1. Celecoxib for JRA: Assessing Risks & Benefits Jeffrey Siegel, M.D. FDA/CDER/ODE2/DAARP Arthritis Advisory Committee November 29, 2006

2. 2 Juvenile Rheumatoid Arthritis (JRA) Serious chronic arthritic condition of children –associated with significant disability in many cases Treatment: –non-steroidal anti-inflammatory drugs (NSAIDs) for anti- inflammatory & analgesic effects –disease-modifying drugs Physicians commonly have to try variety of NSAIDs before finding one that is tolerated and provides adequate pain relief Additional options for pain relief an important goal

3. 3 Risk/Benefit Relationship Since most drugs have at least some side effects, assessing utility involves weighing benefits against the risks Potential benefits generally assessed based on available clinical trial data Risks assessed based on: –Clinical trial data –Post-marketing information –Other information known for products in same class

4. 4 Outline Review efficacy data –Limitations relating to trial design Review safety data –Celecoxib trial in JRA –Post-marketing data –Concerns based on other information for COX-2 selective and non-selective NSAIDs

5. Efficacy

6. 6 Clinical Trial Design Randomized, double-blind, active controlled trial comparing celecoxib 6 or 12 mg/kg/d with naproxen 15 mg/kg/d –3 mo randomized, blinded phase followed by 3 mo open-label celecoxib 12 mg/kg/d Designed to exclude non-inferiority of celecoxib to naproxen

7. 7 Non-Inferiority Trials 0 -10 10 20 30 40 50 60 70 80 -20 Non- inferiority margin 25% Study Drug Active comparator Difference between Treatments Point estimate for active comparator = 60% Percent Responders

8. 8 Results Primary endpoint: JRA DOI 30 that measures improvement in composite of: –Physician and parent/patient global assessment, function, joints with active arthritis, joints with limited ROM, C-reactive protein Trial met prespecified endpoint excluding non-inferiority margin of celecoxib to naproxen of 25%

9. 9 Does Study Result Clearly Demonstrate Efficacy? While FDA reviewed the trial design and agreed that it was in general terms acceptable, there are nonetheless concerns about the conclusions that can be reached from the study Inferring efficacy of celecoxib from study results requires making a judgment about the adequacy of the pre-specified 25% non-inferiority margin If 25% is too large then the statistical demonstration of non-inferiority may not by itself allow a determination of efficacy

10. 10 Caveats with Non-Inferiority Designs Inferring efficacy in a trial comparing drug to active comparator requires making an assumption about how placebo-treated patients would have done if a placebo arm had been included A non-inferiority margin is set to make sure drug is efficacious, i.e., that it retains some portion of the effect size of the active comparator –For example, if placebo response is expected to be 30% and active comparator 60% then margin could be set at 15% (half of 60% minus 30%) to retain at least half of the effect size

11. 11 Non-Inferiority Margins Two methods for setting margins: –Review all placebo-controlled trials of active comparator and set margin at some portion (e.g., 50%) of effect size (response to drug minus response to placebo) –Set margin based on clinically ignorable margin Method used for renal transplant trials where margin often set at 10% when comparing drug to a calcineurin inhibitor

12. 12 Setting Non-Inferiority Margin for Celecoxib For JRA trial using naproxen as active comparator cannot use placebo-controlled trials to set margin because none are available Employing second method to set margin requires making an assumption about the effect size of naproxen: –If effect size is 50%, then 25% margin would exclude loss of half of effect –If effect size is 25%, then 25% margin would not distinguish an effective drug from an ineffective drug

13. 13 Data on Placebo Responses in JRA Trials Few data are available on placebo response rates in trials of JRA patients using JRA DOI 30 A recent placebo-controlled 3-month trial of infliximab reported 48% placebo response If we assume a placebo response rate in celecoxib trial of 48% then 68% response rate with naproxen would imply an effect size of 20% –Other assumptions for placebo response would provide different estimates for naproxen effect size

14. 14 Implications Depending on assumptions for the effect size of active comparator the 25% non- inferiority margin may be too large If pre-specified margin is inadequate then it is necessary to consider the totality of the data to judge whether the trial demonstrated efficacy of celecoxib

15. 15 Other Relevant Data In JRA trial, response rate for celecoxib 6 mg/kg/d was 69%, compared to 68% for naproxen –Excludes non-inferiority of 13% Higher response rate with celecoxib 12 mg/kg/d is informative but this is not dose proposed for marketing –In addition, higher doses of celecoxib in adults shown to be less safe than lower doses in longer-term studies

