title: Novel oral anticoagulants and reversal agents: Considerations for clinical development.
abstract: This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real-world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non-life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies.
authors.affiliation: Janssen Scientific Affairs, LLC, Titusville, NJ. Electronic address: tsarich@its.jnj.com.
authors.forename: Troy C
authors.initials: TC
authors.lastname: Sarich
authors.affiliation: ACI Clinical and Lankenau Heart Institute, Wynnewood, PA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Seltzer
authors.affiliation: Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Berkowitz
authors.affiliation: Perosphere Inc, Danbury, CT.
authors.forename: James
authors.initials: J
authors.lastname: Costin'
authors.affiliation: Portola Pharmaceuticals Inc, South San Francisco, CA.
authors.forename: John T
authors.initials: JT
authors.lastname: Curnutte
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.affiliation: Pathology & Lab Medicine Service, Durham Veterans Affairs Medical Center, Durham, NC.
authors.forename: Maureane
authors.initials: M
authors.lastname: Hoffman
authors.affiliation: Division of Hematology Products, CDER, FDA, Silver Spring, MD.
authors.forename: Edvardas
authors.initials: E
authors.lastname: Kaminskas
authors.affiliation: Duke University Medical Center, Duke Clinical Research Institute, Durham, NC.
authors.forename: Mitchell W
authors.initials: MW
authors.lastname: Krucoff
authors.affiliation: Duke University School of Medicine, Durham, NC.
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
authors.affiliation: Division of Hematology Clinical Review, Office of Blood Research and Review, CBER, FDA, Silver Spring, MD.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Mintz
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
authors.affiliation: Stanford University and Sager Consulting Experts, San Francisco, CA.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Sager
authors.affiliation: Division of General Internal Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Singer
authors.affiliation: Division of Cardiovascular and Renal Products, CDER, FDA, Silver Spring, MD.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
authors.affiliation: Lankenau Heart Institute and Jefferson Medical College, Philadelphia, PA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
mesh_terms: D000284:Administration, Oral; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy; D015951:Factor Xa / Q000627:therapeutic use; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D010879:Piperazines / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D020521:Stroke / Q000517:prevention & control
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010879:Piperazines; D011994:Recombinant Proteins; D001120:Arginine; C000594745:idarucizumab; D015951:Factor Xa; C000593571:PER977