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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 Affairs Bayer HealthCare Consumer Care Division,P-3,Agenda,Regulatory Overview Naproxen ADAPT Trial Safety Evaluation Clinical Pharmacology Clinical Studies Postmarketing Surveillance Observational Studies Conclusions,P-4,Roche/Bayer Presenters and Responders,Presenters: Leonard M. Baum, RPh Vice President, Regulatory Affairs Bayer HealthCare Martin H. Huber, M.D. Vice President, Global Head Drug Safety Risk Management Hoffmann La-Roche Inc. Responders: Susan Sacks, Ph.D. Global Head, Epidemiology Hoffmann La-Roche Inc. Bharat Thakrar, Ph.D. Senior Epidemiologist Hoffmann La-Roche Inc.,Ernst Weidmann, M.D. Head, Global Safety Bayer HealthCare Steve Zlotnick, Pharm.D. Director, Medical Affairs Bayer HealthCare,P-5,Outside Experts,Kay Brune, M.D. Professor and Chairman Department of Experimental and Clinical Pharmacology and Toxicology Friedrich-Alexander University Erlangen - Nuremberg Ian M. Gralnek, M.D., MSHS Assistant Professor of Medicine, Division of Digestive Diseases David Geffen School of Medicine at UCLA,P-6,Regulatory Overview,Naproxen available in the United States since 1976 Prescription currently marketed by multiple manufacturers for the treatment of RA, OA, ankylosing spondylitis, gout, juvenile RA, dysmenorrhea, tendinitis, bursitis, and pain Aleve (OTC) approved in 1994 Currently marketed by Bayer HealthCare for temporary relief of minor aches and pains, and for the temporary reduction of fever Multiple generic versions,P-7,Naproxen,Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), belongs to the chemical class propionic acid derivatives Naproxen has anti-inflammatory, analgesic and antipyretic properties Naproxen known to inhibit platelet aggregation The major differences between members of the NSAID class are potency and pharmacokinetics,P-8,Classes of NSAIDS,Salicylic acid derivatives Aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal Para-aminophenol derivatives Acetaminophen Indole and indene acetic acids Indomethacin, sulindac Heteroaryl acetic acids Tolmetin, diclofenac, ketorolac Propionic acids Naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin Anthranilic acids (fenamates) Mefenamic acid, meclofenamic acid Enolic acids Oxicams (piroxicam, meloxicam) Alkanones Nabumetone Coxibs Celecoxib, 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 known Naproxen is a reference drug for many analgesic clinical trials Naproxen 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 study Bayer provided naproxen sodium for investigational use Study Design Naproxen sodium 220 mg bid Celecoxib 200 mg bid Placebo Patient Population 2400 patients, age 70 years or older, for prevention of Alzheimers disease Study Duration Began 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 inhibitor Widely used Established safety profile Reference standard Unadjudicated 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 Safety Hoffmann-La Roche Inc.,P-15,Safety Evaluation,Clinical Pharmacology Clinical Studies Post-Marketing Safety Surveillance Post-Marketing Clinical Studies Observational Studies,P-16,Pharmacological Difference between Naproxen and COX-2 Inhibitors,Naproxen is a non-selective COX-1 /COX-2 inhibitor Naproxen 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,VIGOR Randomized 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,TARGET Randomized 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 arms Acute 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 Trial Randomized 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 patients 1 non-fatal stroke 1 fatal stroke 2 non-fatal MIs Naproxen (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 time Opportunity to detect/evaluate relatively infrequent events Reflect “real world” use of the drug More heterogeneous populations Concomitant medications, concurrent illnesses Value 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 databases Performed analysis including only one study from GPRD and one study from Tennessee Medicaid