AGGRENOX TM Advisory Committee Meeting. Manfred Haehl, MD. Senior Vice President, Medical & Drug Regulatory Affairs Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut. AGGRENOX TM Proposed Indication.
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Manfred Haehl, MD Senior Vice President, Medical & DrugRegulatory AffairsBoehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, Connecticut
AGGRENOXTM Proposed Indication • To reduce the combined risk of death and non-fatal stroke in patients who have had transient ischemia of the brainor completed ischemic stroke
FDA Approved Aspirin Label (1998) • “To reduce the combined risk of death and non-fatal stroke in patients who have had ischemicstroke or transient ischemia of the brain due to fibrin platelet emboli.” (dose 50–325 mg/d) • Based on relative risk reduction of 13–18%(63 FR 56802)
Nonfatal Stroke in Nine Randomized, Placebo-Controlled Trials1 of Aspirinin TIA or Stroke Patients Odds Reduction Aspirin Placebo (95% CI) P-Value2 ESPS-2 170/1649 213/1649 23 (4, 37) 0.019 Eight Other Studies 399/3406 372/2584 18 (5, 30) 0.010 Combined 569/5055 585/4233 20 (9, 29) <0.001 1AITIA (1977), AITIA (1978), AICLA (1983), DANISH (1983), SWEDISH (1987),SALT (1991), UK-TIA (1991), EAFT (1993). 2Cochran Mantel-Haenszel test, stratified by study.
ESPS-1 • 2500 patients, TID dosing • 75 mg dipyridamole instant/330 mg Aspirin • Placebo
ESPS-2 • 6602 patients, BID dosing • AGGRENOXTM • ASA • ER-DP • Placebo
Dipyridamole depot pellets Dipyridamole HP cellulose protective coating: water soluble polymers ASA Tartaric acid: dipyridamole solubiliser Sustained release coating: water insoluble polymers 200 mg ER–Dipyridamole Granules + 25 mg Immediate Release ASA
AGGRENOXTM ESPS-2 Findings • Highly significant additive risk reduction for stroke • Safety comparable to components • Trend (N.S.) reduction in death consistent with previous ASA findings • Robust and reliable findings
Characteristics of a Single Adequate and Well-Controlled Study for Effectiveness Claim • Large multicenter study • Consistency across study subsets • Multiple studies in a single study • Multiple endpoints involving different events • Statistically very persuasive finding
FDA Regulations for Fixed-Combination Prescription Drugs (21 CFR § 300.50) • Each component makes a contributionto the claimed effects • The dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy
Participants and Guests • J. Donald Easton, MD (Professor and Chairmanof Neurology, Brown University – RI Hospital) • David G. Sherman, MD (Professor and Chief of Neurology, The University of Texas Health Science Center) • Charles Hennekens, MD (Visiting Professor of Epidemiology and Public Health, University of Miami, School of Medicine, Miami, FL and Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK)
Participants and Guests • John Pathy, MD (Director and Emeritus Professor, Health Care Research Unit, University of Wales, Cardiff) • Hans Christoph Diener, MD (Professor and Chairman Department of Neurology, University of Essen, Germany)
Agenda Introduction Manfred Haehl, MD Senior Vice President for Medical & Drug Regulatory Affairs Boehringer Ingelheim Pharmaceuticals Stroke Management Gregory W. Albers, MD Associate Professor of Neurology Director of the Stanford Stroke Center Development Rationale Thomas Müller, MD, PhD Head, Haemostasis Laboratory Blood Transfusion Center of the German Red Cross Oldenburg, Germany Clinical Findings Efficacy James Street, PhD Sr. Biostatistician Boehringer Ingelheim Pharmaceuticals Safety Kenneth J. Rakowski, MD Head, Drug Surveillance and Information Boehringer Ingelheim Pharmaceuticals Conclusions Manfred Haehl, MD