16. 16 Efficacy: Summary Celecoxib 6 mg/kg/d met pre-specified endpoint excluding 25% non-inferiority margin Depending on effect size assumed for naproxen 25% margin may not be optimal Therefore, assessment of efficacy depends on evaluation of totality of the data

17. Safety

18. 18 Exposure in Study 195 242 children enrolled in randomized portion of study receiving celecoxib 6 or 12mg/kg/d or naproxen 15 mg/kg/d for 3 months 202 enrolled in subsequent 3-month open- label phase receiving celecoxib12 mg/kg/d for 3 months

19. 19 Safety in Study 195 At dose proposed for marketing most common adverse events were GI, infections and infestations, and nervous system disorders Respiratory disorders, eye disorders, metabolic disorders more frequent with celecoxib 6 mg/kg/d than naproxen Overall, common adverse events similar in type and frequency to those seen with naproxen

20. 20 Serious Adverse Events In Study 195, SAEs seen more frequently with celecoxib include GI disorders (upper abdominal pain), pyrexia and musculoskeletal, connective tissue and bone disorders –Skin reactions and allergic reactions also observed Overall serious adverse events and severe adverse events seen in children receiving celecoxib represented events seen in this patient population and events known to be associated with other NSAIDs

21. 21 Post-Marketing Reports Review of post-marketing database gave no new safety signals reported for children receiving celecoxib off-label

22. 22 Celecoxib: Toxicology Studies in Juvenile Animals Two juvenile animal models, repeat-dose toxicity studies: –7-Week Study, initiated in 7-day-old rats –5-Month Study, initiated in 10-week-old dogs No toxicity with respect to growth or development; Increased sensitivity to gastrointestinal effects (ulceration with peritonitis) and skin effects (cutaneous/subcutaneous ulcerations) compared to previous toxicity studies in adult animals. “No Effect” levels in juvenile animal studies provide a margin of safety for clinical use in pediatric patients.

23. 23 Celecoxib: Pharmacology and Toxicology (cont.) Reproductive tract effects in juvenile rat: –Unilateral or bilateral enlargement of the testes and prominent tubules in the epididymal fat pad; –Microscopic evidence of spermatocele and minimal to slight unilateral or bilateral dilatation of seminiferous tubules and epididymal hypospermia in all celecoxib- treated groups. Of note: –Similar findings in a single control rat –No dose response in the rat –Findings not observed in juvenile dog or in adults of either species Clinical implications of these findings are under review.

24. 24 Risks Associated with NSAID Class Adverse events associated with NSAID class include cardiovascular toxicity, GI toxicity, fluid retention, edema, renal toxicity, hepatic enzyme elevation and bronchospasm in patients with aspirin-sensitive asthma One case of liver enzyme elevations and one case of severe asthma seen in Study 195 Overall these adverse events not seen at a rate clearly higher than naproxen

25. 25 Risk of GI Bleeding COX-2 selective class of NSAIDs originally developed to reduce life-threatening GI bleeds While celecoxib shown to reduce GI ulcers endoscopically incidence of clinical GI bleeds not shown to be reduced In children, GI bleeding an uncommon adverse event with NSAIDs

26. 26 Cardiovascular Risks Data indicate an increased risk of cardiovascular thromboembolic events, in particular myocardial infarction, in adults treated long-term with COX-2 selective NSAIDs, including celecoxib Risk of cardiovascular events with non- selective NSAIDs not clearly less than COX-2 selective NSAIDs

27. 27 Cardiovascular Risks in Children Given that it is primarily adults who are at risk for cardiovascular thromboembolic events such events were not expected in the celecoxib trial and none were observed However, long-term risk for children treated with celecoxib is unknown Cardiovascular risk a potential concern in children with JRA in view of: –Risk of accelerated atherosclerosis associated with inflammatory rheumatic disease in adults (e.g., SLE, RA) –Recognition that increasing numbers of children have risk factors for cardiovascular disease, e.g., obesity, hypertension, hyperlipidemia, type II DM.

28. 28 Safety: Summary Overall, risk of adverse events was similar in children receiving celecoxib as those receiving naproxen Overall safety profile in study 195 similar to that known for NSAID class

29. 29 Considerations in Assessing Risk/Benefit Relationship In assessing the risk/benefit relationship for celecoxib in JRA it is important to consider: –the observed safety profile of celecoxib in JRA –the known risks of NSAIDs in this patient population –potential long-term risks based on knowledge gained from studies in adults Given potential risks important to consider need for new NSAIDs for children with JRA to supplement products currently available