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29 November 2006

FDA Advisory Committee Meeting. 29 November 2006. Celecoxib in the Treatment of the Signs and Symptoms of Juvenile Rheumatoid Arthritis (JRA). Delegation. Objectives. To highlight the medical need for NSAIDs in the treatment of children with JRA.

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29 November 2006

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

  2. Delegation

  3. Objectives To highlight the medical need for NSAIDs in the treatment of children with JRA 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

  4. 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. 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. Emerging Data in 2004: CV Safety • September 30, 2004: Rofecoxib withdrawn due to increased CV risk vs placebo in the APPROVe trial1,2 • December 2004: Preliminary data from 1 out of 3 long-term trials with celecoxib showed increased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.

  7. 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.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. 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. 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. ADAPT: Composite CV Events Hazard Ratio (95% CI) APTC Celecoxib 1.14 (0.61, 2.15) 1.57 (0.87, 2.81) Naproxen APTC/CHF Celecoxib 1.06 (0.60, 1.88) Naproxen 1.66 (1.00, 2.77) APTC/CHF/TIA Celecoxib 1.10 (0.67, 1.79) Naproxen 1.63 (1.04, 2.55) Favors placebo Favors NSAID APTC events = CV death, nonfatal MI, nonfatal stroke ADAPT Research Group. PLoS Clin Trials; 2006: 1:e33. doi:10.1371/journal.pctr.0010033

  11. CV Risk of NSAIDs Relative CV Risk (95% CI) Naproxen 0.97 (0.87, 1.07) Celecoxib 1.06 (0.91, 1.23) Piroxicam 1.06 (0.70, 1.59) Ibuprofen 1.07 (0.97, 1.18) 1.25 (1.00, 1.55) Meloxicam 1.30 (1.07, 1.60) Indomethacin 1.35 (1.15, 1.59) Rofecoxib 1.40 (1.16, 1.70) Diclofenac Worse than Non-use/Remote Exposure Better than Non-use/Remote Exposure McGettigan and Henry. JAMA 2006; 296(13):1633-1644.

  12. 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

  13. 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

  14. 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. 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)

  16. Celecoxib Pediatric Written RequestKey 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

  17. Celecoxib Pediatric Written RequestKey Elements 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

  18. Recent Regulatory History of NSAIDs in JRA

  19. Recent Regulatory History of NSAIDs in JRA

  20. Recent Regulatory History of NSAIDs in JRA

  21. Recent Regulatory History of NSAIDs in JRA

  22. Study 195Celecoxib vs Naproxen in JRA

  23. 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

  24. 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

  25. Study 195: Exclusion Criteria

  26. Study 195: Study Design Celecoxib 3 mg/kg BID (N= 77) Celecoxib 6 mg/kg BID (N= 82) Screening Celecoxib 6 mg/kg BID (N= 202) Naproxen 7.5 mg/kg BID (N= 83) Visits (Week) 2 4 8 12 16 24 0 Double-blind Open-label NSAIDs were to be discontinued >5 half-lives prior to baseline visit.

  27. 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%

  28. 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

  29. 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

  30. 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

  31. Study 195: Demographic Characteristics

  32. Study 195: Baseline Characteristics

  33. Study 195: Baseline Characteristics DMARDs/biologics used: azathioprine, hydroxychloroquine sulfate, methotrexate, sulfasalazine, etanercept infliximab

  34. Study 195: Baseline Disease Characteristics Mean ± SE

  35. Study 195 Patient DispositionDouble-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 Completed n = 67 (87.0%) Patients Completed n = 71 (86.6%) Patients Completed n = 74 (89.2%)

  36. Study 195 Efficacy

  37. Study 195 ACR Pediatric 30 ResponsePercentage of Responders Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID Percentage of Patients (95% CI) Week Responder: 30% improvement in 3 core set variables and no more than 1 variable worsening by >30%.

  38. 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%) Celecoxib 3 mg/kg BID 13.0%, (-0.2%, 26.3%) Celecoxib 6 mg/kg BID Favors naproxen Favors celecoxib Treatment Difference 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%.

  39. 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 Percentage of Patients (95% CI)

  40. Study 195: Percentage of RespondersCore Set Measures at Week 12 (30% improvement) Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID * p < 0.05 vs celecoxib 3 mg/kg BID

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

  42. Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID Study 195: Joint CountsActive Arthritis and Limited Range of Motion Number of Joints with Active Arthritis Number of Joints with Limited Range of Motion * * * Week *p < 0.05, celecoxib 3 mg/kg BID vs celecoxib 6 mg/kg BID Total joints = 73 Total joints = 67

  43. Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID Study 195: Functional Ability and CRP Functional Ability CRP Week Scale ranges from 0-3

  44. Celecoxib 3 mg/kg BID Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID Study 195: Parent’s Assessment of Child’s Arthritis Pain (VAS) Week Scale ranges from 0-100 mm

  45. Study 195: ACR Pediatric 30 Response JRA Course Celecoxib 3 mg/kg BID Week 12 Celecoxib 6 mg/kg BID Naproxen 7.5 mg/kg BID * Percentage of Patients (95% CI) N = 37 45 46 40 37 37 p < 0.05 vs. celecoxib 3 mg/kg BID and naproxen

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

  47. 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

  48. Study 195 Safety

  49. Study 195: Safety Results • Adverse events • Body weight • Cardiorenal • Hematology and biochemistry

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