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P-1,Joint Meeting of the Arthritis and Drug Safety and Risk Management Advisory Committees,February 16-18, 2005,太原房产网 ,P-2,Leonard M. Baum, RPh,Vice President, Regulatory AffairsBayer HealthCareConsumer Care Division,P-3,Agenda,Regulatory Overview NaproxenADAPT TrialSafety EvaluationClinical PharmacologyClinical Studies Postmarketing SurveillanceObservational StudiesConclusions,P-4,Roche/Bayer Presenters and Responders,Presenters: Leonard M. Baum, RPhVice President, Regulatory AffairsBayer HealthCareMartin H. Huber, M.D.Vice President, Global Head Drug Safety Risk ManagementHoffmann La-Roche Inc.Responders:Susan Sacks, Ph.D.Global Head, EpidemiologyHoffmann La-Roche Inc.Bharat Thakrar, Ph.D.Senior EpidemiologistHoffmann La-Roche Inc.,Ernst Weidmann, M.D.Head, Global SafetyBayer HealthCareSteve Zlotnick, Pharm.D.Director, Medical Affairs Bayer HealthCare,P-5,Outside Experts,Kay Brune, M.D.Professor and ChairmanDepartment of Experimental and Clinical Pharmacology and ToxicologyFriedrich-Alexander University Erlangen - NurembergIan M. Gralnek, M.D., MSHSAssistant Professor of Medicine, Division of Digestive DiseasesDavid Geffen School of Medicine at UCLA,P-6,Regulatory Overview,Naproxen available in the United States since 1976Prescription currently marketed by multiple manufacturers for the treatment of RA, OA, ankylosing spondylitis, gout, juvenile RA, dysmenorrhea, tendinitis, bursitis, and painAleve (OTC) approved in 1994 Currently marketed by Bayer HealthCare for temporary relief of minor aches and pains, and for the temporary reduction of feverMultiple generic versions,P-7,Naproxen,Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), belongs to the chemical class propionic acid derivativesNaproxen has anti-inflammatory, analgesic and antipyretic propertiesNaproxen known to inhibit platelet aggregationThe major differences between members of the NSAID class are potency and pharmacokinetics,P-8,Classes of NSAIDS,Salicylic acid derivativesAspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisalPara-aminophenol derivativesAcetaminophenIndole and indene acetic acidsIndomethacin, sulindacHeteroaryl acetic acidsTolmetin, diclofenac, ketorolacPropionic acidsNaproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozinAnthranilic acids (fenamates)Mefenamic acid, meclofenamic acidEnolic acidsOxicams (piroxicam, meloxicam)AlkanonesNabumetoneCoxibsCelecoxib, valdecoxib, rofecoxib (withdrawn),Source: Goodman and Gilmans The Pharmacological Basis of Therapeutics, 10th edition,P-9,Relevance of Naproxen Data,The safety profile for naproxen is well knownNaproxen is a reference drug for many analgesic clinical trialsNaproxen and other non-selective NSAIDs, are important treatment options for a broad range of patients and conditions,P-10,Naproxen Exposure Data (Rx and OTC),*courses of therapy (2 tab x 10 days),P-11,The ADAPT Trial,NIH sponsored studyBayer provided naproxen sodium for investigational use Study DesignNaproxen sodium 220 mg bidCelecoxib 200 mg bidPlacebo Patient Population 2400 patients, age 70 years or older, for prevention of Alzheimers diseaseStudy DurationBegan in 2001, planned for 7 years, suspended after 3 years,Sources: NIH News Dec 20, 2004; W Feb 1, 2005, written by Woloshin S et al.,P-12,Publicly Reported Events Leading to the Suspension of ADAPT,DSMB review on Dec. 10, 2004 did not recommend stopping the study The APC study was suspended due to indications of an increase in cardiovascular and cerebrovascular risk of celecoxib vs. placebo (Dec. 17, 2004)NIA announced ADAPT trial suspension (Dec. 20, 2004)Information released to public by study group, were based on preliminary findings, not through peer-reviewed journals,Sources: Celebrex News Release Dec 17, 2004; NIH News Dec 20, 2004; W Feb 1, 2005, written by Woloshin S et al.,P-13,Summary,Naproxen is a non-selective COX-1 / COX-2 inhibitorWidely used Established safety profileReference