This report evaluates the level of evidence currently available to support the effectiveness and safety of using recombinant activated coagulation factor VII (rFVIIa) for clinical indications not approved by the U. S. Food and Drug Administration (FDA). rFVIIa is approved for a variety of uses in hemophilia patients who have developed antibody inhibitors that compromise the use of standard factor replacement. Use of this costly biologic product has expanded beyond these hemophilia-related indications to encompass a range of off-label uses, most of which are in-hospital uses. These uses differ substantially from the drug’s FDA approved label. The purpose of this report is two-fold: (1) To document the full range of clinical indications for which rFVIIa is being used and the types of studies available to evaluate these uses and (2) To provide a comparative effectiveness review of rFVIIa vs. usual care for several in-hospital clinical indications: intracranial hemorrhage, massive bleeding secondary to trauma, and the selected surgical procedures of cardiac surgery, liver transplantation, and prostatectomy.
Off-label drug use refers to any use of a medication that deviates from the product labeling approved and required by the FDA. The FDA drug approval process mandates randomized clinical trials that demonstrate efficacy and safety for specific indications prior to marketing. Once approval is given, however, the FDA does not regulate whether drugs are prescribed for off-label indications. In most instances, the data supporting off-label drug use falls short of the rigor that accompanies FDA review. This uncertainty may be acceptable, as when a drug’s use is infrequent. Nevertheless, concerns increase when off-label use is clinically distinct from approved indications, when off-label use becomes frequent, when a drug is costly, or when a drug is used in different clinical settings (e.g., shifts from outpatient to in-hospital use).
rFVIIa is a form of human factor VII produced by recombinant technology. This intravenously delivered product works as a potent procoagulant by effectively bypassing parts of the clotting process normally required for clotting. It can facilitate control of bleeding in situations where standard human blood product transfusions have failed. Novoseven® is the only form of rFVIIa available commercially. Developed in the late 1980s, rFVIIa was approved by the FDA in 1999 for use in patients with Hemophilia A and Hemophilia B with antibody inhibitors that lead to unresponsiveness to factor VIII or factor IX, respectively. Both of these X-linked genetic conditions are rare, and most hemophilia patients never require rFVIIa for treatment of bleeding episodes. While the hemophilia population has remained stable over the past decade, in-hospital, off-label use of rFVIIa has increased.