourceStudyFocusConclusions NonclinicalJuvenile toxicology rat / dog Development Growth No effect on development or growth COX-2 inhibitor use in JRA Rofecoxib study General safetySimilar to naproxen Adult arthritisRCTs General safety GI safety Similar to ns-NSAIDs Favorable GI profile Pediatric adverse reports Spontaneous reports General safetySimilar to adult reports Long-term placebo studies Non-arthritis APC PreSAP ADAPT CV safety CV risk vs placebo in APC CV Meta-analysisRCTsCV safety No increase in CV risk vs ns-NSAIDs Epidemiology studies Case control cohort CV safety CV risk profile similar to ns-NSAIDs Summary of Data Review

85. 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

86. A86 24-Hour Mean Systolic Blood Pressure Change OA Type II Diabetes Mellitus and Hypertensive Patients Rofecoxib 25 mg QD N=138 6 Wks12 Wks Naproxen 500 mg BID N=130 6 Wks12 Wks Celecoxib 200 mg QD N=136 6 Wks12 Wks Sowers et al. Arch Int Med; 2005;165:161-168 Mean SBP Change (mm Hg)

87. 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

88. 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

89. A89 Pharmacovigilance and Postmarketing Activities ToolMethodologyPopulationEvent 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 PRECISIONOngoing RCTAdult OA/RA CV / Cardiorenal events vs. NSAIDs FAP TrialOngoing RCTPediatric FAP populationLatent/Delayed events Expert Pediatric Panel Spontaneous reports All pediatric cases Unexpected or rare events * RCT = randomized clinical trial; FAP = familial adenomatous polyposis; SCAR = severe cutaneous adverse reactions

90. 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