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DAPT: Safety findings, and FDA’s General Approach to Safety Findings Cardiovascular Research Technologies (CRT) 2015 February 24, 2015 Ellis F. Unger, M.D. Director Office of Drug Evaluation-I Office of New Drugs Center for Drug Evaluation and Research (CDER) US FDA 1 I have no financial interests in any drug or medical device. Ellis F. Unger, M.D. Director Office of Drug Evaluation-I Office of New Drugs Center for Drug Evaluation and Research (CDER) US FDA 2 3 …However, in patients with a drug-eluting stent, the overall death rate was higher among those receiving 30 months of dual antiplatelet therapy compared to those receiving 12 months (2.0% vs. 1.5% respectively), explained by an increase in noncardiovascular deaths (1% vs. 0.5%; HR 2.2, p=0.002). The most frequent causes of non-cardiovascular death were cancer (34 vs. 17 deaths) and trauma (8 vs. 2 deaths) for 30 months and 12 months of therapy, respectively. The increase in overall mortality was observed in the clopidogrel cohort (2.2% vs. 1.5%, respectively) but not the prasugrel cohort (1.6% vs. 1.6%). It should be noted that in other large clopidogrel trials, increases in risk of non-cardiovascular death have not been observed. Outcomes in patients receiving bare metal stents are still being evaluated. FDA will continue to evaluate the information from this trial and other available data, and will communicate again when our evaluation is complete. 4 Mortality in DAPT 5 Safety Findings in Clinical Trials: Does FDA simply accept study findings on their face? • Adverse event terms (called ‘preferred terms’) are analyzed by computer algorithms 6 Many seemingly identical preferred terms are tabulated separately: – cardiac failure – cardiac failure, acute – cardiac failure, chronic – cardiac failure, congestive – cardiopulmonary failure – left ventricular failure – ventricular failure. 7 • More examples: – pulmonary edema – acute pulmonary edema 8 Tabulation of safety findings in clinical trials: ‘Pulmonary edema’ is separated from… 9 Tabulation of safety findings in clinical trials: …’Acute pulmonary edema!’ Yes…this is crazy! 10 Thus, FDA will conduct its own analyses of the preferred safety terms (52,299 here) 11 Thus, FDA will conduct its own analyses of the preferred safety terms (52,299 here) 12 Thus, FDA will conduct its own analyses of the preferred safety terms (52,299 here) 13 Multiplicity • Given that we’re always interested in certain safety issues, multiplicity is a problem, for example: – – – – – Myocardial infarction Death (cardiovascular and all-cause) Congestive heart failure Cancer Suicide/suicidality • The possibility of detecting a false positive finding is in important issue. 14 Recent Safety Findings in the Cardiovascular Arena – Not Substantiated: 1. Prasugrel and cancer from TRITON TIMI 38 15 Prasugrel and cancer findings not substantiated in TRILOGY ACS: 16 Prasugrel and cancer findings not substantiated in TRILOGY ACS: “The frequency of new, nonbenign neoplasms in the overall treated population did not differ significantly between the prasugrel group and the clopidogrel group (1.9% vs. 1.8%, P = 0.79)….” 17 2. Dabigatran and Acute MI - From RE-LY 18 Dabigatran and MI From Mini Sentinel, 5/13/14 19 Dabigatran and MI From Mini Sentinel, 5/13/14 20 Bottom Line: Many cardiovascular drugs we regulate are for prevention! - drugs for hypertension and dyslipidemia to prevent stroke and MI - anticoagulants in AF to prevent stroke - antiplatelet agents after ACS, +/- stent to prevent cardiovascular events 21 Bottom Line: FDA will make the public aware of emerging safety signals, and investigate fully. Patients do not adhere to preventive therapies for a variety of reasons. It is critical that we do not alarm the public about safety signals under evaluation! 22 Thank you! 23