standardUnadjudicated preliminary findings of ADAPT needs to be looked at in context of the wide body of data on naproxen,P-14,Martin H. Huber, MD,Global Head, Drug SafetyHoffmann-La Roche Inc.,P-15,Safety Evaluation,Clinical PharmacologyClinical Studies Post-Marketing Safety SurveillancePost-Marketing Clinical StudiesObservational Studies,P-16,Pharmacological Difference between Naproxen and COX-2 Inhibitors,Naproxen is a non-selective COX-1 /COX-2 inhibitorNaproxen is known to inhibit platelet aggregation and thus, is not expected to have an increased risk of myocardial infarction,P-17,Clinical Trials and Post-Marketing Surveillance,Clinical trials in the prescription and OTC naproxen NDAs did not provide any evidence of an increased risk of myocardial infarction or stroke A review of postmarketing surveillance data showed no signal for MI or cerebrovascular accident with exposures to prescription naproxen of more than 110,000,000 patients A review OTC postmarketing surveillance data did not identify a signal for MI or CVA with an estimate of 550,000,000 courses of therapy,P-18,Proportional Reporting Rate (PRR),Source: Evans S et al. Pharmacoepidemiology and Drug Safety 2001; 10: 483-86,P-19,Post-Marketing Clinical Trials,VIGORRandomized RA patients 50 yo (or 40 yo and receiving long-term glucocorticoid therapy) into either rofecoxib 50mg qd (N=4,047) or naproxen 500mg bid (N=4,029)Overall rate of cardiovascular events reported in association with naproxen is consistent with that expected in this population MI: Rofecoxib (0.4%) vs. naproxen (0.1%)Ischemic cerebrovascular events: 0.2% in both arms,Source: Bombardier C et al. NEJM 2000; 343:1520-8,P-20,Post-Marketing Clinical Trials,TARGETRandomized OA patients 50 yo into either lumiracoxib 400mg qd (N=9,156), naproxen 500mg bid (N=4,754) or ibuprofen 800mg tid (N=4,415)Naproxen arm showed lower rates for cerebrovascular events and MI:Stroke: Lumiracoxib (0.34%) vs. naproxen (0.25%)Ischemic stroke: Lumiracoxib (0.32%) vs. naproxen (0.23%)Hemorrhagic stroke: 0.02% in both armsAcute MI: Lumiracoxib (0.38%) vs. naproxen (0.23%),Source: Farkouh ME et al. Lancet 2004; 364: 675-84,P-21,Post-Marketing Clinical Trials,TARGET (cont.)Rate of MI events was lower for naproxen than ibuprofen, using lumiracoxib as the reference point for both studies,Source: Farkouh ME et al. Lancet 2004; 364: 675-84,* Given in percent of patients with confirmed or probable cardiovascular and cerebrovascular events,P-22,Additional Post-Marketing Clinical Trials,Alzheimers TrialRandomized mild to moderate AD patients (mean age: 74 yo) into either rofecoxib 25mg qd, naproxen sodium 220mg bid, or placebo,Source: Aisen PS et al. JAMA 2003; 289: 2819-26,P-23,Trials with Celecoxib,Pooled analysis of 41 celecoxib clinical trials (White et al)2271 naproxen patients1 non-fatal stroke 1 fatal stroke2 non-fatal MIsNaproxen (relative to celecoxib): 4/393 (1.01 per 100 patient years)Celecoxib (relative to NSAIDs): 56/4,969 (1.13 per 100 patient years)Placebo (relative to celecoxib): 3/200 (1.5 per 100 patient years)There is no evidence of an increased risk of MI or stroke compared to either celecoxib or placebo,Source: White et al. Am J Cardiology 2003; 92: 411-18,P-24,Observational Studies,Case control studies and retrospective cohort studies can be performed in a shorter period of timeOpportunity to detect/evaluate relatively infrequent eventsReflect “real world” use of the drug More heterogeneous populationsConcomitant medications, concurrent illnessesValue of observational studies increases when these studies are done in multiple populations,Source: Strom B, Pharmacoepidemiology 2000; Wiley and Sons,P-25,Summary of observational studies of naproxen and MI,Source: Juni et al. Lancet 2004;364:2021-29,P-26,Sensitivity Analysis of Observational Studies,Meta-analysis included multiple studies from same databasesPerformed analysis including only one study from GPRD and one study from Tennessee MedicaidExc