A Novel Approach to Capturing Post-Marketing Safety Information On Recombinant Factor VIIa (rFVIIa) in Acquired Hemophilia: Final Data From the Acquired Hemophilia Surveillance (AHS) Project

Acquired hemophilia (AH) is a rare (1 per 1.5 million), life-threatening autoimmune disorder characterized by autoantibodies to coagulation factor VIII (FVIII). It is associated with life-threatening bleeding and ≈20% mortality. Following approval of recombinant factor VIIa (rFVIIa) by the FDA in 2006 for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with AH, Novo Nordisk agreed to monitor treatment through the IRB-approved Hemostasis and Thrombosis Research Society (HTRS) research registry, although this proved impractical outside of existing registry sites and hemophilia treatment centers (HTCs). Therefore, the Acquired Hemophilia Surveillance (AHS) Project was developed as a web-based, IRB-exempt method to collect additional rFVIIa safety data, and particularly assess for thromboembolic events (TEs) in these generally older patients.

The AHS project was launched in April 2008 as a one page fax-in reporting system and in June 2008 converted to a web-based platform located at novosevensurveillance.com. AHS takes advantage of the HIPAA exclusion for collection of safety information (45 CFR μ164.512(b)(iii)(D)). Reporting HCPs were provided fair market compensation per case entry. Information on demographics, rFVIIa dosing (entered via an optional free text field) and incidence of thrombotic events was collected and reported using descriptive statistics through project completion in 2011.

From April 2008 through November 2011, 38 individual health care professionals submitted 99 case reports (including 65 treated with rFVIIa) via facsimile or electronic data capture interface. The reports were from both HTCs (44) and non-HTCs (48), and more commonly from centers that did not participate in HTRS (84) than did participate (8). Of the 99 patients, 41 (41%) were male and 58 (59%) were female. The mean age was 66.6 years (range 16.4 to 97.3 years). The most common underlying conditions were autoimmune (34 patients), malignancy (12 patients), and post-partum (5 patients). The mean (SD) anti-VIII titer was 154.5 (453.7) Bethesda units (BU) and the median (range) anti-VIII titer was 35(1–3789) BU. Factor VIII levels were reported for 93 of the 99 patients. Fifty-eight percent (57/99) of the subjects had reported factor VIII levels ≤ 1%. The mean (median) factor VIII level in 36 remaining patients (>1% FVIII levels) was 8.1% (4.0%) with a range of 1.8–50%. There were reported to be a mean (median) of 4.3 (2.0) discrete bleeding episodes per patient (range 0–100 episodes). Most of these episodes were spontaneous (84 patients), surgical (14 patients), or related to a procedure (12 patients). Details on specific bleeding episodes were not captured in this brief report format. No bypassing agent was indicated to have been used in 21 case reports. The use of rFVIIa was indicated in 65 case reports (83%), including 50 first-line treated cases (77%), 14 second-line treated cases (22%), and 1 with unspecified line of treatment. A bypassing agent other than rFVIIa was indicated to have been used in 13 case reports (17%). AH was reported to have been resolved in 51 cases (52%) and not resolved in 30 cases (30%). The mean (median) time to AH resolution was 7.5 (2.0) months with a range of 1–52 months. There were 5 reported deaths. The reporters affirmed that none of the 99 cases suffered an adverse event that was considered possibly/probably related to rFVIIa.

For rare disorders or rare complications of common disorders, the standard post-marketing surveillance approach of an IRB-approved observational or product registry may have significant limitations and barriers at the site implementation level. AHS provides an innovative approach for HTCs, hematology/oncology practices, and even critical care physicians/pharmacists to capture basic surveillance data for AH patients exposed to rFVIIa. The AHS project reaffirms the safety of rFVIIa and the low rate of thrombotic complications. However, AHS lacks the detailed information available through traditional research registries at large centers, such as data on individual bleeds, treatment of individual bleeding episodes, rFVIIa dosing, time to hemostasis, and the relationship of immunosuppressive treatments to AH resolution.

Lentz:Novo Nordisk A/S: Consultancy, Investigator Other. Tandra:Novo Nordisk Inc.: Investigator Other. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.