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NDAs 21-389/772 Etoricoxib. Robert B. Shibuya, M.D. Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products. Efficacy. 30 mg dose Four Phase 3 studies (2 vs. placebo and ibuprofen, 2 vs. placebo and celecoxib) All positive 60 mg dose
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NDAs 21-389/772Etoricoxib Robert B. Shibuya, M.D. Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products
Efficacy • 30 mg dose • Four Phase 3 studies (2 vs. placebo and ibuprofen, 2 vs. placebo and celecoxib) • All positive • 60 mg dose • Two Phase 3 studies (both vs. placebo and naproxen) • Both positive
Cross-study comparison of etoricoxib efficacy at 30 and 60 mg
MEDAL Program • MEDAL/EDGE/EDGE II Studies • R, DB, AC, PG trials of the “large simple” design • MEDAL enrolled OA/RA • EDGE enrolled OA • EDGE II enrolled RA • Active control = diclofenac 150 mg/day • Etoricoxib dosed at 60 or 90 mg/day
MEDAL Program • Endpoints • MEDAL = CV • EDGE/EDGE II = GI • All used identical adjudication procedures • N = 34,701, mean f/u = 20,19, and 9 months • EDGE/EDGE II collected data on less severe AEs • ASA/GPAs permitted
Non-MEDAL database • Comprised of 18 conventional Phase 2/3 studies • Populations: OA, RA, AS, CLBP • N = ~4,500 • Duration: 4 to 52 weeks • Controls: Placebo, Ibuprofen, Diclofenac, Naproxen, Celecoxib • Doses of etoricoxib: 5-120 • Collected data for all AEs • ASA/GPAs sometimes permitted, sometimes not
Relative vs. Attributable Risk • Relative Risk = Quotient of the rate in Group A and the rate in Group B (estimated by Cox Proportional Hazards Model) • Attributable Risk = Arithmetic difference in rates between Groups A & B
Mortality/Morbidity based on Attributable Risk Subgroup Analysis • Based on the point estimate, if etoricoxib were prescribed to 1,000,000 patients: • 490 excess patients would experience an APTC event on etoricoxib 60 mg than if they had taken diclofenac. • High estimate (upper limit of the 95% CI) - 2,300 excess events could occur compared to diclofenac treatment • Low estimate (lower limit of the 95% CI) – 1,300 fewer events could occur compared to diclofenac treatment
CV safety-non-MEDAL * Patient-years at risk ‡ Per 100 PYR ** Relative risk using Cox model stratified by therapeutic block where the number of cases is at least 11, otherwise relative risk is ratio of rates
GI Event Adjudication • Categorize • Confirmed vs. unconfirmed • Complicated vs. not complicated
UGI safety-non-MEDAL, confirmed PUBs only- *Number of events per 100 person-years **Relative risk was calculated using a Cox model stratified by protocol and with terms for treatment and the 3 risk factors. The p-value for testing the proportionality assumption is 0.546.
Prospective Studies Collaboration Lancet 2002 (Stroke mortality, left panel, IHD mortality, right panel)
Renovascular Safety Program • Effects on Blood Pressure • Discontinuations for HTN-related AEs • HTN-related AEs • Mean difference in baseline for systolic and diastolic BP • Proportions meeting prespecified increases in systolic and diastolic BP • Congestive Heart Failure • Edema • Pertinent laboratory abnormalities
Summary of Efficacy Findings • Etoricoxib is effective at doses of 30 and 60 mg/day. • One Phase 2 clinical trial shows some evidence of dose response between 5 and 60 mg with wide confidence intervals after 6 weeks of treatment. The differences between doses diminish as the study progressed beyond 6 weeks. • Cross-study comparisons do not show evidence of added benefit for the 60 mg dose.
Summary of Safety Findings • Cardiovascular thromboembolic events • As assessed by relative risk, the pooled MEDAL data show comparable CV risk versus diclofenac. • However, given the 95% CI, the attributable risk for etoricoxib compared to diclofenac could be as high as 2,300 excess events per million patient-years. • The non-MEDAL database suggests that etoricoxib is inferior to naproxen.
Summary of Safety Findings • Renovascular Safety • Etoricoxib 90 mg causes more hypertension, edema, and congestive heart failure than diclofenac. • Etoricoxib 60 mg causes more hypertension and slightly more edema and CHF than diclofenac. • Compared to other NSAIDs (celecoxib, ibuprofen, and naproxen), 30 and 60 mg of etoricoxib appears mixed for renovascular safety (conclusions less robust due to relatively low exposures compared to diclofenac).
Summary of Safety Findings • Gastrointestinal events • For medically significant upper GI events, etoricoxib approximates diclofenac and appears to be superior to naproxen. • For nonserious GI-related symptoms, etoricoxib is superior to diclofenac and naproxen.
